1
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Nascimento AA, Pereira-Figueiredo D, Borges-Martins VP, Kubrusly RC, Calaza KC. GABAergic system and chloride cotransporters as potential therapeutic targets to mitigate cell death in ischemia. J Neurosci Res 2024; 102:e25355. [PMID: 38808645 DOI: 10.1002/jnr.25355] [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: 08/25/2023] [Revised: 04/17/2024] [Accepted: 05/06/2024] [Indexed: 05/30/2024]
Abstract
Gamma aminobutyric acid (GABA) is a critical inhibitory neurotransmitter in the central nervous system that plays a vital role in modulating neuronal excitability. Dysregulation of GABAergic signaling, particularly involving the cotransporters NKCC1 and KCC2, has been implicated in various pathologies, including epilepsy, schizophrenia, autism spectrum disorder, Down syndrome, and ischemia. NKCC1 facilitates chloride influx, whereas KCC2 mediates chloride efflux via potassium gradient. Altered expression and function of these cotransporters have been associated with excitotoxicity, inflammation, and cellular death in ischemic events characterized by reduced cerebral blood flow, leading to compromised tissue metabolism and subsequent cell death. NKCC1 inhibition has emerged as a potential therapeutic approach to attenuate intracellular chloride accumulation and mitigate neuronal damage during ischemic events. Similarly, targeting KCC2, which regulates chloride efflux, holds promise for improving outcomes and reducing neuronal damage under ischemic conditions. This review emphasizes the critical roles of GABA, NKCC1, and KCC2 in ischemic pathologies and their potential as therapeutic targets. Inhibiting or modulating the activity of these cotransporters represents a promising strategy for reducing neuronal damage, preventing excitotoxicity, and improving neurological outcomes following ischemic events. Furthermore, exploring the interactions between natural compounds and NKCC1/KCC2 provides additional avenues for potential therapeutic interventions for ischemic injury.
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Affiliation(s)
- A A Nascimento
- Neurobiology of the Retina Laboratory, Department of Neurobiology and Graduate Program of Neurosciences, Institute of Biology, Fluminense Federal University, Niterói, Brazil
| | - D Pereira-Figueiredo
- Graduate Program in Biomedical Sciences (Physiology and Pharmacology), Fluminense Federal University, Niterói, Brazil
| | - V P Borges-Martins
- Laboratory of Neuropharmacology, Department of Physiology and Pharmacology, Biomedical Institute, Fluminense Federal University, Niterói, Brazil
| | - R C Kubrusly
- Laboratory of Neuropharmacology, Department of Physiology and Pharmacology, Biomedical Institute, Fluminense Federal University, Niterói, Brazil
| | - K C Calaza
- Neurobiology of the Retina Laboratory, Department of Neurobiology and Graduate Program of Neurosciences, Institute of Biology, Fluminense Federal University, Niterói, Brazil
- Graduate Program in Biomedical Sciences (Physiology and Pharmacology), Fluminense Federal University, Niterói, Brazil
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2
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Delpire E, Terker AS, Gagnