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Kaufman MJ, Meloni EG. Xenon gas as a potential treatment for opioid use disorder, alcohol use disorder, and related disorders. Med Gas Res 2025; 15:234-253. [PMID: 39812023 PMCID: PMC11918480 DOI: 10.4103/mgr.medgasres-d-24-00063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 09/26/2024] [Indexed: 01/16/2025] Open
Abstract
Xenon gas is considered to be a safe anesthetic and imaging agent. Research on its other potentially beneficial effects suggests that xenon may have broad efficacy for treating health disorders. A number of reviews on xenon applications have been published, but none have focused on substance use disorders. Accordingly, we review xenon effects and targets relevant to the treatment of substance use disorders, with a focus on opioid use disorder and alcohol use disorder. We report that xenon inhaled at subsedative concentrations inhibits conditioned memory reconsolidation and opioid withdrawal symptoms. We review work by others reporting on the antidepressant, anxiolytic, and analgesic properties of xenon, which could diminish negative affective states and pain. We discuss research supporting the possibility that xenon could prevent analgesic- or stress-induced opioid tolerance and, by so doing could reduce the risk of developing opioid use disorder. The rapid kinetics, favorable safety and side effect profiles, and multitargeting capability of xenon suggest that it could be used as an ambulatory on-demand treatment to rapidly attenuate maladaptive memory, physical and affective withdrawal symptoms, and pain drivers of substance use disorders when they occur. Xenon may also have human immunodeficiency virus and oncology applications because its effects relevant to substance use disorders could be exploited to target human immunodeficiency virus reservoirs, human immunodeficiency virus protein-induced abnormalities, and cancers. Although xenon is expensive, low concentrations exert beneficial effects, and gas separation, recovery, and recycling advancements will lower xenon costs, increasing the economic feasibility of its therapeutic use. More research is needed to better understand the remarkable repertoire of effects of xenon and its potential therapeutic applications.
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Affiliation(s)
- Marc J Kaufman
- McLean Hospital, Harvard Medical School, Belmont, MA, USA
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Bertollo AG, Mingoti MED, Ignácio ZM. Neurobiological mechanisms in the kynurenine pathway and major depressive disorder. Rev Neurosci 2025; 36:169-187. [PMID: 39245854 DOI: 10.1515/revneuro-2024-0065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2024] [Accepted: 08/20/2024] [Indexed: 09/10/2024]
Abstract
Major depressive disorder (MDD) is a prevalent psychiatric disorder that has damage to people's quality of life. Tryptophan is the precursor to serotonin, a critical neurotransmitter in mood modulation. In mammals, most free tryptophan is degraded by the kynurenine pathway (KP), resulting in a range of metabolites involved in inflammation, immune response, and neurotransmission. The imbalance between quinolinic acid (QA), a toxic metabolite, and kynurenic acid (KynA), a protective metabolite, is a relevant phenomenon involved in the pathophysiology of MDD. Proinflammatory cytokines increase the activity of the enzyme indoleamine 2,3-dioxygenase (IDO), leading to the degradation of tryptophan in the KP and an increase in the release of QA. IDO activates proinflammatory genes, potentiating neuroinflammation and deregulating other physiological mechanisms related to chronic stress and MDD. This review highlights the physiological mechanisms involved with stress and MDD, which are underlying an imbalance of the KP and discuss potential therapeutic targets.
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Affiliation(s)
- Amanda Gollo Bertollo
- Laboratory of Physiology, Pharmacology and Psychopathology, Graduate Program in Biomedical Sciences, Federal University of Fronteira Sul, Chapecó, SC, Brazil
| | - Maiqueli Eduarda Dama Mingoti
- Laboratory of Physiology, Pharmacology and Psychopathology, Graduate Program in Biomedical Sciences, Federal University of Fronteira Sul, Chapecó, SC, Brazil
| | - Zuleide Maria Ignácio
- Laboratory of Physiology, Pharmacology and Psychopathology, Graduate Program in Biomedical Sciences, Federal University of Fronteira Sul, Chapecó, SC, Brazil
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Pretzel CW, Borba JV, Resmim CM, De Abreu MS, Kalueff AV, Fontana BD, Canzian J, Rosemberg DB. Ketamine modulates the exploratory dynamics and homebase-related behaviors of adult zebrafish. Pharmacol Biochem Behav 2024; 245:173892. [PMID: 39378930 DOI: 10.1016/j.pbb.2024.173892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2024] [Revised: 09/26/2024] [Accepted: 10/02/2024] [Indexed: 10/10/2024]
Abstract
Anxiety can be a protective emotion when animals face aversive conditions, but is commonly associated with various neuropsychiatric disorders when pathologically exacerbated. Drug repurposing has emerged as a valuable strategy based on utilizing the existing pharmaceuticals for new therapeutic purposes. Ketamine, traditionally used as an anesthetic, acts as a non-competitive antagonist of the glutamate N-methyl-d-aspartate (NMDA) receptor, and shows potential anxiolytic and antidepressant effects at subanesthetic doses. However, the influence of ketamine on multiple behavioral domains in vertebrates is not completely understood. Here, we evaluated the potential modulatory effect of ketamine on the spatio-temporal exploratory dynamics and homebase-related behaviors in adult zebrafish using the open field test (OFT). Animals were exposed to subanesthetic concentrations of ketamine (0, 2, 20, and 40 mg/L) for 20 min and their locomotion-, exploration- and homebase-related behaviors were assessed in a single 30-min trial. Our data revealed that acute ketamine (20 and 40 mg/L) induced hyperlocomotion, as verified by the increased total distance traveled. All concentrations tested elicited circling behavior, a stereotyped-like response which gradually reduced across the periods of test. We also observed modulatory effects of ketamine on the spatio-temporal exploratory pattern, in which the reduced thigmotaxis and homebase activity, associated with the increased average length of trips, suggest anxiolytic-like effects. Collectively, our findings support the modulatory effects of ketamine on the spatio-temporal exploratory activity, and corroborate the utility of homebase-related measurements to evaluate the behavioral dynamics in zebrafish models.
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Affiliation(s)
- Camilla W Pretzel
- Laboratory of Experimental Neuropsychobiology, Department of Biochemistry and Molecular Biology, Natural and Exact Sciences Center, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - João V Borba
- Laboratory of Experimental Neuropsychobiology, Department of Biochemistry and Molecular Biology, Natural and Exact Sciences Center, Federal University of Santa Maria, Santa Maria, RS, Brazil; Graduate Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Cássio M Resmim
- Laboratory of Experimental Neuropsychobiology, Department of Biochemistry and Molecular Biology, Natural and Exact Sciences Center, Federal University of Santa Maria, Santa Maria, RS, Brazil; Graduate Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Murilo S De Abreu
- Graduate Program in Health Sciences, Federal University of Health Sciences of Porto Alegre, Porto Alegre, RS, Brazil; Western Caspian University, Baku, Azerbaijan
| | - Allan V Kalueff
- Institute of Translational Biomedicine (ITBM), St. Petersburg State University, St. Petersburg, Russia; Institute of Experimental Medicine, Almazov National Medical Research Centre, Ministry of Healthcare of Russian Federation, St. Petersburg, Russia; Department of Biological Sciences, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China; Suzhou Key Laboratory on Neurobiology and Cell Signaling, Department of Biological Sciences, School of Science, Xi'an Jiaotong-Liverpool University, Suzhou, China
| | - Barbara D Fontana
- Laboratory of Experimental Neuropsychobiology, Department of Biochemistry and Molecular Biology, Natural and Exact Sciences Center, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Julia Canzian
- Laboratory of Experimental Neuropsychobiology, Department of Biochemistry and Molecular Biology, Natural and Exact Sciences Center, Federal University of Santa Maria, Santa Maria, RS, Brazil
| | - Denis B Rosemberg
- Laboratory of Experimental Neuropsychobiology, Department of Biochemistry and Molecular Biology, Natural and Exact Sciences Center, Federal University of Santa Maria, Santa Maria, RS, Brazil; Graduate Program in Biological Sciences: Toxicological Biochemistry, Federal University of Santa Maria, Santa Maria, RS, Brazil; The International Zebrafish Neuroscience Research Consortium (ZNRC), USA.
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Goto T, Saligan LN. Mechanistic insights into behavioral clusters associated with cancer-related systemic inflammatory response. Curr Opin Support Palliat Care 2024; 18:161-167. [PMID: 38814249 DOI: 10.1097/spc.0000000000000706] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/31/2024]
Abstract
PURPOSE OF REVIEW This focused, narrative review mostly describes our team's investigations into the potential inflammatory mechanisms that contribute to the development of cancer-related gastrointestinal (GI) mucositis and its associated symptoms. This review summarizes details of our clinical and preclinical findings to test the role of inflammation in the development and occurrence of these cancer-related conditions. RECENT FINDINGS GI mucositis (GIM) is a common, distressing condition reported by cancer patients. GIM is often clustered with other behaviors including fatigue, pain, anorexia, depression, and diarrhea. It is hypothesized that there is a common biologic mechanism underpinning this symptom cluster. Our multi-platform investigations revealed that GIM and its associated cluster of behaviors may be triggered by local inflammation spreading systemically causing pro-inflammatory-mediated toxicities, leading to alterations in immune, metabolic, and nervous system functions and activities. For example, behavioral toxicities related to local irradiation for non-metastatic cancer may be triggered by mGluR5 activation influencing prolonged T cell as well as NF-κB transcription factor activities. Thus, interventions targeting inflammation and associated pathways may be a reasonable strategy to alleviate GIM and its symptom cluster. SUMMARY GIM may be a sign of a broader systemic inflammatory response triggered by cancer or its treatment. Addressing GIM and its associated symptoms primarily involves supportive care strategies focused on relieving symptoms, promoting healing, and preventing complications.
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Affiliation(s)
- Taichi Goto
- Symptoms Biology Unit, National Institute of Nursing Research, National Institutes of Health, Bethesda, Maryland, USA
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Bartman AE, Raeisi M, Peiris CD, Jacobsen IE, Martin DB, Doorn JA. A Novel Analog of the Natural Product Fraxinellone Protects against Endogenous and Exogenous Neurotoxicants. ACS Chem Neurosci 2024; 15:2612-2622. [PMID: 38925635 PMCID: PMC11258694 DOI: 10.1021/acschemneuro.4c00090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Revised: 06/12/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024] Open
Abstract
Numerous insults, both endogenous (e.g., glutamate) and exogenous (e.g., pesticides), compromise the function of the nervous system and pose risk factors for damage or later disease. In previous reports, limonoids such as fraxinellone showed significant neuroprotective activity against glutamate (Glu) excitotoxicity and reactive oxygen species (ROS) production in vitro, albeit with minimal mechanistic information provided. Given these findings, a library of novel fraxinellone analogs (including analogs 1 and 2 described here) was synthesized with the goal of identifying compounds exhibiting neuroprotection against insults. Analog 2 was found to be protective against Glu-mediated excitotoxicity with a measured EC50 of 44 and 39 nM for in vitro assays using PC12 and SH-SY5Y cells, respectively. Pretreatment with analog 2 yielded rapid induction of antioxidant genes, namely, Gpx4, Sod1, and Nqo1, as measured via qPCR. Analog 2 mitigated Glu-mediated ROS. Cytoprotection could be replicated using sulforaphane (SFN), a Nrf2 activator, and inhibited via ML-385, which inhibits Nrf2 binding to regulatory DNA sequences, thereby blocking downstream gene expression. Nrf2 DNA-binding activity was demonstrated using a Nrf2 ELISA-based transcription factor assay. In addition, we found that pretreatment with the thiol N-acetyl Cys completely mitigated SFN-mediated induction of antioxidant genes but had no effect on the activity of analog 2, suggesting thiol modification is not critical for its mechanism of action. In summary, our data demonstrate a fraxinellone analog to be a novel, potent, and rapid activator of the Nrf2-mediated antioxidant defense system, providing robust protection against insults.
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Affiliation(s)
- Anna E. Bartman
- Department
of Pharmaceutical Sciences & Experimental Therapeutics, College
of Pharmacy, University of Iowa, Iowa City, Iowa 52242, United States
| | - Mersad Raeisi
- Department
of Chemistry, College of Liberal Arts & Sciences, University of Iowa, Iowa City, Iowa 52242, United States
| | - Clarence D. Peiris
- Department
of Chemistry, College of Liberal Arts & Sciences, University of Iowa, Iowa City, Iowa 52242, United States
| | - Isabella E. Jacobsen
- Department
of Chemistry, College of Liberal Arts & Sciences, University of Iowa, Iowa City, Iowa 52242, United States
| | - David B.C. Martin
- Department
of Chemistry, College of Liberal Arts & Sciences, University of Iowa, Iowa City, Iowa 52242, United States
| | - Jonathan A. Doorn
- Department
of Pharmaceutical Sciences & Experimental Therapeutics, College
of Pharmacy, University of Iowa, Iowa City, Iowa 52242, United States
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Le GH, Wong S, Badulescu S, Au H, Di Vincenzo JD, Gill H, Phan L, Rhee TG, Ho R, Teopiz KM, Kwan ATH, Rosenblat JD, Mansur RB, McIntyre RS. Spectral signatures of psilocybin, lysergic acid diethylamide (LSD) and ketamine in healthy volunteers and persons with major depressive disorder and treatment-resistant depression: A systematic review. J Affect Disord 2024; 355:342-354. [PMID: 38570038 DOI: 10.1016/j.jad.2024.03.165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 03/27/2024] [Accepted: 03/28/2024] [Indexed: 04/05/2024]
Abstract
BACKGROUND Electrophysiologic measures provide an opportunity to inform mechanistic models and possibly biomarker prediction of response. Serotonergic psychedelics (SPs) (i.e., psilocybin, lysergic acid diethylamide (LSD)) and ketamine represent new investigational and established treatments in mood disorders respectively. There is a need to better characterize the mechanism of action of these agents. METHODS We conducted a systematic review investigating the spectral signatures of psilocybin, LSD, and ketamine in persons with major depressive disorder (MDD), treatment-resistant depression (TRD), and healthy controls. RESULTS Ketamine and SPs are associated with increased theta power in persons with depression. Ketamine and SPs are also associated with decreased spectral power in the alpha, beta and delta bands in healthy controls and persons with depression. When administered with SPs, theta power was increased in persons with MDD when administered with SPs. Ketamine is associated with increased gamma band power in both healthy controls and persons with MDD. LIMITATIONS The studies included in our review were heterogeneous in their patient population, exposure, dosing of treatment and devices used to evaluate EEG and MEG signatures. Our results were extracted entirely from persons who were either healthy volunteers or persons with MDD or TRD. CONCLUSIONS Extant literature evaluating EEG and MEG spectral signatures indicate that ketamine and SPs have reproducible effects in keeping with disease models of network connectivity. Future research vistas should evaluate whether observed spectral signatures can guide further discovery of therapeutics within the psychedelic and dissociative classes of agents, and its prediction capability in persons treated for depression.
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Affiliation(s)
- Gia Han Le
- Mood Disorder and Psychopharmacology Unit, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; Brain and Cognition Discovery Foundation, Toronto, Canada.
| | - Sabrina Wong
- Mood Disorder and Psychopharmacology Unit, University Health Network, Toronto, Canada; Brain and Cognition Discovery Foundation, Toronto, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, Canada.
| | - Sebastian Badulescu
- Mood Disorder and Psychopharmacology Unit, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; Brain and Cognition Discovery Foundation, Toronto, Canada.
| | - Hezekiah Au
- Brain and Cognition Discovery Foundation, Toronto, Canada.
| | - Joshua D Di Vincenzo
- Mood Disorder and Psychopharmacology Unit, University Health Network, Toronto, Canada.
| | - Hartej Gill
- Mood Disorder and Psychopharmacology Unit, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada.
| | - Lee Phan
- Mood Disorder and Psychopharmacology Unit, University Health Network, Toronto, Canada; Brain and Cognition Discovery Foundation, Toronto, Canada.
| | - Taeho Greg Rhee
- Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Department of Public Health Sciences, Farmington, CT, USA.
| | - Roger Ho
- Department of Psychological Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Institute for Health Innovation and Technology (iHealthtech), National University of Singapore, Singapore, Singapore.
| | - Kayla M Teopiz
- Brain and Cognition Discovery Foundation, Toronto, Canada.
| | - Angela T H Kwan
- Brain and Cognition Discovery Foundation, Toronto, Canada; Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
| | - Joshua D Rosenblat
- Mood Disorder and Psychopharmacology Unit, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, Canada.
| | - Rodrigo B Mansur
- Mood Disorder and Psychopharmacology Unit, University Health Network, Toronto, Canada; Institute of Medical Science, University of Toronto, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada.
| | - Roger S McIntyre
- Mood Disorder and Psychopharmacology Unit, University Health Network, Toronto, Canada; Brain and Cognition Discovery Foundation, Toronto, Canada; Department of Pharmacology & Toxicology, University of Toronto, Toronto, Canada; Department of Psychiatry, University of Toronto, Toronto, Canada.
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Marashli S, Janz P, Redondo RL. Auditory brainstem responses are resistant to pharmacological modulation in Sprague Dawley wild-type and Neurexin1α knockout rats. BMC Neurosci 2024; 25:18. [PMID: 38491350 PMCID: PMC10941391 DOI: 10.1186/s12868-024-00861-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Accepted: 03/11/2024] [Indexed: 03/18/2024] Open
Abstract
Sensory processing in the auditory brainstem can be studied with auditory brainstem responses (ABRs) across species. There is, however, a limited understanding of ABRs as tools to assess the effect of pharmacological interventions. Therefore, we set out to understand how pharmacological agents that target key transmitter systems of the auditory brainstem circuitry affect ABRs in rats. Given previous studies, demonstrating that Nrxn1α KO Sprague Dawley rats show substantial auditory processing deficits and altered sensitivity to GABAergic modulators, we used both Nrxn1α KO and wild-type littermates in our study. First, we probed how different commonly used anesthetics (isoflurane, ketamine/xylazine, medetomidine) affect ABRs. In the next step, we assessed the effects of different pharmacological compounds (diazepam, gaboxadol, retigabine, nicotine, baclofen, and bitopertin) either under isoflurane or medetomidine anesthesia. We found that under our experimental conditions, ABRs are largely unaffected by diverse pharmacological modulation. Significant modulation was observed with (i) nicotine, affecting the late ABRs components at 90 dB stimulus intensity under isoflurane anesthesia in both genotypes and (ii) retigabine, showing a slight decrease in late ABRs deflections at 80 dB stimulus intensity, mainly in isoflurane anesthetized Nrxn1α KO rats. Our study suggests that ABRs in anesthetized rats are resistant to a wide range of pharmacological modulators, which has important implications for the applicability of ABRs to study auditory brainstem physiology.
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Affiliation(s)
- Samuel Marashli
- Roche Pharma Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland
- Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland
| | - Philipp Janz
- Roche Pharma Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland
| | - Roger L Redondo
- Roche Pharma Research and Early Development, Neuroscience and Rare Diseases, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, 4070, Basel, Switzerland.
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Hanson JE, Yuan H, Perszyk RE, Banke TG, Xing H, Tsai MC, Menniti FS, Traynelis SF. Therapeutic potential of N-methyl-D-aspartate receptor modulators in psychiatry. Neuropsychopharmacology 2024; 49:51-66. [PMID: 37369776 PMCID: PMC10700609 DOI: 10.1038/s41386-023-01614-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/24/2023] [Accepted: 05/15/2023] [Indexed: 06/29/2023]
Abstract
N-methyl-D-aspartate (NMDA) receptors mediate a slow component of excitatory synaptic transmission, are widely distributed throughout the central nervous system, and regulate synaptic plasticity. NMDA receptor modulators have long been considered as potential treatments for psychiatric disorders including depression and schizophrenia, neurodevelopmental disorders such as Rett Syndrome, and neurodegenerative conditions such as Alzheimer's disease. New interest in NMDA receptors as therapeutic targets has been spurred by the findings that certain inhibitors of NMDA receptors produce surprisingly rapid and robust antidepressant activity by a novel mechanism, the induction of changes in the brain that well outlast the presence of drug in the body. These findings are driving research into an entirely new paradigm for using NMDA receptor antagonists in a host of related conditions. At the same time positive allosteric modulators of NMDA receptors are being pursued for enhancing synaptic function in diseases that feature NMDA receptor hypofunction. While there is great promise, developing the therapeutic potential of NMDA receptor modulators must also navigate the potential significant risks posed by the use of such agents. We review here the emerging pharmacology of agents that target different NMDA receptor subtypes, offering new avenues for capturing the therapeutic potential of targeting this important receptor class.
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Affiliation(s)
- Jesse E Hanson
- Department of Neuroscience, Genentech Inc., South San Francisco, CA, 94080, USA
| | - Hongjie Yuan
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Riley E Perszyk
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Tue G Banke
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Hao Xing
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Ming-Chi Tsai
- Department of Neuroscience, Genentech Inc., South San Francisco, CA, 94080, USA
| | - Frank S Menniti
- MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, 02881, USA.
| | - Stephen F Traynelis
- Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
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Kukułowicz J, Pietrzak-Lichwa K, Klimończyk K, Idlin N, Bajda M. The SLC6A15-SLC6A20 Neutral Amino Acid Transporter Subfamily: Functions, Diseases, and Their Therapeutic Relevance. Pharmacol Rev 2023; 76:142-193. [PMID: 37940347 DOI: 10.1124/pharmrev.123.000886] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 09/07/2023] [Accepted: 11/02/2023] [Indexed: 11/10/2023] Open
Abstract
The neutral amino acid transporter subfamily that consists of six members, consecutively SLC6A15-SLC620, also called orphan transporters, represents membrane, sodium-dependent symporter proteins that belong to the family of solute carrier 6 (SLC6). Primarily, they mediate the transport of neutral amino acids from the extracellular milieu toward cell or storage vesicles utilizing an electric membrane potential as the driving force. Orphan transporters are widely distributed throughout the body, covering many systems; for instance, the central nervous, renal, or intestinal system, supplying cells into molecules used in biochemical, signaling, and building pathways afterward. They are responsible for intestinal absorption and renal reabsorption of amino acids. In the central nervous system, orphan transporters constitute a significant medium for the provision of neurotransmitter precursors. Diseases related with aforementioned transporters highlight their significance; SLC6A19 mutations are associated with metabolic Hartnup disorder, whereas altered expression of SLC6A15 has been associated with a depression/stress-related disorders. Mutations of SLC6A18-SLCA20 cause iminoglycinuria and/or hyperglycinuria. SLC6A18-SLC6A20 to reach the cellular membrane require an ancillary unit ACE2 that is a molecular target for the spike protein of the SARS-CoV-2 virus. SLC6A19 has been proposed as a molecular target for the treatment of metabolic disorders resembling gastric surgery bypass. Inhibition of SLC6A15 appears to have a promising outcome in the treatment of psychiatric disorders. SLC6A19 and SLC6A20 have been suggested as potential targets in the treatment of COVID-19. In this review, we gathered recent advances on orphan transporters, their structure, functions, related disorders, and diseases, and in particular their relevance as therapeutic targets. SIGNIFICANCE STATEMENT: The following review systematizes current knowledge about the SLC6A15-SLCA20 neutral amino acid transporter subfamily and their therapeutic relevance in the treatment of different diseases.
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Affiliation(s)
- Jędrzej Kukułowicz
- Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
| | - Krzysztof Pietrzak-Lichwa
- Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
| | - Klaudia Klimończyk
- Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
| | - Nathalie Idlin
- Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
| | - Marek Bajda
- Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland
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Rech TDST, Strelow DN, Krüger LD, Neto JSS, Blödorn GB, Alves D, Brüning CA, Bortolatto CF. Pharmacological evidence for glutamatergic pathway involvement in the antidepressant-like effects of 2-phenyl-3-(phenylselanyl)benzofuran in male Swiss mice. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:3033-3044. [PMID: 37160481 DOI: 10.1007/s00210-023-02508-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/04/2023] [Accepted: 04/20/2023] [Indexed: 05/11/2023]
Abstract
Depression is a multifactorial and heterogeneous disease with several neurobiological mechanisms underlying its pathophysiology, including dysfunctional glutamatergic neurotransmission, which makes the exploration of the glutamate pathway an interesting strategy for developing novel rapid-acting antidepressant treatments. In the present study, we aimed to evaluate the possible glutamatergic pathway relation in the antidepressant-like action of 2-phenyl-3-(phenylselanyl)benzofuran (SeBZF1) in Swiss mice employing the tail suspension test (TST). Male Swiss mice received drugs targeting glutamate receptors before acute SeBZF1 administration at effective (50 mg/kg) or subeffective (1 mg/kg) doses by intragastric route (ig). TST and the open-field test (OFT) were employed in all behavioral experiments. The pretreatment of mice with N-methyl-D-aspartate (NMDA) (0.1 pmol/site, intracerebroventricular, icv, a selective agonist of the NMDA receptors), D-serine (30 µg/site, icv, a co-agonist at the NMDA receptor), arcaine (1 mg/kg, intraperitoneal, ip, an antagonist of the polyamine-binding site at the NMDA receptor), and 6,7-dinitroquinoxaline-2,3-dione (DNQX) (2,5 µg/site, icv, an antagonist of the AMPA/kainate type of glutamate receptors) inhibited the antidepressant-like effects of SeBZF1 (50 mg/kg, ig) in the TST. Coadministration of a subeffective dose of SeBZF1 with low doses of MK-801 (0.001 mg/kg, ip, a non-competitive NMDA receptor antagonist) or ketamine (0.1 mg/kg, ip, a non-selective antagonist of the NMDA receptors) produced significant antidepressant-like effects (synergistic action). These findings suggest the involvement of the glutamatergic system, probably through modulation of ionotropic glutamate receptors, in the antidepressant-like action of SeBZF1 in mice and contribute to a better understanding of the mechanisms underlying its pharmacological effects.
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Affiliation(s)
- Taís da Silva Teixeira Rech
- Programa de Pós-Graduação em Bioquímica e Bioprospecção (PPGBBio), Laboratório de Bioquímica e Neurofarmacologia Molecular (LABIONEM), Grupo de Pesquisa em Neurobiotecnologia (GPN), Centro de Ciências Químicas, Farmacêuticas e de Alimentos (CCQFA), Universidade Federal de Pelotas (UFPel), RS, CEP 96010-900, Pelotas, Brazil
| | - Dianer Nornberg Strelow
- Programa de Pós-Graduação em Bioquímica e Bioprospecção (PPGBBio), Laboratório de Bioquímica e Neurofarmacologia Molecular (LABIONEM), Grupo de Pesquisa em Neurobiotecnologia (GPN), Centro de Ciências Químicas, Farmacêuticas e de Alimentos (CCQFA), Universidade Federal de Pelotas (UFPel), RS, CEP 96010-900, Pelotas, Brazil
| | - Letícia Devantier Krüger
- Programa de Pós-Graduação em Bioquímica e Bioprospecção (PPGBBio), Laboratório de Bioquímica e Neurofarmacologia Molecular (LABIONEM), Grupo de Pesquisa em Neurobiotecnologia (GPN), Centro de Ciências Químicas, Farmacêuticas e de Alimentos (CCQFA), Universidade Federal de Pelotas (UFPel), RS, CEP 96010-900, Pelotas, Brazil
| | | | - Gustavo Bierhals Blödorn
- Programa de Pós-Graduação em Química (PPGQ), Laboratório de Síntese Orgânica Limpa (LASOL), Centro de Ciências Químicas, Farmacêuticas e de Alimentos (CCQFA), Universidade Federal de Pelotas (UFPel), RS, CEP 96010-900, Pelotas, Brazil
| | - Diego Alves
- Programa de Pós-Graduação em Química (PPGQ), Laboratório de Síntese Orgânica Limpa (LASOL), Centro de Ciências Químicas, Farmacêuticas e de Alimentos (CCQFA), Universidade Federal de Pelotas (UFPel), RS, CEP 96010-900, Pelotas, Brazil
| | - César Augusto Brüning
- Programa de Pós-Graduação em Bioquímica e Bioprospecção (PPGBBio), Laboratório de Bioquímica e Neurofarmacologia Molecular (LABIONEM), Grupo de Pesquisa em Neurobiotecnologia (GPN), Centro de Ciências Químicas, Farmacêuticas e de Alimentos (CCQFA), Universidade Federal de Pelotas (UFPel), RS, CEP 96010-900, Pelotas, Brazil.
| | - Cristiani Folharini Bortolatto
- Programa de Pós-Graduação em Bioquímica e Bioprospecção (PPGBBio), Laboratório de Bioquímica e Neurofarmacologia Molecular (LABIONEM), Grupo de Pesquisa em Neurobiotecnologia (GPN), Centro de Ciências Químicas, Farmacêuticas e de Alimentos (CCQFA), Universidade Federal de Pelotas (UFPel), RS, CEP 96010-900, Pelotas, Brazil.
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11
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Li Q, Gao K, Yang S, Yang S, Xu S, Feng Y, Bai Z, Ping A, Luo S, Li L, Wang L, Shi G, Duan K, Wang S. Predicting efficacy of sub-anesthetic ketamine/esketamine i.v. dose during course of cesarean section for PPD prevention, utilizing traditional logistic regression and machine learning models. J Affect Disord 2023; 339:264-270. [PMID: 37451434 DOI: 10.1016/j.jad.2023.07.048] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 06/29/2023] [Accepted: 07/08/2023] [Indexed: 07/18/2023]
Abstract
OBJECTIVE Increasing researches supported that intravenous ketamine/esketamine during the perioperative period of cesarean section could prevent postpartum depression(PPD). With the effective rate ranging from 87.2 % to 95.5 % in PPD, ketamine/esketamine's responsiveness was individualized. To optimize ketamine dose/form based on puerpera prenatal characteristics, reducing adverse events and improving the total efficacy rate, prediction models were developed to predict ketamine/esketamine's efficacy. METHOD Based on two randomized controlled trials, 12 prenatal features of 507 women administered the ketamine/esketamine intervention were collected. Traditional logistics regression, SVM, random forest, KNN and XGBoost prediction models were established with prenatal features and dosage regimen as predictors. RESULTS According to the logistic regression model (ain = 0.10, aout = 0.15, area under the receiver operating characteristic curve, AUC = 0.728), prenatal Edinburgh Postnatal Depression Scale (EPDS) score ≥ 10, thoughts of self-injury and bad mood during pregnancy were associated with poorer ketamine efficacy in PPD prevention, whilst a high dose of esketamine (0.25 mg/kg loading dose+2 mg/kg PCIA) was the most effective dosage regimen and esketamine was more recommended rather than ketamine in PPD. The AUCvalidation set of KNN and XGBoost model were 0.815 and 0.651, respectively. CONCLUSION Logistic regression and machine learning algorithm, especially the KNN model, could predict the effectiveness of ketamine/esketamine iv. during the course of cesarean section for PPD prevention. An individualized preventative strategy could be developed after entering puerpera clinical features into the model, possessing great clinical practice value in reducing PPD incidence.
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Affiliation(s)
- Qiuwen Li
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Kai Gao
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Siqi Yang
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Shuting Yang
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Shouyu Xu
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Yunfei Feng
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Zhihong Bai
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Anqi Ping
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Shichao Luo
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Lishan Li
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Liangfeng Wang
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Guoxun Shi
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China
| | - Kaiming Duan
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China.
| | - Saiying Wang
- Department of Anesthesiology, Third Xiangya Hospital of Central South University, Changsha 410013, China.
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12
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Zhou C, Tajima N. Structural insights into NMDA receptor pharmacology. Biochem Soc Trans 2023; 51:1713-1731. [PMID: 37431773 PMCID: PMC10586783 DOI: 10.1042/bst20230122] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 06/12/2023] [Accepted: 06/16/2023] [Indexed: 07/12/2023]
Abstract
N-methyl-d-aspartate receptors (NMDARs) comprise a subfamily of ionotropic glutamate receptors that form heterotetrameric ligand-gated ion channels and play fundamental roles in neuronal processes such as synaptic signaling and plasticity. Given their critical roles in brain function and their therapeutic importance, enormous research efforts have been devoted to elucidating the structure and function of these receptors and developing novel therapeutics. Recent studies have resolved the structures of NMDARs in multiple functional states, and have revealed the detailed gating mechanism, which was found to be distinct from that of other ionotropic glutamate receptors. This review provides a brief overview of the recent progress in understanding the structures of NMDARs and the mechanisms underlying their function, focusing on subtype-specific, ligand-induced conformational dynamics.
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Affiliation(s)
- Changping Zhou
- Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, U.S.A
| | - Nami Tajima
- Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH, U.S.A
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13
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Chaib S, Bouillot C, Bouvard S, Vidal B, Zimmer L, Levigoureux E. Single subanesthetic dose of ketamine produces delayed impact on brain [ 18F]FDG PET imaging and metabolic connectivity in rats. Front Neurosci 2023; 17:1213941. [PMID: 37521685 PMCID: PMC10372660 DOI: 10.3389/fnins.2023.1213941] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 06/23/2023] [Indexed: 08/01/2023] Open
Abstract
Introduction Ketamine, a glutamate NMDA receptor antagonist, is suggested to act very rapidly and durably on the depressive symptoms including treatment-resistant patients but its mechanisms of action remain unclear. There is a requirement for non-invasive biomarkers, such as imaging techniques, which hold promise in monitoring and elucidating its therapeutic impact. Methods We explored the glucose metabolism with [18F]FDG positron emission tomography (PET) in ten male rats in a longitudinal study designed to compare imaging patterns immediately after acute subanaesthetic ketamine injection (i.p. 10 mg/kg) with its sustained effects, 5 days later. Changes in [18F]FDG uptake following ketamine administration were estimated using a voxel-based analysis with SPM12 software, and a region of interest (ROI) analysis. A metabolic connectivity analysis was also conducted to estimate the immediate and delayed effects of ketamine on the inter-individual metabolic covariance between the ROIs. Results No significant difference was observed in brain glucose metabolism immediately following acute subanaesthetic ketamine injection. However, a significant decrease of glucose uptake appeared 5 days later, reflecting a sustained and delayed effect of ketamine in the frontal and the cingulate cortex. An increase in the raphe, caudate and cerebellum was also measured. Moreover, metabolic connectivity analyses revealed a significant decrease between the hippocampus and the thalamus at day 5 compared to the baseline. Discussion This study showed that the differences in metabolic profiles appeared belatedly, 5 days after ketamine administration, particularly in the cortical regions. Finally, this methodology will help to characterize the effects of future molecules for the treatment of treatment resistant depression.
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Affiliation(s)
- Sarah Chaib
- Université Claude Bernard Lyon 1, Lyon Neuroscience Research Center, CNRS, INSERM, Lyon, France
- Hospices Civils de Lyon, Lyon, France
| | | | - Sandrine Bouvard
- Université Claude Bernard Lyon 1, Lyon Neuroscience Research Center, CNRS, INSERM, Lyon, France
| | - Benjamin Vidal
- Université Claude Bernard Lyon 1, Lyon Neuroscience Research Center, CNRS, INSERM, Lyon, France
| | - Luc Zimmer
- Université Claude Bernard Lyon 1, Lyon Neuroscience Research Center, CNRS, INSERM, Lyon, France
- Hospices Civils de Lyon, Lyon, France
- CERMEP-Imaging Platform, Bron, France
| | - Elise Levigoureux
- Université Claude Bernard Lyon 1, Lyon Neuroscience Research Center, CNRS, INSERM, Lyon, France
- Hospices Civils de Lyon, Lyon, France
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14
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Cheng A, Zhang Y, Sun J, Huang D, Sulaiman JE, Huang X, Wu L, Ye W, Wu C, Lam H, Shi Y, Qian PY. Pterosin sesquiterpenoids from Pteris laeta Wall. ex Ettingsh. protect cells from glutamate excitotoxicity by modulating mitochondrial signals. JOURNAL OF ETHNOPHARMACOLOGY 2023; 308:116308. [PMID: 36822346 DOI: 10.1016/j.jep.2023.116308] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 02/09/2023] [Accepted: 02/19/2023] [Indexed: 06/18/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The genus Pteris (Pteridaceae) has been used as a traditional herb for a long time. In particular, Pteris laeta Wall. ex Ettingsh. has been widely used in traditional Chinese medicine to treat nervous system diseases and some pterosin sesquiterpenes from Pteris show neuroprotective activity, but their underlying molecular mechanisms remain elusive. Therefore, to investigate the neuroprotective activity and working mechanism of pterosin sesquiterpenes from P. laeta Wall. ex Ettingsh. will provide a better understanding and guidance in using P. laeta Wall. ex Ettingsh. as a traditional Chinese medicine. AIM OF THE STUDY We aim to develop effective treatments for neurodegenerative diseases from pterosin sesquiterpenes by evaluating their neuroprotective activity and investigating their working mechanisms. MATERIALS AND METHODS Primary screening on the glutamate-induced excitotoxicity cell model was assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) assay. Fluorescent-activated cell sorting (FACS) was used to analyze the activation level of glutamate receptors and mitochondria membrane potential after treatment. Transcriptomics and proteomics analysis was performed to identify possible targets of pterosin B. The key pathways were enriched by the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis through the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The core targets were visualized by a protein-protein interaction network using STRING. The mRNA and protein expressions were evaluated using real-time quantitative polymerase chain reaction (Q-PCR) and western blot, respectively. Immunocytochemistry was performed to monitor mitochondrial and apoptotic proteins. Cellular reactive oxygen species (ROS) were measured by ROS assay, and Ca2+ was stained with Fluo-4 AM to quantify intracellular Ca2+ levels. RESULTS We found pterosin B from Pteris laeta Wall. ex Ettingsh. showed significant neuroprotective activity against glutamate excitotoxicity, enhancing cell viability from 43.8% to 105% (p-value: <0.0001). We demonstrated that pterosin B worked on the downstream signaling pathways of glutamate excitotoxicity rather than directly blocking the activation of glutamate receptors. Pterosin B restored mitochondria membrane potentials, alleviated intracellular calcium overload from 107.4% to 95.47% (p-value: 0.0006), eliminated cellular ROS by 36.55% (p-value: 0.0143), and partially secured cells from LPS-induced inflammation by increasing cell survival from 46.75% to 58.5% (p-value: 0.0114). Notably, pterosin B enhanced the expression of nuclear factor-erythroid factor 2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1) by 2.86-fold (p-value: 0.0006) and 4.24-fold (p-value: 0.0012), and down-regulated Kelch-like ECH-associated protein 1 (KEAP1) expression by 2.5-fold (p-value: 0.0107), indicating that it possibly promotes mitochondrial biogenesis and mitophagy to maintain mitochondria quality control and homeostasis, and ultimately inhibits apoptotic cell death. CONCLUSIONS Our work revealed that pterosin B protected cells from glutamate excitotoxicity by targeting the downstream mitochondrial signals, making it a valuable candidate for developing potential therapeutic agents in treating neurodegenerative diseases.
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Affiliation(s)
- Aifang Cheng
- Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, 511458, China; Department of Ocean Science and Hong Kong Branch of Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), The Hong Kong University of Science and Technology, Hong Kong, 999077, China
| | - Yan Zhang
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, 510515, China; Institute for Advancing Translational Medicine in Bone and Joint Diseases (TMBJ), School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, 999077, China
| | - Jin Sun
- Institute of Evolution and Marine Biodiversity, Ocean University of China, Qingdao, 266003, China
| | - Duli Huang
- Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, 511458, China; Department of Ocean Science and Hong Kong Branch of Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), The Hong Kong University of Science and Technology, Hong Kong, 999077, China
| | - Jordy Evan Sulaiman
- Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Hong Kong, 999077, China
| | - Xin Huang
- Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, 511458, China; Department of Ocean Science and Hong Kong Branch of Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), The Hong Kong University of Science and Technology, Hong Kong, 999077, China
| | - Long Wu
- Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Hong Kong, 999077, China
| | - Wenkang Ye
- Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, 511458, China; Department of Ocean Science and Hong Kong Branch of Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), The Hong Kong University of Science and Technology, Hong Kong, 999077, China; SZU-HKUST Joint Ph.D. Program in Marine Environmental Science, Shenzhen University, Shenzhen, 518060, China
| | - Chuanhai Wu
- Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, 511458, China; Department of Ocean Science and Hong Kong Branch of Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), The Hong Kong University of Science and Technology, Hong Kong, 999077, China
| | - Henry Lam
- Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Hong Kong, 999077, China
| | - Yusheng Shi
- National-Local Joint Engineering Research Center for Drug-Research and Development (R&D) of Neurodegenerative Diseases, Dalian Medical University, Dalian, 116044, China; Academy of Integrative Medicine, Dalian Medical University, Dalian, 116044, China.
| | - Pei-Yuan Qian
- Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou, 511458, China; Department of Ocean Science and Hong Kong Branch of Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), The Hong Kong University of Science and Technology, Hong Kong, 999077, China.
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15
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Maraone A, Trebbastoni A, Di Vita A, D'Antonio F, De Lena C, Pasquini M. Memantine for Refractory Obsessive-Compulsive Disorder: Protocol for a Pragmatic, Double-blind, Randomized, Parallel-Group, Placebo-Controlled, Monocenter Trial. JMIR Res Protoc 2023; 12:e39223. [PMID: 37166948 DOI: 10.2196/39223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 03/15/2023] [Accepted: 03/21/2023] [Indexed: 05/12/2023] Open
Abstract
BACKGROUND Obsessive-compulsive disorder (OCD) is a psychiatric syndrome characterized by unwanted and repetitive thoughts and repeated ritualistic compulsions for decreasing distress. Symptoms can cause severe distress and functional impairment. OCD affects 2% to 3% of the population and is ranked within the 10 leading neuropsychiatric causes of disability. Cortico-striatal-thalamo-cortical circuitry dysfunction has been implicated in OCD, including altered brain activation and connectivity. Complex glutamatergic signaling dysregulation within cortico-striatal circuitry has been proposed in OCD. Data obtained by several studies indicate reduced glutamatergic concentrations in the anterior cingulate cortex, combined with overactive glutamatergic signaling in the striatum and orbitofrontal cortex. A growing number of randomized controlled trials have assessed the utility of different glutamate-modulating drugs as augmentation medications or monotherapies for OCD, including refractory OCD. However, there are relevant variations among studies in terms of patients' treatment resistance, comorbidity, age, and gender. At present, 4 randomized controlled trials are available on the efficacy of memantine as an augmentation medication for refractory OCD. OBJECTIVE Our study's main purpose is to conduct a double-blind, randomized, parallel-group, placebo-controlled, monocenter trial to assess the efficacy and safety of memantine as an augmentative agent to a selective serotonin reuptake inhibitor in the treatment of moderate to severe OCD. The study's second aim is to evaluate the effect of memantine on cognitive functions in patients with OCD. The third aim is to investigate if responses to memantine are modulated by variables such as gender, symptom subtypes, and the duration of untreated illness. METHODS Investigators intend to conduct a double-blind, randomized, parallel-group, placebo-controlled, monocenter trial to assess the efficacy and safety of memantine as an augmentative agent to a selective serotonin reuptake inhibitor in the treatment of patients affected by severe refractory OCD. Participants will be rated via the Yale-Brown Obsessive Compulsive Scale at baseline and at 2, 4, 6, 8, 10, and 12 months. During the screening period and T4 and T6 follow-up visits, all participants will undergo an extensive neuropsychological evaluation. The 52-week study duration will consist of 4 distinct periods, including memantine titration and follow-up periods. RESULTS Recruitment has not yet started. The study will be conducted from June 2023 to December 2024. Results are expected to be available in January 2025. Throughout the slow-titration period, we will observe the minimum effective dose of memantine, and the follow-up procedure will detail its residual efficacy after drug withdrawal. CONCLUSIONS The innovation of this research proposal is not limited to the evaluation of the efficacy and safety of memantine as an augmentation medication for OCD. We will also test if memantine acts as a pure antiobsessive medication or if memantine's ability to improve concentration and attention mimics an antiobsessive effect. TRIAL REGISTRATION ClinicalTrials.gov NCT05015595; https://clinicaltrials.gov/ct2/show/NCT05015595. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID) PRR1-10.2196/39223.
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Affiliation(s)
| | | | | | | | - Carlo De Lena
- Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele, Rome, Italy
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16
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Brain function changes reveal rapid antidepressant effects of nitrous oxide for treatment-resistant depression:Evidence from task-state EEG. Psychiatry Res 2023; 322:115072. [PMID: 36791487 DOI: 10.1016/j.psychres.2023.115072] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 01/15/2023] [Accepted: 01/22/2023] [Indexed: 01/28/2023]
Abstract
Nitrous oxide has rapid antidepressant effects in patients with treatment-resistant depression (TRD), but its underlying mechanisms of therapeutic actions are not well understood. Moreover, most of the current studies lack objective biological indicators to evaluate the changes of nitrous oxide-induced brain function for TRD. Therefore, this study assessed the effect of nitrous oxide on brain function for TRD based on event-related potential (ERP) components and functional connectivity networks (FCNs) methods. In this randomized, longitudinal, placebo-controlled trial, all TRD participants were divided into two groups to receive either a 1-hour inhalation of nitrous oxide or a placebo treatment, and they took part in the same task-state electroencephalogram (EEG) experiment before and after treatment. The experimental results showed that nitrous oxide improved depressive symptoms better than placebo in terms of 17-Hamilton Depression Rating Scale score (HAMD-17). Statistical analysis based on ERP components showed that nitrous oxide-induced significant differences in amplitude and latency of N1, P1, N2, P2. In addition, increased brain functional connectivity was found after nitrous oxide treatment. And the change of network metrics has a significant correlation with decreased depressive symptoms. These findings may suggest that nitrous oxide improves depression symptoms for TRD by modifying brain function.
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17
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Ragnhildstveit A, Roscoe J, Bass LC, Averill CL, Abdallah CG, Averill LA. The potential of ketamine for posttraumatic stress disorder: a review of clinical evidence. Ther Adv Psychopharmacol 2023; 13:20451253231154125. [PMID: 36895431 PMCID: PMC9989422 DOI: 10.1177/20451253231154125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2022] [Accepted: 01/13/2023] [Indexed: 03/08/2023] Open
Abstract
Posttraumatic stress disorder (PTSD) is a devastating condition, for which there are few pharmacological agents, often with a delayed onset of action and poor efficacy. Trauma-focused psychotherapies are further limited by few trained providers and low patient engagement. This frequently results in disease chronicity as well as psychiatric and medical comorbidity, with considerable negative impact on quality of life. As such, off-label interventions are commonly used for PTSD, particularly in chronic refractory cases. Ketamine, an N-methyl-D-aspartate (NDMA) receptor antagonist, has recently been indicated for major depression, exhibiting rapid and robust antidepressant effects. It also shows transdiagnostic potential for an array of psychiatric disorders. Here, we synthesize clinical evidence on ketamine in PTSD, spanning case reports, chart reviews, open-label studies, and randomized trials. Overall, there is high heterogeneity in clinical presentation and pharmacological approach, yet encouraging signals of therapeutic safety, efficacy, and durability. Avenues for future research are discussed.
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Affiliation(s)
- Anya Ragnhildstveit
- Integrated Research Literacy Group, Draper, UT, USA.,Department of Psychiatry, University of Cambridge, Cambridge, UK.,Department of Psychology and Neuroscience, Duke University, Durham, NC, USA
| | - Jeremy Roscoe
- Integrated Research Literacy Group, Draper, UT, USA.,Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA
| | - Lisa C Bass
- Integrated Research Literacy Group, Draper, UT, USA.,Neuroscience Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA, USA
| | - Christopher L Averill
- Baylor College of Medicine, Houston, TX, USA.,Michael E. DeBakey VA Medical Center, Houston, TX, USA.,Yale School of Medicine, New Haven, CT, USA.,National Center for PTSD, West Haven, CT, USA
| | - Chadi G Abdallah
- Baylor College of Medicine, Houston, TX, USA.,Michael E. DeBakey VA Medical Center, Houston, TX, USA.,Yale School of Medicine, New Haven, CT, USA.,National Center for PTSD, West Haven, CT, USA
| | - Lynnette A Averill
- Baylor College of Medicine, 1977 Butler Avenue, 4-E-187, Houston, TX 77030, USA.,Yale School of Medicine, New Haven, CT, USA.,Michael E. DeBakey Veterans Affairs Medical Center, Houston, TX, USA.,National Center for PTSD, West Haven, CT, USA
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18
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Vargas-Perez H, Grieder TE, van der Kooy D. Neural Plasticity in the Ventral Tegmental Area, Aversive Motivation during Drug Withdrawal and Hallucinogenic Therapy. J Psychoactive Drugs 2023; 55:62-72. [PMID: 35114904 DOI: 10.1080/02791072.2022.2033889] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Aberrant glutamatergic signaling has been closely related to several pathologies of the central nervous system. Glutamatergic activity can induce an increase in neural plasticity mediated by brain-derived neurotrophic factor (BDNF) in the ventral tegmental area (VTA), a nodal point in the mesolimbic dopamine system. Recent studies have related BDNF dependent plasticity in the VTA with the modulation of aversive motivation to deal with noxious environmental stimuli. The disarray of these learning mechanisms would produce an abnormal augmentation in the representation of the emotional information related to aversion, sometimes even in the absence of external environmental trigger, inducing pathologies linked to mood disorders such as depression and drug addiction. Recent studies point out that serotonin (5-hydroxytryptamine, 5-HT) receptors, especially the 2a (5-HT2a) subtype, play an important role in BDNF-related neural plasticity in the VTA. It has been observed that a single administration of a 5HT2a agonist can both revert an animal to a nondependent state from a drug-dependent state (produced by the chronic administration of a substance of abuse). The 5HT2a agonist also reverted the BDNF-induced neural plasticity in the VTA, suggesting that the administration of 5-HT2a agonists could be used as effective therapeutic agents to treat drug addiction. These findings could explain the neurobiological correlate of the therapeutic use of 5HT2a agonists, which can be found in animals, plants and fungi during traditional medicine ceremonies and rituals to treat mood related disorders.
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Affiliation(s)
- Hector Vargas-Perez
- The Nierika Intercultural Medicine Institute, Ocuilan, México.,Postgrado En Ciencias Cognitivas, Universidad Autonoma Del Estado de Morelos, Cuernavaca, Mexico
| | - Taryn Elizabeth Grieder
- Institute of Medical Science and Department of Molecular Genetics, University of Toronto, Toronto, Canada
| | - Derek van der Kooy
- Institute of Medical Science and Department of Molecular Genetics, University of Toronto, Toronto, Canada
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Langhein M, Seitz-Holland J, Lyall AE, Pasternak O, Chunga N, Cetin-Karayumak S, Kubicki A, Mulert C, Espinoza RT, Narr KL, Kubicki M. Association between peripheral inflammation and free-water imaging in Major Depressive Disorder before and after ketamine treatment - A pilot study. J Affect Disord 2022; 314:78-85. [PMID: 35779673 PMCID: PMC11186306 DOI: 10.1016/j.jad.2022.06.043] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Revised: 05/27/2022] [Accepted: 06/20/2022] [Indexed: 10/17/2022]
Abstract
BACKGROUND Alterations in the peripheral inflammatory profile and white matter (WM) deterioration are frequent in Major Depressive Disorder (MDD). The present study applies free-water imaging to investigate the relationship between altered peripheral inflammation and WM microstructure and their predictive value in determining response to ketamine treatment in MDD. METHODS Ten individuals with MDD underwent diffusion-weighted magnetic resonance imaging and a blood-draw before and 24 h after ketamine infusion. We utilized MANCOVAs and ANCOVAs to compare tissue-specific fractional anisotropy (FAT) and free-water (FW) of the forceps and cingulum, and the ratio of pro-inflammatory interleukin(IL)-8/anti-inflammatory IL-10 between individuals with MDD and 15 healthy controls at baseline. Next, we compared all baseline measures between ketamine responders (6) and non-responders (4) and analyzed changes in imaging and blood data after ketamine infusion. RESULTS The MDD group exhibited an increased IL-8/IL-10 ratio compared to controls at baseline (p = .040), which positively correlated with average FW across regions of interest (p = .013). Ketamine responders demonstrated higher baseline FAT in the left cingulum than non-responders (p = .023). Ketamine infusion did not influence WM microstructure but decreased the IL-8/IL-10 ratio (p = .043). LIMITATIONS The small sample size and short follow-up period limit the conclusion regarding the longer-term effects of ketamine in MDD. CONCLUSIONS This pilot study provides evidence for the role of inflammation in MDD by illustrating an association between peripheral inflammation and WM microstructure. Additionally, we demonstrate that free-water diffusion-weighted imaging might be a valuable tool to determine which individuals with MDD benefit from the anti-inflammatory mediated effects of ketamine treatment.
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Affiliation(s)
- Mina Langhein
- Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Psychiatry Neuroimaging Branch, Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Johanna Seitz-Holland
- Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Amanda E Lyall
- Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Ofer Pasternak
- Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Natalia Chunga
- Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Suheyla Cetin-Karayumak
- Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Antoni Kubicki
- Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, Geffen School of Medicine at the University of California, Los Angeles, CA, USA
| | - Christoph Mulert
- Centre for Psychiatry, Justus-Liebig-University, Giessen, Germany
| | - Randall T Espinoza
- Jane and Terry Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, Geffen School of Medicine at the University of California, Los Angeles, CA, USA
| | - Katherine L Narr
- Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, Geffen School of Medicine at the University of California, Los Angeles, CA, USA; Jane and Terry Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, Geffen School of Medicine at the University of California, Los Angeles, CA, USA
| | - Marek Kubicki
- Psychiatry Neuroimaging Laboratory, Department of Psychiatry, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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20
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Choi Y, Jung IC, Kim JY, Cho SH, Kim Y, Chung SY, Kwak HY, Lee DS, Lee W, Nam IJ, Yang C, Lee MY. Efficacy and safety of Gyejibokryeong-hwan (GBH) in major depressive disorder: study protocol for multicentre randomised controlled trial. Trials 2022; 23:447. [PMID: 35650612 PMCID: PMC9158297 DOI: 10.1186/s13063-022-06339-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Accepted: 04/23/2022] [Indexed: 11/23/2022] Open
Abstract
Background Gyejibokryeong-hwan (GBH) is an herbal medicine composed of five herbs. It has been widely used to treat gynaecological diseases in traditional East Asian medicine. Recent animal studies suggest antidepressant effects of GBH. In this trial, we explore the efficacy and safety of GBH in patients with major depressive disorder and to identify the optimal dose for the next phase III trial. Methods This trial will enrol 126 patients diagnosed with major depressive disorder and not treated with antidepressants. Participants will be randomised to receive a high or a low dose of GBH or placebo granules. The study drugs will be administered three times a day, for 8 weeks. The 17-item Hamilton Depression Rating Scale (HDRS) will be used to measure the severity of depressive symptoms at weeks 2, 4, 6, 8, and 12. The primary efficacy endpoint is the change from baseline in HDRS-17 total score post-treatment at week 8. Analysis of covariance will be based on the baseline HDRS-17 total score and site as the covariates. Safety assessment will be based on the frequency of adverse events. The severity and causality of the study drug will be assessed. Discussion This study is designed to evaluate the efficacy and safety of GBH granules compared with placebo in patients with major depressive disorder. Trial registration Clinical Research Information Service KCT0004417. Registered on November 1, 2019 (prospective registration)
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Affiliation(s)
- Yujin Choi
- KM Science Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea
| | - In Chul Jung
- Department of Oriental Neuropsychiatry, College of Korean Medicine, Daejeon University, Daejeon, 34520, Republic of Korea
| | - Ju Yeon Kim
- Department of Neuropsychiatry, Daejeon Korean Medicine Hospital of Daejeon University, Daejeon, 35235, Republic of Korea
| | - Seung-Hun Cho
- Department of Neuropsychiatry, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.,Research group of Neuroscience, East-West Medical Research Institute, WHO Collaborating Center, Kyung Hee University, Seoul, Republic of Korea.,Department of Clinical Korean Medicine, Graduated School, Kyung Hee University, Seoul, Republic of Korea
| | - Yunna Kim
- Department of Neuropsychiatry, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.,Research group of Neuroscience, East-West Medical Research Institute, WHO Collaborating Center, Kyung Hee University, Seoul, Republic of Korea.,Department of Clinical Korean Medicine, Graduated School, Kyung Hee University, Seoul, Republic of Korea
| | - Sun-Yong Chung
- Department of Neuropsychiatry, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Hui-Yong Kwak
- Department of Neuropsychiatry, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Doo Suk Lee
- R&D Center for Innovative Medicines, Helixmith Co., Ltd., Seoul, Republic of Korea
| | - Wonwoo Lee
- R&D Center for Innovative Medicines, Helixmith Co., Ltd., Seoul, Republic of Korea
| | - In-Jeong Nam
- R&D Center for Innovative Medicines, Helixmith Co., Ltd., Seoul, Republic of Korea
| | - Changsop Yang
- KM Science Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea.
| | - Mi Young Lee
- KM Convergence Research Division, Korea Institute of Oriental Medicine, Daejeon, Republic of Korea.
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21
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Rayff da Silva P, Diniz Nunes Pazos N, Karla Silva do Nascimento Gonzaga T, Cabral de Andrade J, Brito Monteiro Á, Caroline Ribeiro Portela A, Fernandes Oliveira Pires H, Dos Santos Maia M, Vilar da Fonsêca D, T Scotti M, Maria Barbosa Filho J, Pergentino de Sousa D, Francisco Bezerra Felipe C, Nóbrega de Almeida R, Scotti L. Anxiolytic and antidepressant-like effects of monoterpene tetrahydrolinalool and in silico approach of new potential targets. Curr Top Med Chem 2022; 22:1530-1552. [PMID: 35524664 DOI: 10.2174/1568026622666220505104726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 02/03/2022] [Accepted: 02/16/2022] [Indexed: 11/22/2022]
Abstract
INTRODUCTION- The drugs currently available for treatment of anxiety and depression act through modulation of the neurotransmission systems involved in the neurobiology of the disorder, yet they of-ten present side effects, which can impair patient adherence to treatment. METHOD- This, has driven the search for new molecules with anxiolytic and antidepressant potential. Aromatic plants are rich in essential oils, and their chemical constituents, such as monoterpenes, are be-ing studied for these disorders. This study aims to evaluate the anxiolytic and antidepressant-like poten-tial of the monoterpene tetrahydrolinalool in in vivo animal models, and review pharmacological targets with validation through molecular docking. Male Swiss mice (Mus musculus) were treated with THL (37.5-600 mg kg-1 p.o.) and submitted to the elevated plus maze, open field, rota rod, and forced swim tests. In the elevated plus-maze, THL at doses of 37.5 and 75 mg kg-1 induced a significant increase in the percentage of entries (72.7 and 64.3% respectively), and lengths of stay (80.3 and 76.8% respective-ly) in the open arms tests. RESULT- These doses did not compromise locomotor activity or motor coordination in the animals. In the open field, rota rod tests, and the forced swimming model, treatment with THL significantly reduced immobility times at doses of 150, 300, and 600 mg kg-1, and by respective percentages of 69.3, 60.9 and 68.7%. CONCLUSION- In molecular docking assay, which investigated potential targets, THL presented sat-isfactory energy values for: nNOs, SGC, IL-6, 5-HT1A, NMDAr, and D1. These demonstrate the po-tential of THL (a derivative of natural origin) in in vivo and in silico models, making it a drug candidate.
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Affiliation(s)
- Pablo Rayff da Silva
- Psychopharmacology Laboratory, Institute of Drugs and Medicines Research, Federal University of Paraíba, 58051-085, Via Ipê Amarelo, S/N, João Pessoa, Paraíba, Brazil
| | - Natalia Diniz Nunes Pazos
- Psychopharmacology Laboratory, Institute of Drugs and Medicines Research, Federal University of Paraíba, 58051-085, Via Ipê Amarelo, S/N, João Pessoa, Paraíba, Brazil
| | | | - Jéssica Cabral de Andrade
- Psychopharmacology Laboratory, Institute of Drugs and Medicines Research, Federal University of Paraíba, 58051-085, Via Ipê Amarelo, S/N, João Pessoa, Paraíba, Brazil
| | - Álefe Brito Monteiro
- Psychopharmacology Laboratory, Institute of Drugs and Medicines Research, Federal University of Paraíba, 58051-085, Via Ipê Amarelo, S/N, João Pessoa, Paraíba, Brazil
| | - Anne Caroline Ribeiro Portela
- Psychopharmacology Laboratory, Institute of Drugs and Medicines Research, Federal University of Paraíba, 58051-085, Via Ipê Amarelo, S/N, João Pessoa, Paraíba, Brazil
| | - Hugo Fernandes Oliveira Pires
- Psychopharmacology Laboratory, Institute of Drugs and Medicines Research, Federal University of Paraíba, 58051-085, Via Ipê Amarelo, S/N, João Pessoa, Paraíba, Brazil
| | - Mayara Dos Santos Maia
- Cheminformatics Laboratory, Institute of Drugs and Medicines Research, Federal University of Paraíba, 58051-900, Via Ipê Amarelo, S/N, João Pessoa, Paraíba, Brazil
| | - Diogo Vilar da Fonsêca
- Collegiate of Medicine, Federal University of São Francisco Valley, 48607-190, Rua Aurora, S/N, Bahia, Brazil
| | - Marcus T Scotti
- Cheminformatics Laboratory, Institute of Drugs and Medicines Research, Federal University of Paraíba, 58051-900, Via Ipê Amarelo, S/N, João Pessoa, Paraíba, Brazil
| | - José Maria Barbosa Filho
- Pharmaceutical Chemistry Laboratory, Department of Pharmaceutical Sciences, Federal University of Paraíba, 58051-900, Via Ipê Amarelo, S/N, João Pessoa, Brazil
| | - Damião Pergentino de Sousa
- Pharmaceutical Chemistry Laboratory, Department of Pharmaceutical Sciences, Federal University of Paraíba, 58051-900, Via Ipê Amarelo, S/N, João Pessoa, Brazil
| | - Cícero Francisco Bezerra Felipe
- Psychopharmacology Laboratory, Institute of Drugs and Medicines Research, Federal University of Paraíba, 58051-085, Via Ipê Amarelo, S/N, João Pessoa, Paraíba, Brazil
| | - Reinaldo Nóbrega de Almeida
- Psychopharmacology Laboratory, Institute of Drugs and Medicines Research, Federal University of Paraíba, 58051-085, Via Ipê Amarelo, S/N, João Pessoa, Paraíba, Brazil
| | - Luciana Scotti
- Cheminformatics Laboratory, Institute of Drugs and Medicines Research, Federal University of Paraíba, 58051-900, Via Ipê Amarelo, S/N, João Pessoa, Paraíba, Brazil
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22
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Dean RL, Marquardt T, Hurducas C, Spyridi S, Barnes A, Smith R, Cowen PJ, McShane R, Hawton K, Malhi GS, Geddes J, Cipriani A. Ketamine and other glutamate receptor modulators for depression in adults with bipolar disorder. Cochrane Database Syst Rev 2021; 10:CD011611. [PMID: 34623633 PMCID: PMC8499740 DOI: 10.1002/14651858.cd011611.pub3] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Glutamergic system dysfunction has been implicated in the pathophysiology of bipolar depression. This is an update of the 2015 Cochrane Review for the use of glutamate receptor modulators for depression in bipolar disorder. OBJECTIVES 1. To assess the effects of ketamine and other glutamate receptor modulators in alleviating the acute symptoms of depression in people with bipolar disorder. 2. To review the acceptability of ketamine and other glutamate receptor modulators in people with bipolar disorder who are experiencing depressive symptoms. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Ovid MEDLINE, Embase and PsycINFO all years to July 2020. We did not apply any restrictions to date, language or publication status. SELECTION CRITERIA RCTs comparing ketamine or other glutamate receptor modulators with other active psychotropic drugs or saline placebo in adults with bipolar depression. DATA COLLECTION AND ANALYSIS Two review authors independently selected studies for inclusion, assessed trial quality and extracted data. Primary outcomes were response rate and adverse events. Secondary outcomes included remission rate, depression severity change scores, suicidality, cognition, quality of life, and dropout rate. The GRADE framework was used to assess the certainty of the evidence. MAIN RESULTS Ten studies (647 participants) were included in this review (an additional five studies compared to the 2015 review). There were no additional studies added to the comparisons identified in the 2015 Cochrane review on ketamine, memantine and cytidine versus placebo. However, three new comparisons were found: ketamine versus midazolam, N-acetylcysteine versus placebo, and riluzole versus placebo. The glutamate receptor modulators studied were ketamine (three trials), memantine (two), cytidine (one), N-acetylcysteine (three), and riluzole (one). Eight of these studies were placebo-controlled and two-armed. In seven trials the glutamate receptor modulators had been used as add-on drugs to mood stabilisers. Only one trial compared ketamine with an active comparator, midazolam. The treatment period ranged from a single intravenous administration (all ketamine studies), to repeated administration for riluzole, memantine, cytidine, and N-acetylcysteine (with a follow-up of eight weeks, 8 to 12 weeks, 12 weeks, and 16 to 20 weeks, respectively). Six of the studies included sites in the USA, one in Taiwan, one in Denmark, one in Australia, and in one study the location was unclear. All participants had a primary diagnosis of bipolar disorder and were experiencing an acute bipolar depressive episode, diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders fourth edition (IV) or fourth edition text revision (IV-TR). Among all glutamate receptor modulators included in this review, only ketamine appeared to be more efficacious than placebo 24 hours after infusion for response rate (odds ratio (OR) 11.61, 95% confidence interval (CI) 1.25 to 107.74; P = 0.03; participants = 33; studies = 2; I² = 0%, low-certainty evidence). Ketamine seemed to be more effective in reducing depression rating scale scores (MD -11.81, 95% CI -20.01 to -3.61; P = 0.005; participants = 32; studies = 2; I2 = 0%, very low-certainty evidence). There was no evidence of ketamine's efficacy in producing remission over placebo at 24 hours (OR 5.16, 95% CI 0.51 to 52.30; P = 0.72; participants = 33; studies = 2; I2 = 0%, very low-certainty evidence). Evidence on response, remission or depression rating scale scores between ketamine and midazolam was uncertain at 24 hours due to very low-certainty evidence (OR 3.20, 95% CI 0.23 to 45.19). In the one trial assessing ketamine and midazolam, there were no dropouts due to adverse effects or for any reason (very low-certainty evidence). Placebo may have been more effective than N-acetylcysteine in reducing depression rating scale scores at three months, although this was based on very low-certainty evidence (MD 1.28, 95% CI 0.24 to 2.31; participants = 58; studies = 2). Very uncertain evidence found no difference in response at three months (OR 0.82, 95% CI 0.32 to 2.14; participants = 69; studies = 2; very low-certainty evidence). No data were available for remission or acceptability. Extremely limited data were available for riluzole vs placebo, finding only very-low certainty evidence of no difference in dropout rates (OR 2.00, 95% CI 0.31 to 12.84; P = 0.46; participants = 19; studies = 1; I2 = 0%). AUTHORS' CONCLUSIONS It is difficult to draw reliable conclusions from this review due to the certainty of the evidence being low to very low, and the relatively small amount of data usable for analysis in bipolar disorder, which is considerably less than the information available for unipolar depression. Nevertheless, we found uncertain evidence in favour of a single intravenous dose of ketamine (as add-on therapy to mood stabilisers) over placebo in terms of response rate up to 24 hours, however ketamine did not show any better efficacy for remission in bipolar depression. Even though ketamine has the potential to have a rapid and transient antidepressant effect, the efficacy of a single intravenous dose may be limited. We did not find conclusive evidence on adverse events with ketamine, and there was insufficient evidence to draw meaningful conclusions for the remaining glutamate receptor modulators. However, ketamine's psychotomimetic effects (such as delusions or delirium) may have compromised study blinding in some studies, and so we cannot rule out the potential bias introduced by inadequate blinding procedures. To draw more robust conclusions, further methodologically sound RCTs (with adequate blinding) are needed to explore different modes of administration of ketamine, and to study different methods of sustaining antidepressant response, such as repeated administrations.
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Affiliation(s)
| | | | | | - Styliani Spyridi
- Department of Rehabilitation Sciences, Faculty of Health Sciences, Cyprus University of Technology, Lemesos, Cyprus
| | | | | | - Philip J Cowen
- Department of Psychiatry, University of Oxford, Oxford, UK
| | - Rupert McShane
- Department of Psychiatry, University of Oxford, Oxford, UK
| | - Keith Hawton
- Centre for Suicide Research, University Department of Psychiatry, Warneford Hospital, Oxford, UK
| | - Gin S Malhi
- Discipline of Psychiatry, Northern Clinical School, University of Sydney, Sydney, Australia
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23
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Hansen KB, Wollmuth LP, Bowie D, Furukawa H, Menniti FS, Sobolevsky AI, Swanson GT, Swanger SA, Greger IH, Nakagawa T, McBain CJ, Jayaraman V, Low CM, Dell'Acqua ML, Diamond JS, Camp CR, Perszyk RE, Yuan H, Traynelis SF. Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels. Pharmacol Rev 2021; 73:298-487. [PMID: 34753794 PMCID: PMC8626789 DOI: 10.1124/pharmrev.120.000131] [Citation(s) in RCA: 342] [Impact Index Per Article: 85.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Many physiologic effects of l-glutamate, the major excitatory neurotransmitter in the mammalian central nervous system, are mediated via signaling by ionotropic glutamate receptors (iGluRs). These ligand-gated ion channels are critical to brain function and are centrally implicated in numerous psychiatric and neurologic disorders. There are different classes of iGluRs with a variety of receptor subtypes in each class that play distinct roles in neuronal functions. The diversity in iGluR subtypes, with their unique functional properties and physiologic roles, has motivated a large number of studies. Our understanding of receptor subtypes has advanced considerably since the first iGluR subunit gene was cloned in 1989, and the research focus has expanded to encompass facets of biology that have been recently discovered and to exploit experimental paradigms made possible by technological advances. Here, we review insights from more than 3 decades of iGluR studies with an emphasis on the progress that has occurred in the past decade. We cover structure, function, pharmacology, roles in neurophysiology, and therapeutic implications for all classes of receptors assembled from the subunits encoded by the 18 ionotropic glutamate receptor genes. SIGNIFICANCE STATEMENT: Glutamate receptors play important roles in virtually all aspects of brain function and are either involved in mediating some clinical features of neurological disease or represent a therapeutic target for treatment. Therefore, understanding the structure, function, and pharmacology of this class of receptors will advance our understanding of many aspects of brain function at molecular, cellular, and system levels and provide new opportunities to treat patients.
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Affiliation(s)
- Kasper B Hansen
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Lonnie P Wollmuth
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Derek Bowie
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Hiro Furukawa
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Frank S Menniti
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Alexander I Sobolevsky
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Geoffrey T Swanson
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Sharon A Swanger
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Ingo H Greger
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Terunaga Nakagawa
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Chris J McBain
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Vasanthi Jayaraman
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Chian-Ming Low
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Mark L Dell'Acqua
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Jeffrey S Diamond
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Chad R Camp
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Riley E Perszyk
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Hongjie Yuan
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
| | - Stephen F Traynelis
- Center for Structural and Functional Neuroscience, Center for Biomolecular Structure and Dynamics, Division of Biological Sciences, University of Montana, Missoula, MT (K.B.H.); Department of Neurobiology and Behavior, Center for Nervous System Disorders, Stony Brook University, Stony Brook, NY (L.P.W.); Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada (D.B.); WM Keck Structural Biology Laboratory, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY (H.F.); MindImmune Therapeutics, Inc., The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI (F.S.M.); Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY (A.I.S.); Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, IL (G.T.S.); Fralin Biomedical Research Institute at Virginia Tech Carilion, Virginia Tech, Roanoke, VA and Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Tech, Blacksburg, VA (S.A.S.); Neurobiology Division, MRC Laboratory of Molecular Biology, Cambridge, United Kingdom (I.H.G.); Department of Molecular Physiology and Biophysics, Center for Structural Biology, Vanderbilt Brain Institute, Vanderbilt University, School of Medicine, Nashville, TN (T.N.); Eunice Kennedy Shriver National Institute of Child Health and Human Development (C.J.M.), and Synaptic Physiology Section, NINDS Intramural Research Program, National Institutes of Health, Bethesda, MD (J.S.D.); Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX (V.J.); Department of Pharmacology, Department of Anaesthesia, Healthy Longevity Translational Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore (C.-M.L.); Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO (M.L.D.); and Department of Pharmacology and Chemical Biology, Emory University School of Medicine, Atlanta, GA (C.R.C., R.E.P., H.Y., S.F.T.)
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Maraone A, Tarsitani L, Pinucci I, Pasquini M. Antiglutamatergic agents for obsessive-compulsive disorder: Where are we now and what are possible future prospects? World J Psychiatry 2021; 11:568-580. [PMID: 34631461 PMCID: PMC8474998 DOI: 10.5498/wjp.v11.i9.568] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 07/25/2021] [Accepted: 08/06/2021] [Indexed: 02/06/2023] Open
Abstract
Recent data suggest that obsessive-compulsive disorder (OCD) is driven by an imbalance among the habit learning system and the goal-directed system. The frontostriatal loop termed cortico-striatal-thalamo-cortical (CSTC) circuitry loop is involved in habits and their dysfunction plays an important role in OCD. Glutamatergic neurotransmission is the principal neurotransmitter implicated in the CSTC model of OCD. Hyperactivity in the CSTC loop implies a high level of glutamate in the cortical-striatal pathways as well as a dysregulation of GABAergic transmission, and could represent the pathophysiology of OCD. Moreover, the dysregulation of glutamate levels can lead to neurotoxicity, acting as a neuronal excitotoxin. The hypothesis of a role of neurotoxicity in the pathophysiology of OCD clinically correlates to the importance of an early intervention for patients. Indeed, some studies have shown that a reduction of duration of untreated illness is related to an earlier onset of remission. Although robust data supporting a progression of such brain changes are not available so far, an early intervention could help interrupt damage from neurotoxicity. Moreover, agents targeting glutamate neurotransmission may represent promising therapeutical option in OCD patients.
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Affiliation(s)
- Annalisa Maraone
- Department of Human Neurosciences, Sapienza University of Rome, Rome 00185, Lazio, Italy
| | - Lorenzo Tarsitani
- Department of Human Neurosciences, Sapienza University of Rome, Rome 00185, Lazio, Italy
| | - Irene Pinucci
- Department of Human Neurosciences, Sapienza University of Rome, Rome 00185, Lazio, Italy
| | - Massimo Pasquini
- Department of Human Neurosciences, Sapienza University of Rome, Rome 00185, Lazio, Italy
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25
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Blaze J, Navickas A, Phillips HL, Heissel S, Plaza-Jennings A, Miglani S, Asgharian H, Foo M, Katanski CD, Watkins CP, Pennington ZT, Javidfar B, Espeso-Gil S, Rostandy B, Alwaseem H, Hahn CG, Molina H, Cai DJ, Pan T, Yao WD, Goodarzi H, Haghighi F, Akbarian S. Neuronal Nsun2 deficiency produces tRNA epitranscriptomic alterations and proteomic shifts impacting synaptic signaling and behavior. Nat Commun 2021; 12:4913. [PMID: 34389722 PMCID: PMC8363735 DOI: 10.1038/s41467-021-24969-x] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Accepted: 07/16/2021] [Indexed: 02/07/2023] Open
Abstract
Epitranscriptomic mechanisms linking tRNA function and the brain proteome to cognition and complex behaviors are not well described. Here, we report bi-directional changes in depression-related behaviors after genetic disruption of neuronal tRNA cytosine methylation, including conditional ablation and transgene-derived overexpression of Nsun2 in the mouse prefrontal cortex (PFC). Neuronal Nsun2-deficiency was associated with a decrease in tRNA m5C levels, resulting in deficits in expression of 70% of tRNAGly isodecoders. Altogether, 1488/5820 proteins changed upon neuronal Nsun2-deficiency, in conjunction with glycine codon-specific defects in translational efficiencies. Loss of Gly-rich proteins critical for glutamatergic neurotransmission was associated with impaired synaptic signaling at PFC pyramidal neurons and defective contextual fear memory. Changes in the neuronal translatome were also associated with a 146% increase in glycine biosynthesis. These findings highlight the methylation sensitivity of glycinergic tRNAs in the adult PFC. Furthermore, they link synaptic plasticity and complex behaviors to epitranscriptomic modifications of cognate tRNAs and the proteomic homeostasis associated with specific amino acids.
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Affiliation(s)
- J Blaze
- Department of Neuroscience, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
- Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
| | - A Navickas
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
| | - H L Phillips
- Departments of Psychiatry and Behavioral Sciences, Neuroscience and Physiology, Upstate Medical University, Syracuse, NY, USA
| | - S Heissel
- The Rockefeller University Proteomics Resource Center, The Rockefeller University, New York, NY, USA
| | - A Plaza-Jennings
- Department of Psychiatry, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
| | - S Miglani
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
| | - H Asgharian
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
| | - M Foo
- Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA
| | - C D Katanski
- Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA
| | - C P Watkins
- Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA
| | - Z T Pennington
- Department of Neuroscience, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
- Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
| | - B Javidfar
- Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
| | - S Espeso-Gil
- Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
| | - B Rostandy
- The Rockefeller University Proteomics Resource Center, The Rockefeller University, New York, NY, USA
| | - H Alwaseem
- The Rockefeller University Proteomics Resource Center, The Rockefeller University, New York, NY, USA
| | - C G Hahn
- Department of Neurosciences, Thomas Jefferson University, Philadelphia, PA, USA
| | - H Molina
- The Rockefeller University Proteomics Resource Center, The Rockefeller University, New York, NY, USA
| | - D J Cai
- Department of Neuroscience, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
- Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
| | - T Pan
- Department of Biochemistry and Molecular Biology, University of Chicago, Chicago, IL, USA
| | - W D Yao
- Departments of Psychiatry and Behavioral Sciences, Neuroscience and Physiology, Upstate Medical University, Syracuse, NY, USA
| | - H Goodarzi
- Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA
| | - F Haghighi
- Department of Neuroscience, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
- Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
- Department of Psychiatry, Icahn School of Medicine at Mt. Sinai, New York, NY, USA
- Research and Development Service, James J. Peters Veterans Affairs Medical Center, Bronx, NY, USA
| | - S Akbarian
- Department of Neuroscience, Icahn School of Medicine at Mt. Sinai, New York, NY, USA.
- Friedman Brain Institute, Icahn School of Medicine at Mt. Sinai, New York, NY, USA.
- Department of Psychiatry, Icahn School of Medicine at Mt. Sinai, New York, NY, USA.
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Abstract
The efficacy of standard antidepressants is limited for many patients with mood disorders such as major depressive disorder (MDD) and bipolar depression, underscoring the urgent need to develop novel therapeutics. Both clinical and preclinical studies have implicated glutamatergic system dysfunction in the pathophysiology of mood disorders. In particular, rapid reductions in depressive symptoms have been observed in response to subanesthetic doses of the glutamatergic modulator racemic (R,S)-ketamine in individuals with mood disorders. These results have prompted investigation into other glutamatergic modulators for depression, both as monotherapy and adjunctively. Several glutamate receptor-modulating agents have been tested in proof-of-concept studies for mood disorders. This manuscript gives a brief overview of the glutamate system and its relevance to rapid antidepressant response and discusses the existing clinical evidence for glutamate receptor-modulating agents, including (1) broad glutamatergic modulators ((R,S)-ketamine, esketamine, (R)-ketamine, (2R,6R)-hydroxynorketamine [HNK], dextromethorphan, Nuedexta [a combination of dextromethorphan and quinidine], deudextromethorphan [AVP-786], axsome [AXS-05], dextromethadone [REL-1017], nitrous oxide, AZD6765, CLE100, AGN-241751); (2) glycine site modulators (D-cycloserine [DCS], NRX-101, rapastinel [GLYX-13], apimostinel [NRX-1074], sarcosine, 4-chlorokynurenine [4-Cl-KYN/AV-101]); (3) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (eliprodil [EVT-101], traxoprodil [CP-101,606], rislenemdaz [MK-0657/CERC-301]); (4) metabotropic glutamate receptor (mGluR) modulators (basimglurant, AZD2066, RG1578, TS-161); and (5) mammalian target of rapamycin complex 1 (mTORC1) activators (NV-5138). Many of these agents are still in the preliminary stages of development. Furthermore, to date, most have demonstrated relatively modest effects compared with (R,S)-ketamine and esketamine, though some have shown more favorable characteristics. Of these novel agents, the most promising, and the ones for which the most evidence exists, appear to be those targeting ionotropic glutamate receptors.
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Bortolozzi A, Manashirov S, Chen A, Artigas F. Oligonucleotides as therapeutic tools for brain disorders: Focus on major depressive disorder and Parkinson's disease. Pharmacol Ther 2021; 227:107873. [PMID: 33915178 DOI: 10.1016/j.pharmthera.2021.107873] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 04/05/2021] [Indexed: 12/25/2022]
Abstract
Remarkable advances in understanding the role of RNA in health and disease have expanded considerably in the last decade. RNA is becoming an increasingly important target for therapeutic intervention; therefore, it is critical to develop strategies for therapeutic modulation of RNA function. Oligonucleotides, including antisense oligonucleotide (ASO), small interfering RNA (siRNA), microRNA mimic (miRNA), and anti-microRNA (antagomir) are perhaps the most direct therapeutic strategies for addressing RNA. Among other mechanisms, most oligonucleotide designs involve the formation of a hybrid with RNA that promotes its degradation by activation of endogenous enzymes such as RNase-H (e.g., ASO) or the RISC complex (e.g. RNA interference - RNAi for siRNA and miRNA). However, the use of oligonucleotides for the treatment of brain disorders is seriously compromised by two main limitations: i) how to deliver oligonucleotides to the brain compartment, avoiding the action of peripheral RNAses? and once there, ii) how to target specific neuronal populations? We review the main molecular pathways in major depressive disorder (MDD) and Parkinson's disease (PD), and discuss the challenges associated with the development of novel oligonucleotide therapeutics. We pay special attention to the use of conjugated ligand-oligonucleotide approach in which the oligonucleotide sequence is covalently bound to monoamine transporter inhibitors (e.g. sertraline, reboxetine, indatraline). This strategy allows their selective accumulation in the monoamine neurons of mice and monkeys after their intranasal or intracerebroventricular administration, evoking preclinical changes predictive of a clinical therapeutic action after knocking-down disease-related genes. In addition, recent advances in oligonucleotide therapeutic clinical trials are also reviewed.
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Affiliation(s)
- Analia Bortolozzi
- Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), 08036 Barcelona, Spain; Institut d'Investigacions August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain.
| | - Sharon Manashirov
- Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain; miCure Therapeutics LTD., Tel-Aviv, Israel; Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, 80804 Munich, Germany
| | - Alon Chen
- Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, 80804 Munich, Germany; Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Francesc Artigas
- Institut d'Investigacions Biomèdiques de Barcelona (IIBB), Consejo Superior de Investigaciones Científicas (CSIC), 08036 Barcelona, Spain; Institut d'Investigacions August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), ISCIII, Madrid, Spain
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Guimarães MC, Guimarães TM, Hallak JE, Abrão J, Machado-de-Sousa JP. Nitrous oxide as an adjunctive therapy in major depressive disorder: a randomized controlled double-blind pilot trial. BRAZILIAN JOURNAL OF PSYCHIATRY 2021; 43:484-493. [PMID: 33605397 PMCID: PMC8555644 DOI: 10.1590/1516-4446-2020-1543] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Accepted: 11/28/2020] [Indexed: 11/21/2022]
Abstract
OBJECTIVE Major depressive disorder (MDD) is related to glutamatergic dysfunction. Antagonists of glutamatergic N-methyl-D-aspartate receptor (NMDAR), such as ketamine, have antidepressant properties. Nitrous oxide (N2O) is also a NMDAR antagonist. Thus, this study aimed to evaluate the effects of augmenting antidepressant treatment with N2O. METHODS This double blind, placebo-controlled randomized parallel pilot trial was conducted from June 2016 to June 2018 at the Hospital das Clínicas, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo. Twenty-three subjects with MDD (aged 18 to 65, on antidepressants, with a score > 17 on the 17-item-Hamilton Depression Rating Scale [HAM-D17]) received 50% N2O (n=12; 37.17±13.59 years) or placebo (100% oxygen) (n=11; 37.18±12.77 years) for 60 minutes twice a week for 4 weeks. The primary outcome was changes in HAM-D17 from baseline to week 4. RESULTS Depressive symptoms improved significantly in the N2O group (N2O: from 22.58±3.83 to 5.92±4.08; placebo: from 22.44±3.54 to 12.89±5.39, p < 0.005). A total of 91.7% and 75% of the N2O group subjects achieved response (≥ 50% reduction in HAM-D17 score) and remission (HAM-D17 < 7), respectively. The predominant adverse effects of N2O treatment were nausea, vomiting, and headache. CONCLUSION N2O treatment led to a statistically significant reduction in HAM-D17 scores compared to placebo. CLINICAL TRIAL REGISTRATION Brazilian Register of Clinical Trials, RBR-5rz5ch.
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Affiliation(s)
- Mara C Guimarães
- Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil
| | - Tiago M Guimarães
- Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil
| | - Jaime E Hallak
- Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil.,Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Ribeirão Preto, SP, Brazil
| | - João Abrão
- Departamento de Ortopedia e Anestesiologia, Faculdade de Medicina de Ribeirão Preto, USP, Ribeirão Preto, SP, Brazil
| | - João P Machado-de-Sousa
- Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil.,Instituto Nacional de Ciência e Tecnologia Translacional em Medicina (INCT-TM), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Ribeirão Preto, SP, Brazil
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29
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De Berardis D, Tomasetti C, Pompili M, Serafini G, Vellante F, Fornaro M, Valchera A, Perna G, Volpe U, Martinotti G, Fraticelli S, Di Giannantonio M, Kim YK, Orsolini L. An Update on Glutamatergic System in Suicidal Depression and on the Role of Esketamine. Curr Top Med Chem 2021; 20:554-584. [PMID: 32003691 DOI: 10.2174/1568026620666200131100316] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 11/15/2019] [Accepted: 12/09/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND A research on mood disorder pathophysiology has hypothesized abnormalities in glutamatergic neurotransmission, by suggesting further investigation on glutamatergic N-methyl-Daspartate (NMDA) receptor modulators in treating Major Depressive Disorder (MDD). Esketamine (ESK), an NMDA receptor antagonist able to modulate glutamatergic neurotransmission has been recently developed as an intranasal formulation for treatment-resistant depression (TRD) and for rapid reduction of depressive symptomatology, including suicidal ideation in MDD patients at imminent risk for suicide. OBJECTIVE The present study aims at investigating recent clinical findings on research on the role of the glutamatergic system and ESK in treating suicidal depression in MDD and TRD. METHODS A systematic review was here carried out on PubMed/Medline, Scopus and the database on U.S. N.I.H. Clinical Trials (https://clinicaltrials.gov) and the European Medical Agency (EMA) (https://clinicaltrialsregister.eu) from inception until October 2019. RESULTS Intravenous infusion of ESK is reported to elicit rapid-acting and sustained antidepressant activity in refractory patients with MDD and TRD. In phase II studies, intranasal ESK demonstrated a rapid onset and a persistent efficacy in patients with TRD as well as in MDD patients at imminent risk for suicide. However, some data discrepancies have emerged in phase III studies. CONCLUSION The U.S. Food and Drug Administration (FDA) granted fast track and Breakthrough Therapy Designation to Janssen Pharmaceuticals®, Inc. for intranasal ESK in 2013 for treatment-resistant depression (TRD) and in 2016 for the treatment of MDD with an imminent risk of suicide. However, further studies should be implemented to investigate the long-term efficacy and safety of intranasal ESK.
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Affiliation(s)
- Domenico De Berardis
- Department of Neuroscience, Imaging and Clinical Science, University of "G. D'Annunzio", Chieti, Italy.,National Health Service, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital "G. Mazzini", ASL 4 Teramo, Italy.,Polyedra, Teramo, Italy
| | - Carmine Tomasetti
- Polyedra, Teramo, Italy.,Department of Psychiatry, Federico II University, Naples, Italy.,NHS, Department of Mental Health, Psychiatric Service of Diagnosis and Treatment, Hospital "SS. Annunziata", ASL 4 Giulianova, Italy
| | - Maurizio Pompili
- Department of Neurosciences, Mental Health and Sensory Organs, Suicide Prevention Center, S. Andrea Hospital, Sapienza University, Rome, Italy
| | - Gianluca Serafini
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Section of Psychiatry, University of Genoa, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - Federica Vellante
- Department of Neuroscience, Imaging and Clinical Science, University of "G. D'Annunzio", Chieti, Italy
| | - Michele Fornaro
- Polyedra, Teramo, Italy.,Department of Psychiatry, Federico II University, Naples, Italy
| | - Alessandro Valchera
- Polyedra, Teramo, Italy.,Villa S. Giuseppe Hospital, Hermanas Hospitalarias, Ascoli Piceno, Italy
| | - Giampaolo Perna
- Department of Clinical Neurosciences, Hermanas Hospitalarias, Villa San Benedetto Menni Hospital, FoRiPsi, Albese con Cassano, Como, Italy.,Department of Psychiatry and Neuropsychology, Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, The Netherlands.,Department of Psychiatry and Behavioral Sciences, Leonard Miller School of Medicine, Miami University, Miami 786, United States
| | - Umberto Volpe
- Department of Clinical Neurosciences/DIMSC, School of Medicine, Section of Psychiatry, Polytechnic University of Marche, Ancona, Italy
| | - Giovanni Martinotti
- Department of Neuroscience, Imaging and Clinical Science, University of "G. D'Annunzio", Chieti, Italy
| | - Silvia Fraticelli
- Department of Neuroscience, Imaging and Clinical Science, University of "G. D'Annunzio", Chieti, Italy
| | - Massimo Di Giannantonio
- Department of Neuroscience, Imaging and Clinical Science, University of "G. D'Annunzio", Chieti, Italy
| | - Yong-Ku Kim
- Department of Psychiatry, Korea University College of Medicine, Seoul, Korea
| | - Laura Orsolini
- Polyedra, Teramo, Italy.,Department of Psychopharmacology, Drug Misuse and Novel Psychoactive Substances Research Unit, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, Herts, United Kingdom.,Neomesia Mental Health, Villa Jolanda Hospital, Maiolati Spontini, Italy
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30
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Gonzalez S, Vasavada M, Njau S, Sahib AK, Espinoza R, Narr KL, Leaver AM. Acute changes in cerebral blood flow after single-infusion ketamine in major depression: a pilot study. NEUROLOGY, PSYCHIATRY, AND BRAIN RESEARCH 2020; 38:5-11. [PMID: 34887623 PMCID: PMC8653983 DOI: 10.1016/j.npbr.2020.08.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
BACKGROUND Ketamine provides rapid antidepressant response in those struggling with major depressive disorder (MDD). This study measured acute changes in brain activity over 24 hours after a single infusion of ketamine using arterial spin labeled (ASL) functional magnetic resonance imaging (fMRI) in patients with MDD. ASL is a novel technique that provides quantitative values to measure cerebral blood flow (CBF). METHODS A single sub-anesthetic dose (0.5 mg/kg) of ketamine was delivered intravenously. Treatment-refractory patients (n=11) were assessed at: Baseline (pre-infusion), and approximately 1hr, 6hrs, and 24hrs post-infusion. Linear mixed-effects models detected changes in CBF with respect to treatment outcome, and results were corrected for false discovery rate (FDR). RESULTS After ketamine infusion, increased CBF was observed in the thalamus, while decreased CBF was observed in lateral occipital cortex in all patients. Time-by-response interactions were noted in ventral basal ganglia and medial prefrontal cortex, where CBF change differed according to antidepressant response. LIMITATIONS Modest sample size is a limitation of this pilot study; strict statistical correction and visualization of single-subject data attempted to ameliorate this issue. CONCLUSION In this pilot study, a sub-anesthetic dose of ketamine was associated with acute neurofunctional changes that may be consistent with altered attention, specifically increased thalamus activity coupled with decreased cortical activity. By contrast, antidepressant response to ketamine was associated with changes in reward-system regions, specifically ventral basal ganglia and medial prefrontal cortex. Further work is needed to determine whether these results generalize to larger samples and/or serial ketamine infusions associated with longer-lasting clinical effects.
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Affiliation(s)
- Sara Gonzalez
- Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, University of California Los Angeles
| | - Megha Vasavada
- Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, University of California Los Angeles
| | - Stephanie Njau
- Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, University of California Los Angeles
| | - Ashish K. Sahib
- Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, University of California Los Angeles
| | - Randall Espinoza
- Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, University of California Los Angeles
- Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles
| | - Katherine L. Narr
- Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, University of California Los Angeles
- Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles
| | - Amber M. Leaver
- Ahmanson-Lovelace Brain Mapping Center, Department of Neurology, University of California Los Angeles
- Center for Translational Imaging, Department of Radiology, Northwestern University
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Guarraci FA, Ali M, Gonzalez CMF, Lucero D, Clemons LW, Davis LK, Henneman EL, Odell SE, Meerts SH. I. Antidepressants and sexual behavior: Weekly ketamine injections increase sexual behavior initially in female and male rats. Pharmacol Biochem Behav 2020; 199:173039. [PMID: 32926881 DOI: 10.1016/j.pbb.2020.173039] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Revised: 09/03/2020] [Accepted: 09/07/2020] [Indexed: 12/28/2022]
Abstract
The present study characterized the effects of weekly ketamine injections on sexual behavior and anxiety in female and male rats, using a dosing protocol that mimics human therapeutic treatment for depression. In Experiment 1A, ketamine (10 mg/kg, i.p.) or saline was injected once per week for four consecutive weeks. The partner preference paradigm was used to measure sexual motivation 30 min after each weekly injection. Briefly, subjects were first given a 10-min test during which they could choose to spend time in the vicinity of a sexually receptive female stimulus or a sexually experienced male stimulus, however physical contact was restricted (no-contact). Immediately after, subjects were given unrestricted access to the stimulus animals (contact). After a washout period, subjects received four additional weekly injections of ketamine or saline, and then were tested for anxiety-like behavior on the elevated plus maze (EPM) after the last injection (Experiment 1B). For Experiment 2, similar procedures were used to test the effects of weekly ketamine injections on sexual motivation (Experiment 2A) and anxiety (Experiment 2B) in male subjects. In female subjects, ketamine increased sexual motivation as measured by greater time spent with the male stimulus, decreased likelihood of leaving after receiving mounts, and shorter return latencies after receiving intromissions, when compared to saline controls. In male subjects, ketamine shortened latency to first mount and first intromission, as well as increased time spent with the female stimulus. Very little anxiety was observed in either group (ketamine or saline) of female or male subjects when tested on the EPM. In conclusion, even after four weeks of ketamine exposure, sexual dysfunction did not emerge in either females or males. In contrast, ketamine increased sexual motivation in both females and males, with an initial robust response. However, as both groups gained sexual experience, the impact of ketamine diminished.
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Affiliation(s)
- Fay A Guarraci
- Department of Psychology, Southwestern University, Georgetown, TX 78626, USA.
| | - Maryam Ali
- Department of Psychology, Southwestern University, Georgetown, TX 78626, USA
| | | | - Devon Lucero
- Department of Psychology, Southwestern University, Georgetown, TX 78626, USA
| | - Larry W Clemons
- Department of Psychology, Southwestern University, Georgetown, TX 78626, USA
| | - Lourdes K Davis
- Department of Psychology, Southwestern University, Georgetown, TX 78626, USA
| | | | - Shannon E Odell
- Department of Psychology, Southwestern University, Georgetown, TX 78626, USA
| | - Sarah H Meerts
- Neuroscience Program and Department of Psychology, Carleton College, Northfield, MN 55057, USA
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Banerjee P, Donello JE, Hare B, Duman RS. Rapastinel, an NMDAR positive modulator, produces distinct behavioral, sleep, and EEG profiles compared with ketamine. Behav Brain Res 2020; 391:112706. [PMID: 32461133 DOI: 10.1016/j.bbr.2020.112706] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 05/13/2020] [Accepted: 05/13/2020] [Indexed: 12/27/2022]
Abstract
Rapastinel, a positive NMDAR modulator, produces rapid-acting and long-lasting antidepressant-like effects; however, unlike ketamine, the abuse potential for rapastinel is minimal. Ketamine has also been shown to induce psychotomimetic/dissociative side effects, aberrant gamma oscillations, and effects similar to sleep deprivation, which may potentially limit its clinical use. In this study, we compared the side effect profile and potential sleep-altering properties of rapastinel (3, 10, and 30 mg/kg) to ketamine (30 mg/kg) in rodents. In addition, we investigated corresponding changes in transcriptomics and proteomics. Rapastinel exhibited no effect on locomotor activity and prepulse inhibition in mice, while ketamine induced a significant increase in locomotor activity and a significant decrease in prepulse inhibition, which are indications of a psychosis-like state. The effects of rapastinel on sleep architecture were minimal, and rapastinel did not alter gamma frequency oscillations. In contrast, ketamine administration resulted in a greater latency to slow wave and REM sleep, disrupted duration of sleep, and affected duration of wakefulness during sleep. Further, ketamine increased cortical oscillations in the gamma frequency range, which is a property associated with psychosis. Rapastinel induced similar plasticity-related changes in transcriptomics to ketamine in rats but differed in several gene ontology classes, some of which may be involved in the regulation of sleep. In conclusion, rapastinel demonstrated a lower propensity than ketamine to induce CNS-related adverse side effects and sleep disturbances.
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Affiliation(s)
| | | | - Brendan Hare
- Yale University School of Medicine, New Haven, CT, USA
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Marek GJ, Salek AA. Extending the Specificity of DRL 72-s Behavior for Screening Antidepressant-Like Effects of Glutamatergic Clinically Validated Anxiolytic or Antidepressant Drugs in Rats. J Pharmacol Exp Ther 2020; 374:200-210. [PMID: 32265323 PMCID: PMC7318837 DOI: 10.1124/jpet.119.264069] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 03/13/2020] [Indexed: 12/26/2022] Open
Abstract
Both an agonist and its associated prodrug for metabotropic glutamate2/3 (mGlu2/3) receptors demonstrated anxiolytic efficacy in large, randomized, multicenter, double-blind, placebo-controlled trials studying patients with generalized anxiety disorder (GAD). These mGlu2/3 receptor agonists produced robust preclinical anxiolytic-like effects in rodent models. Several different metabotropic glutamate2 receptor positive allosteric modulators have been found to produce antidepressant-like effects on several preclinical screening paradigms, including differential-reinforcement-of-low-rate 72-second (DRL 72-s) behavior [increased reinforcers, decreased response rate, and cohesive rightward shifts in inter-response time distributions]. Although mGlu2/3 receptor agonists have not been tested formally for therapeutic effects in treating patients with major depressive disorder, these compounds generally fail to exert antidepressant-like effects in preclinical screening paradigms and did not improve depressive symptoms in GAD trials. Thus, the present studies were designed to test the potential antidepressant-like effects of the mGlu2/3 receptor agonist 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicarboxylate monohydrate (LY354740) on the DRL 72-s schedule. LY354740 did not test similarly to clinically validated antidepressant drugs when administered alone or when coadministered with the selective serotonin reuptake inhibitor fluoxetine in rats. Another glutamate-based antidepressant drug, the uncompetitive N-methyl-D-aspartate channel blocker racemic ketamine, exerted antidepressant-like effects when administered at subanesthetic doses in rats. The findings further support the specificity of rat DRL 72-s behavior when screening for anxiolytic versus antidepressant drugs and extend testing of compounds with glutamatergic mechanisms of action. SIGNIFICANCE STATEMENT: The metabotropic glutamate2/3 receptor agonist and clinically validated anxiolytic drug 1S,2S,5R,6S-2-aminobicyclo[3.1.0]hexane-2,6-bicarboxylate monohydrate did not test similar to antidepressant drugs (increased reinforcers, decreased response rate, and cohesive rightward shifts in the inter-response time distribution) when tested on differential-reinforcement-of-low-rate 72-second (DRL 72-s) behavior and also did not enhance the antidepressant-like effects of the serotonin reuptake inhibitor fluoxetine. The uncompetitive N-methyl-D-aspartate receptor antagonist ketamine increased the reinforcement rate, decreased the response rate, and induced a rightward shift in the inter-response time distribution similar to antidepressant drugs; these results confirm the utility of DRL 72-s schedule of reinforcement when testing clinically validated anxiolytic versus antidepressant glutamatergic drugs.
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Affiliation(s)
- Gerard J Marek
- Yale School of Medicine Department of Psychiatry, Ribicoff Research Facilities of the Connecticut Mental Health Center, New Haven, Connecticut
| | - Allyson A Salek
- Yale School of Medicine Department of Psychiatry, Ribicoff Research Facilities of the Connecticut Mental Health Center, New Haven, Connecticut
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Pribish A, Wood N, Kalava A. A Review of Nonanesthetic Uses of Ketamine. Anesthesiol Res Pract 2020; 2020:5798285. [PMID: 32308676 PMCID: PMC7152956 DOI: 10.1155/2020/5798285] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2019] [Revised: 02/07/2020] [Accepted: 03/05/2020] [Indexed: 12/20/2022] Open
Abstract
Ketamine, a nonselective NMDA receptor antagonist, is used widely in medicine as an anesthetic agent. However, ketamine's mechanisms of action lead to widespread physiological effects, some of which are now coming to the forefront of research for the treatment of diverse medical disorders. This paper aims at reviewing recent data on key nonanesthetic uses of ketamine in the current literature. MEDLINE, CINAHL, and Google Scholar databases were queried to find articles related to ketamine in the treatment of depression, pain syndromes including acute pain, chronic pain, and headache, neurologic applications including neuroprotection and seizures, and alcohol and substance use disorders. It can be concluded that ketamine has a potential role in the treatment of all of these conditions. However, research in this area is still in its early stages, and larger studies are required to evaluate ketamine's efficacy for nonanesthetic purposes in the general population.
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Affiliation(s)
- Abby Pribish
- Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | - Nicole Wood
- Department of Medicine, Cleveland Clinic, Cleveland, OH, USA
| | - Arun Kalava
- Department of Anesthesiology, University of Central Florida College of Medicine, Orlando, FL, USA
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Yi F, Rouzbeh N, Hansen KB, Xu Y, Fanger CM, Gordon E, Paschetto K, Menniti FS, Volkmann RA. PTC-174, a positive allosteric modulator of NMDA receptors containing GluN2C or GluN2D subunits. Neuropharmacology 2020; 173:107971. [PMID: 31987864 DOI: 10.1016/j.neuropharm.2020.107971] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 01/14/2020] [Accepted: 01/16/2020] [Indexed: 01/14/2023]
Abstract
NMDA receptors are ionotropic glutamate receptors that mediate excitatory neurotransmission. The diverse functions of these receptors are tuned by deploying different combinations of GluN1 and GluN2 subunits (GluN2A-D) to form either diheteromeric NMDA receptors, which contain two GluN1 and two identical GluN2 subunits, or triheteromeric NMDA receptors, which contain two GluN1 and two distinct GluN2 subunits. Here, we characterize PTC-174, a novel positive allosteric modulator (PAM) of receptors containing GluN2C or GluN2D subunits. PTC-174 potentiates maximal current amplitudes by 1.8-fold for diheteromeric GluN1/2B receptors and by > 10-fold for GluN1/2C and GluN1/2D receptors. PTC-174 also potentiates responses from triheteromeric GluN1/2B/2D and GluN1/2A/2C receptors by 4.5-fold and 1.7-fold, respectively. By contrast, PTC-174 produces partial inhibition of responses from diheteromeric GluN1/2A and triheteromeric GluN1/2A/2B receptors. PTC-174 increases potencies of co-agonists glutamate and glycine by 2- to 5-fold at GluN1/2C and GluN1/2D receptors, and NMDA receptor activation facilitates allosteric modulation by PTC-174. At native NMDA receptors in GluN2D-expressing subthalamic nucleus neurons, PTC-174 increases the amplitude of responses to NMDA application and slows the decay of excitatory postsynaptic currents (EPSCs) evoked by internal capsule stimulation. Furthermore, PTC-174 increases the amplitude and slows the decay of EPSCs in hippocampal interneurons, but has not effect on the amplitudes of NMDA receptor-mediated EPSCs in hippocampal CA1 pyramidal neurons. Thus, PTC-174 provides a useful new pharmacological tool to investigate the molecular pharmacology and physiology of GluN2C- and GluN2D-containing NMDA receptors.
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Affiliation(s)
- Feng Yi
- Department of Biomedical and Pharmaceutical Sciences, Center for Biomolecular Structure and Dynamics, Center for Structural and Functional Neuroscience, University of Montana, Missoula, MT, 59812, USA
| | - Nirvan Rouzbeh
- Department of Biomedical and Pharmaceutical Sciences, Center for Biomolecular Structure and Dynamics, Center for Structural and Functional Neuroscience, University of Montana, Missoula, MT, 59812, USA
| | - Kasper B Hansen
- Department of Biomedical and Pharmaceutical Sciences, Center for Biomolecular Structure and Dynamics, Center for Structural and Functional Neuroscience, University of Montana, Missoula, MT, 59812, USA
| | - Yuelian Xu
- Chinglu Pharmaceutical Research LLC, Newington, CT, 06111, USA
| | | | - Earl Gordon
- Reaction Biology Corporation, Malvern, PA, 19355, USA
| | - Kathy Paschetto
- Jubilant Discovery Services, Inc. 365 Phoenixville Pike, Malvern, PA, 19355, USA
| | - Frank S Menniti
- The George & Anne Ryan Institute for Neuroscience, University of Rhode Island, Kingston, RI, 02881, USA.
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Furuyashiki T, Kitaoka S. Neural mechanisms underlying adaptive and maladaptive consequences of stress: Roles of dopaminergic and inflammatory responses. Psychiatry Clin Neurosci 2019; 73:669-675. [PMID: 31215710 DOI: 10.1111/pcn.12901] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 06/03/2019] [Accepted: 06/10/2019] [Indexed: 12/13/2022]
Abstract
Stress caused by adverse and demanding conditions, a risk factor for mental illnesses, induces adaptive or maladaptive neural and behavioral consequences, depending on the conditions. Studies using rodent stress models have revealed multiple mechanisms related to dopamine and inflammation for stress-induced neural and behavioral changes. Thus, repeated stress alters activities of ventral tegmental area dopamine neurons projecting to the nucleus accumbens and the medial prefrontal cortex in distinct manners. In the nucleus accumbens, repeated stress decreases activities of D1 receptor-expressing neurons. In the medial prefrontal cortex, single stress increases dopamine D1 receptor signaling, leading to dendritic hypertrophy of excitatory neurons and stress resilience. These changes are attenuated with repetition of stress via prostaglandin E2 , an inflammation-related lipid mediator. Repeated stress activates microglia in the medial prefrontal cortex and the hippocampus. Innate immune receptors, such as the toll-like receptor 2/4 and P2X7, are crucial for repeated stress-induced microglial activation, leading to neural and behavioral changes through proinflammatory cytokines. In addition, repeated stress induces monocyte infiltration to the brain, and impairs the blood-brain barrier in the nucleus accumbens, leading to cytokine leakage to the brain. These monocyte-derived responses are involved in stress-induced behavioral changes. These findings show crucial roles of the accumbal and prefrontal dopamine pathways and inflammatory responses in the brain and body to direct adaptive and maladaptive consequences of stress, and pave the way for identifying a neural origin of stress and understanding the stress-related pathology of mental illnesses.
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Affiliation(s)
- Tomoyuki Furuyashiki
- Division of Pharmacology, Graduate School of Medicine, Kobe University, Kobe, Japan.,Japan Agency for Medical Research and Development, Tokyo, Japan
| | - Shiho Kitaoka
- Division of Pharmacology, Graduate School of Medicine, Kobe University, Kobe, Japan.,Japan Agency for Medical Research and Development, Tokyo, Japan
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Trujillo KA, Heller CY. Ketamine sensitization: Influence of dose, environment, social isolation and treatment interval. Behav Brain Res 2019; 378:112271. [PMID: 31593791 DOI: 10.1016/j.bbr.2019.112271] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 09/12/2019] [Accepted: 09/30/2019] [Indexed: 12/18/2022]
Abstract
Ketamine is a dissociative anesthetic first developed in the 1960s but is increasingly used at subanesthetic doses for both clinical and non-clinical purposes. There is evidence from human recreational users of compulsive use and addiction. Sensitization is an increase in an effect of a drug with repeated use that is thought to be important in the development of addiction. Research on psychomotor stimulants has shown the development of sensitization in laboratory animals to be modified by factors that influence addiction. In the current paper we describe four experiments on the development of sensitization in laboratory rats aimed at determining if ketamine sensitization is also influenced by factors thought to be important in addiction. Adult, male Sprague-Dawley rats received ketamine (5, 10, 20 or 50 mg/kg i.p.) for five or more days and the development of locomotor sensitization was followed. Experiment 1 examined the ability of low doses of ketamine to produce sensitization and found sensitization at 5, 10 and 20 mg/kg. Experiment 2 examined the influence of environmental context and found that ketamine sensitization (20 mg/kg) was greater when administration occurred in a novel environment (the experimental apparatus) than in home cages. Experiment 3 found that ketamine sensitization (20 mg/kg) did not occur when animals were housed in social isolation but occurred readily in pair-housed animals. Finally, Experiment 4 found that ketamine sensitization (20 or 50 mg/kg) was similar whether drug was administered daily or at 3-day intervals. Together, the results demonstrate that ketamine sensitization is robust and reliable, occurring under a variety of circumstances. Moreover, ketamine sensitization is influenced by factors that influence the development of addiction in humans. The current results may lead to a better understanding of ketamine abuse and addiction and may help inform clinical use of the drug.
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Affiliation(s)
- Keith A Trujillo
- Department of Psychology and Office for Training, Research, and Education in the Sciences, California State University San Marcos, 333 S. Twin Oaks Valley Road, San Marcos, CA 92096-0001, USA.
| | - Colleen Y Heller
- Department of Psychology and Office for Training, Research, and Education in the Sciences, California State University San Marcos, 333 S. Twin Oaks Valley Road, San Marcos, CA 92096-0001, USA
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Sun LJ, Zhang LM, Liu D, Xue R, Liu YQ, Li L, Guo Y, Shang C, Yao JQ, Zhang YZ, Li YF. The faster-onset antidepressant effects of hypidone hydrochloride (YL-0919). Metab Brain Dis 2019; 34:1375-1384. [PMID: 31236807 DOI: 10.1007/s11011-019-00439-8] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Accepted: 05/20/2019] [Indexed: 12/19/2022]
Abstract
Hypidone hydrochloride (YL-0919), is a novel structural antidepressant candidate as a triple selective serotonin re-uptake inhibitor (SSRI), 5-HT1A partial agonist and 5-HT6 agonist. Here, we investigated the rapid onset antidepressant-like effects of YL-0919 and the possible mechanism in rats exposed to a chronic unpredictable stress (CUS) paradigm. In the CUS rats, it was found that fluoxetine (FLX, 10 mg/kg) treatment exerted antidepressant actions on 20-22d, while YL-0919 or vilazodone (VLZ, a dual 5-HT1A partial agonist and SSRI) administrated once daily exerted faster antidepressant-like behaviors [4 days in the sucrose preference test (SPT) and 6 days in the novelty suppressed feeding test (NSF)]. Thereafter, the serum corticosterone (CORT) and adrenocorticotropic hormone (ACTH) levels were reversed by treatment with YL-0919 for 7 days. Furthermore, YL-0919 treatment for 5 days reversed the brain derived neurotrophic factor (BDNF)-mammalian target of rapamycin (mTOR) signaling and the key synaptic proteins, such as post-synaptic density (PSD95), GluR1 and presynaptic protein synapsin1. Meanwhile, the dendritic complexity of pyramidal neurons in prefrontal cortex (PFC) were also increased in the CUS rats. These data suggest that YL-0919 exerts a faster antidepressant-like effect on behaviors and this effect maybe at least partially mediated by the BDNF-mTOR signaling related dendritic complexity increase in the PFC.
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Affiliation(s)
- Li-Jun Sun
- Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Haidian, Beijing, 100850, China
| | - Li-Ming Zhang
- Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Haidian, Beijing, 100850, China
| | - Dan Liu
- Central Blood Station of Hengshui, Hengshui, 053000, China
| | - Rui Xue
- Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Haidian, Beijing, 100850, China
| | - Yan-Qin Liu
- Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Haidian, Beijing, 100850, China
| | - Lei Li
- Department of Anesthesiology, Beijing Chuiyangliu Hospital, Beijing, 10022, China
| | - Ying Guo
- Department of Anesthesiology, General Hospital of PLA, Beijing, 100853, China
| | - Chao Shang
- Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Haidian, Beijing, 100850, China
| | - Jun-Qi Yao
- Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Haidian, Beijing, 100850, China
| | - You-Zhi Zhang
- Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Haidian, Beijing, 100850, China.
| | - Yun-Feng Li
- Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, 27 Taiping Road, Haidian, Beijing, 100850, China.
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Abstract
LEARNING OBJECTIVE After participating in this activity, learners should be better able to evaluate the evidence supporting the antidepressant effects of glutamatergic modulators.Both preclinical and clinical studies have implicated glutamatergic system dysfunction in the pathophysiology of mood disorders such as bipolar depression and major depressive disorder. In particular, rapid reductions in depressive symptoms have been noted in response to subanesthetic doses of the glutamatergic modulator ketamine in subjects with major depressive disorder or bipolar depression. These results have prompted the repurposing or development of other glutamatergic modulators, both as monotherapy or adjunctive to other therapies. Here, we highlight the evidence supporting the antidepressant effects of various glutamatergic modulators, including (1) broad glutamatergic modulators (ketamine, esketamine, dextromethorphan, dextromethorphan-quinidine [Nuedexta], AVP-786, nitrous oxide [N2O], AZD6765), (2) subunit (NR2B)-specific N-methyl-D-aspartate (NMDA) receptor antagonists (CP-101,606/traxoprodil, MK-0657 [CERC-301]), (3) glycine-site partial agonists (D-cycloserine, GLYX-13, sarcosine, AV-101), and (4) metabotropic glutamate receptor modulators (AZD2066, RO4917523/basimglurant, JNJ40411813/ADX71149, R04995819 [RG1578]).
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Affiliation(s)
- Ioline D Henter
- From the Experimental Therapeutics and Pathophysiology Branch, Intramural Research Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD
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Prados-Pardo Á, Martín-González E, Mora S, Merchán A, Flores P, Moreno M. Increased Fear Memory and Glutamatergic Modulation in Compulsive Drinker Rats Selected by Schedule-Induced Polydipsia. Front Behav Neurosci 2019; 13:100. [PMID: 31133835 PMCID: PMC6514533 DOI: 10.3389/fnbeh.2019.00100] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2019] [Accepted: 04/23/2019] [Indexed: 12/18/2022] Open
Abstract
Compulsive behavior is observed in several neuropsychiatric disorders such as obsessive-compulsive disorder (OCD), anxiety, depression, phobia, and schizophrenia. Thus, compulsivity has been proposed as a transdiagnostic symptom with a highly variable pharmacological treatment. Recent evidence shows that glutamate pharmacotherapy may be of benefit in impaired inhibitory control. The purpose of the present study was: first, to test the comorbidity between compulsivity and other neuropsychiatric symptoms on different preclinical behavioral models; second, to assess the therapeutic potential of different glutamate modulators in a preclinical model of compulsivity. Long Evans rats were selected as either high (HD) or low (LD) drinkers corresponding with their water intake in schedule-induced polydipsia (SIP). We assessed compulsivity in LD and HD rats by marble burying test (MBT), depression by forced swimming test (FST), anxiety by elevated plus maze (EPM) and fear behavior by fear conditioning (FC) test. After that, we measured the effects of acute administration (i.p.) of glutamatergic drugs: N-Acetylcysteine (NAC; 25, 50, 100 and 200 mg/kg), memantine (3.1 and 6.2 mg/kg) and lamotrigine (15 and 30 mg/kg) on compulsive drinking on SIP. The results obtained showed a relation between high compulsive drinking on SIP and a higher number of marbles partially buried in MBT, as well as a higher percentage of freezing on the retrieval day of FC test. We did not detect any significant differences between LD and HD rats in FST, nor in EPM. The psychopharmacological study of glutamatergic drugs revealed that memantine and lamotrigine, at all doses tested, decreased compulsive water consumption in HD rats compared to LD rats on SIP. NAC did not produce any significant effect on SIP. These results indicate that the symptom clusters of different forms of compulsivity and phobia might be found in the compulsive phenotype of HD rats selected by SIP. The effects of memantine and lamotrigine in HD rats point towards a dysregulation in the glutamatergic signaling as a possible underlying mechanism in the vulnerability to compulsive behavior on SIP. Further studies on SIP, could help to elucidate the therapeutic role of glutamatergic drugs as a pharmacological strategy on compulsive spectrum disorders.
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Affiliation(s)
- Ángeles Prados-Pardo
- Department of Psychology, Health Research Center, University of Almería, Campus de Excelencia Internacional Agroalimentario CeiA3, Almería, Spain
| | - Elena Martín-González
- Department of Psychology, Health Research Center, University of Almería, Campus de Excelencia Internacional Agroalimentario CeiA3, Almería, Spain
| | - Santiago Mora
- Department of Psychology, Health Research Center, University of Almería, Campus de Excelencia Internacional Agroalimentario CeiA3, Almería, Spain
| | - Ana Merchán
- Department of Psychology, Health Research Center, University of Almería, Campus de Excelencia Internacional Agroalimentario CeiA3, Almería, Spain
| | - Pilar Flores
- Department of Psychology, Health Research Center, University of Almería, Campus de Excelencia Internacional Agroalimentario CeiA3, Almería, Spain
| | - Margarita Moreno
- Department of Psychology, Health Research Center, University of Almería, Campus de Excelencia Internacional Agroalimentario CeiA3, Almería, Spain
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David J, Gormley S, McIntosh A, Kebede V, Thuery G, Varidaki A, Coffey E, Harkin A. L-alpha-amino adipic acid provokes depression-like behaviour and a stress related increase in dendritic spine density in the pre-limbic cortex and hippocampus in rodents. Behav Brain Res 2019; 362:90-102. [DOI: 10.1016/j.bbr.2019.01.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2018] [Revised: 01/08/2019] [Accepted: 01/08/2019] [Indexed: 12/17/2022]
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Srikumar BN, Naidu PS, Kalidindi N, Paschapur M, Adepu B, Subramani S, Nagar J, Srivastava R, Sreedhara MV, Prasad DS, Das ML, Louis JV, Kuchibhotla VK, Dudhgaonkar S, Pieschl RL, Li YW, Bristow LJ, Ramarao M, Vikramadithyan RK. Diminished responses to monoaminergic antidepressants but not ketamine in a mouse model for neuropsychiatric lupus. J Psychopharmacol 2019; 33:25-36. [PMID: 30484737 DOI: 10.1177/0269881118812102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND A significant proportion of patients suffering from major depression fail to remit following treatment and develop treatment-resistant depression. Developing novel treatments requires animal models with good predictive validity. MRL/lpr mice, an established model of systemic lupus erythematosus, show depression-like behavior. AIMS We evaluated responses to classical antidepressants, and associated immunological and biochemical changes in MRL/lpr mice. METHODS AND RESULTS MRL/lpr mice showed increased immobility in the forced swim test, decreased wheel running and sucrose preference when compared with the controls, MRL/MpJ mice. In MRL/lpr mice, acute fluoxetine (30 mg/kg, intraperitoneally (i.p.)), imipramine (10 mg/kg, i.p.) or duloxetine (10 mg/kg, i.p.) did not decrease the immobility time in the Forced Swim Test. Interestingly, acute administration of combinations of olanzapine (0.03 mg/kg, subcutaneously)+fluoxetine (30 mg/kg, i.p.) or bupropion (10 mg/kg, i.p.)+fluoxetine (30 mg/kg, i.p.) retained efficacy. A single dose of ketamine but not three weeks of imipramine (10 mg/kg, i.p.) or escitalopram (5 mg/kg, i.p.) treatment in MRL/lpr mice restored sucrose preference. Further, we evaluated inflammatory, immune-mediated and neuronal mechanisms. In MRL/lpr mice, there was an increase in autoantibodies' titers, [3H]PK11195 binding and immune complex deposition. There was a significant infiltration of the brain by macrophages, neutrophils and T-lymphocytes. p11 mRNA expression was decreased in the prefrontal cortex. Further, there was an increase in the 5-HT2aR expression, plasma corticosterone and indoleamine 2,3-dioxygenase activity. CONCLUSION In summary, the MRL/lpr mice could be a useful model for Treatment Resistant Depression associated with immune dysfunction with potential to expedite antidepressant drug discovery.
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Affiliation(s)
- Bettadapura N Srikumar
- 1 Disease Sciences and Technology, Biocon-Bristol-Myers Squibb R&D Center, Bangalore, India
| | - Pattipati S Naidu
- 1 Disease Sciences and Technology, Biocon-Bristol-Myers Squibb R&D Center, Bangalore, India
| | | | - Mahesh Paschapur
- 1 Disease Sciences and Technology, Biocon-Bristol-Myers Squibb R&D Center, Bangalore, India
| | - Bharath Adepu
- 1 Disease Sciences and Technology, Biocon-Bristol-Myers Squibb R&D Center, Bangalore, India
| | - Siva Subramani
- 1 Disease Sciences and Technology, Biocon-Bristol-Myers Squibb R&D Center, Bangalore, India
| | - Jignesh Nagar
- 1 Disease Sciences and Technology, Biocon-Bristol-Myers Squibb R&D Center, Bangalore, India
| | - Ratika Srivastava
- 1 Disease Sciences and Technology, Biocon-Bristol-Myers Squibb R&D Center, Bangalore, India
| | - Muppana V Sreedhara
- 1 Disease Sciences and Technology, Biocon-Bristol-Myers Squibb R&D Center, Bangalore, India
| | - Durga Shiva Prasad
- 1 Disease Sciences and Technology, Biocon-Bristol-Myers Squibb R&D Center, Bangalore, India
| | - Manish Lal Das
- 1 Disease Sciences and Technology, Biocon-Bristol-Myers Squibb R&D Center, Bangalore, India
| | - Justin V Louis
- 1 Disease Sciences and Technology, Biocon-Bristol-Myers Squibb R&D Center, Bangalore, India
| | - Vijaya K Kuchibhotla
- 1 Disease Sciences and Technology, Biocon-Bristol-Myers Squibb R&D Center, Bangalore, India
| | - Shailesh Dudhgaonkar
- 1 Disease Sciences and Technology, Biocon-Bristol-Myers Squibb R&D Center, Bangalore, India
| | - Rick L Pieschl
- 2 Neuroscience Biology, Bristol-Myers Squibb Company, Wallingford, CT, USA
| | - Yu-Wen Li
- 2 Neuroscience Biology, Bristol-Myers Squibb Company, Wallingford, CT, USA
| | - Linda J Bristow
- 2 Neuroscience Biology, Bristol-Myers Squibb Company, Wallingford, CT, USA
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Mechanism underlying NMDA blockade-induced inhibition of aggression in post-weaning socially isolated mice. Neuropharmacology 2018; 143:95-105. [DOI: 10.1016/j.neuropharm.2018.09.019] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2018] [Revised: 08/22/2018] [Accepted: 09/11/2018] [Indexed: 11/18/2022]
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Ketamine Anesthesia Does Not Improve Depression Scores in Electroconvulsive Therapy: A Randomized Clinical Trial. J Neurosurg Anesthesiol 2018; 30:305-313. [DOI: 10.1097/ana.0000000000000511] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Godfrey KEM, Gardner AC, Kwon S, Chea W, Muthukumaraswamy SD. Differences in excitatory and inhibitory neurotransmitter levels between depressed patients and healthy controls: A systematic review and meta-analysis. J Psychiatr Res 2018; 105:33-44. [PMID: 30144668 DOI: 10.1016/j.jpsychires.2018.08.015] [Citation(s) in RCA: 102] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 08/10/2018] [Accepted: 08/10/2018] [Indexed: 12/14/2022]
Abstract
Dysfunction of gamma-aminobutyric acid (GABA) and/or glutamate neurotransmitter systems have increasingly been implicated in the aetiology of Major Depressive Disorder (MDD). It has been proposed that alterations in GABA and/or glutamate result in an imbalance of inhibition and excitation. In a review of the current literature, we identified studies using Magnetic Resonance Spectroscopy (MRS) to examine the neurotransmitters GABA, glutamate, and the composite glutamate/glutamine measure Glx in patients diagnosed with MDD and healthy controls. Results showed patients with MDD had significantly lower GABA levels compared to controls (-0.35 [-0.61,-0.10], p = 0.007). No significant difference was found between levels of glutamate. Sub-analyses were performed, including only studies where the Anterior Cingulate Cortex (ACC) was the region of interest. GABA and Glx levels were lower in the ACC of MDD patients (-0.56 [-0.93,-0.18] p = 0.004, and 0.40 [-0.81,0.01] p = 0.05). This review indicates widespread cortical reduction of GABA in MDD, with a trend towards a localised reduction of Glx in the ACC. However, given both GABA and glutamate appear decreased a simple interpretation in terms of an imbalance of overall excitation-inhibition is not feasible.
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Affiliation(s)
- Kate E M Godfrey
- The University of Auckland, School of Pharmacy, 85 Park Road, Auckland, 1023, New Zealand.
| | - Abby C Gardner
- The University of Auckland, School of Pharmacy, 85 Park Road, Auckland, 1023, New Zealand
| | - Sarah Kwon
- The University of Auckland, School of Pharmacy, 85 Park Road, Auckland, 1023, New Zealand
| | - William Chea
- The University of Auckland, School of Pharmacy, 85 Park Road, Auckland, 1023, New Zealand
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Arabzadeh S, Hakkikazazi E, Shahmansouri N, Tafakhori A, Ghajar A, Jafarinia M, Akhondzadeh S. Does oral administration of ketamine accelerate response to treatment in major depressive disorder? Results of a double-blind controlled trial. J Affect Disord 2018; 235:236-241. [PMID: 29660637 DOI: 10.1016/j.jad.2018.02.056] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Revised: 02/16/2018] [Accepted: 02/19/2018] [Indexed: 10/18/2022]
Abstract
BACKGROUND Major depressive disorder (MDD) exerts a high health and financial burden on society. The conventional pharmacotherapies for MDD are partially effective and the response to medication often starts with some delay. There are recent reports of antidepressant effects for oral ketamine. METHODS We employed a double-blind controlled trial to examine the time course of the therapeutic effect of ketamine when combined with the conventional administration of sertraline. A total of 81 patients participated in the study and were scored with the Hamilton Depression Rating Scale (HDRS) at baseline and at 2, 4 and 6 weeks after the start of the trial RESULTS: General linear model repeated measures demonstrated significant effect for time × treatment interaction on the HDRS scores, with significant difference at all time points post treatment. Early improvement was significantly greater in the ketamine group (85.4%) compared to the placebo group (42.5%). We did not observe any side effects for ketamine administration. LIMITATIONS Our follow up was limited to 6 weeks post initiation of treatment and cannot reveal the potential long-term adverse effects of oral ketamine and the sustainability of its benefit. CONCLUSION Altogether, our results suggest that oral ketamine may be considered as suitable adjuvant to sertraline in relieving depressive symptoms.
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Affiliation(s)
- Somaye Arabzadeh
- Psychiatric Research Center, Roozbeh Hospital, Tehran University of Medical sciences, Tehran, Iran
| | - Elham Hakkikazazi
- Psychiatric Research Center, Roozbeh Hospital, Tehran University of Medical sciences, Tehran, Iran
| | - Nazila Shahmansouri
- Psychosomatic Research Center, Tehran University of Medical sciences, Tehran, Iran
| | - Abbas Tafakhori
- Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Science, Iran
| | - Alireza Ghajar
- Psychiatric Research Center, Roozbeh Hospital, Tehran University of Medical sciences, Tehran, Iran
| | - Morteza Jafarinia
- Psychosomatic Research Center, Tehran University of Medical sciences, Tehran, Iran
| | - Shahin Akhondzadeh
- Psychiatric Research Center, Roozbeh Hospital, Tehran University of Medical sciences, Tehran, Iran.
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Hansen KB, Yi F, Perszyk RE, Furukawa H, Wollmuth LP, Gibb AJ, Traynelis SF. Structure, function, and allosteric modulation of NMDA receptors. J Gen Physiol 2018; 150:1081-1105. [PMID: 30037851 PMCID: PMC6080888 DOI: 10.1085/jgp.201812032] [Citation(s) in RCA: 362] [Impact Index Per Article: 51.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2018] [Accepted: 07/03/2018] [Indexed: 12/22/2022] Open
Abstract
Hansen et al. review recent structural data that have provided insight into the function and allosteric modulation of NMDA receptors. NMDA-type glutamate receptors are ligand-gated ion channels that mediate a Ca2+-permeable component of excitatory neurotransmission in the central nervous system (CNS). They are expressed throughout the CNS and play key physiological roles in synaptic function, such as synaptic plasticity, learning, and memory. NMDA receptors are also implicated in the pathophysiology of several CNS disorders and more recently have been identified as a locus for disease-associated genomic variation. NMDA receptors exist as a diverse array of subtypes formed by variation in assembly of seven subunits (GluN1, GluN2A-D, and GluN3A-B) into tetrameric receptor complexes. These NMDA receptor subtypes show unique structural features that account for their distinct functional and pharmacological properties allowing precise tuning of their physiological roles. Here, we review the relationship between NMDA receptor structure and function with an emphasis on emerging atomic resolution structures, which begin to explain unique features of this receptor.
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Affiliation(s)
- Kasper B Hansen
- Department of Biomedical and Pharmaceutical Sciences and Center for Biomolecular Structure and Dynamics, University of Montana, Missoula, MT
| | - Feng Yi
- Department of Biomedical and Pharmaceutical Sciences and Center for Biomolecular Structure and Dynamics, University of Montana, Missoula, MT
| | - Riley E Perszyk
- Department of Pharmacology, Emory University School of Medicine, Atlanta, GA
| | - Hiro Furukawa
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY
| | - Lonnie P Wollmuth
- Departments of Neurobiology & Behavior and Biochemistry & Cell Biology, Stony Brook University, Stony Brook, NY
| | - Alasdair J Gibb
- Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK
| | - Stephen F Traynelis
- Department of Pharmacology, Emory University School of Medicine, Atlanta, GA
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Musazzi L, Tornese P, Sala N, Popoli M. What Acute Stress Protocols Can Tell Us About PTSD and Stress-Related Neuropsychiatric Disorders. Front Pharmacol 2018; 9:758. [PMID: 30050444 PMCID: PMC6052084 DOI: 10.3389/fphar.2018.00758] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 06/22/2018] [Indexed: 12/28/2022] Open
Abstract
Posttraumatic stress disorder (PTSD), the fifth most prevalent mental disorder in the United States, is a chronic, debilitating mental illness with as yet limited options for treatment. Hallmark symptoms of PTSD include intrusive memory of trauma, avoidance of reminders of the event, hyperarousal and hypervigilance, emotional numbing, and anhedonia. PTSD is often triggered by exposure to a single traumatic experience, such as a traffic accident, a natural catastrophe, or an episode of violence. This suggests that stressful events have a primary role in the pathogenesis of the disorder, although genetic background and previous life events are likely involved. However, pathophysiology of this mental disorder, as for major depression and anxiety disorders, is still poorly understood. In particular, it is unknown how can a single traumatic, stressful event induce a disease that can last for years or decades. A major shift in the conceptual framework investigating neuropsychiatric disorders has occurred in recent years, from a monoamine-oriented hypothesis (which dominated pharmacological research for over half a century) to a neuroplasticity hypothesis, which posits that structural and functional changes in brain circuitry (largely in the glutamate system) mediate psychopathology and also therapeutic action. Rodent stress models are very useful to understand pathophysiology of PTSD. Recent studies with acute or subacute stress models have shown that exposure to short-time stressors (from several minutes to a few hours) can induce not only rapid, but also sustained changes in synaptic function (glutamate release, synaptic transmission/plasticity), neuroarchitecture (dendritic morphology, synaptic spines), and behavior (cognitive functions). Some of these changes, e.g., stress-induced increased glutamate release and dendrite retraction, are likely connected and occur more rapidly than previously thought. We propose here to use a modified version of a simple and validated protocol of footshock stress to explore different trajectories in the individual response to acute stress. This new conceptual framework may enable us to identify determinants of resilient versus vulnerable response as well as new targets for treatment, in particular for rapid-acting antidepressants. It will be interesting to investigate the putative prophylactic action of ketamine toward the maladaptive effects of acute stress in this new protocol.
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Affiliation(s)
- Laura Musazzi
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics - Dipartimento di Scienze Farmacologiche e Biomolecolari and Center of Excellence on Neurodegenerative Diseases, University of Milano, Milan, Italy
| | - Paolo Tornese
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics - Dipartimento di Scienze Farmacologiche e Biomolecolari and Center of Excellence on Neurodegenerative Diseases, University of Milano, Milan, Italy
| | - Nathalie Sala
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics - Dipartimento di Scienze Farmacologiche e Biomolecolari and Center of Excellence on Neurodegenerative Diseases, University of Milano, Milan, Italy
| | - Maurizio Popoli
- Laboratory of Neuropsychopharmacology and Functional Neurogenomics - Dipartimento di Scienze Farmacologiche e Biomolecolari and Center of Excellence on Neurodegenerative Diseases, University of Milano, Milan, Italy
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Jha S, Read S, Hurd P, Crespi B. Segregating polymorphism in the NMDA receptor gene GRIN2A, schizotypy, and mental rotation among healthy individuals. Neuropsychologia 2018; 117:347-351. [PMID: 29958946 DOI: 10.1016/j.neuropsychologia.2018.06.021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2017] [Revised: 05/23/2018] [Accepted: 06/22/2018] [Indexed: 11/30/2022]
Abstract
Common alleles associated with psychiatric disorders are often regarded as deleterious genes that influence vulnerability to disease, but they may also be considered as mediators of variation in adaptively structured cognitive phenotypes among healthy individuals. The schizophrenia-associated gene GRIN2A (glutamate ionotropic receptor NMDA type subunit 2a) codes for a protein subunit of the NMDA (N-methyl-D-aspartate) receptor that underlies central aspects of human cognition. Pharmacological NMDA blockage recapitulates the major features of schizophrenia in human subjects, and represents a key model for the neurological basis of this disorder. We genotyped two functional GRIN2A polymorphisms in a large population of healthy individuals who were scored for schizotypy and mental imagery/manipulation (the mental rotation test). Rare-allele homozygosity of the promoter microsatellite rs3219790 was associated with high total schizotypy (after adjustment for multiple comparisons) and with enhanced mental rotation ability (nominally, but not after adjustment for multiple comparisons), among males. These findings provide preliminary evidence regarding a genetic basis to previous reports of enhanced mental imagery in schizophrenia and schizotypy. The results also suggest that some schizophrenia-related alleles may be subject to cognitive tradeoffs involving both positive and negative effects on psychological phenotypes, which may help to explain the maintenance of psychiatric-disorder risk alleles in human populations.
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Affiliation(s)
- Siddharth Jha
- Department of Biological Sciences, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada
| | - Silven Read
- Department of Biological Sciences, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada
| | - Peter Hurd
- Department of Psychology and Centre for Neuroscience, University of Alberta, Edmonton T6G 2R3, Canada
| | - Bernard Crespi
- Department of Biological Sciences, Simon Fraser University, Burnaby, British Columbia V5A 1S6, Canada.
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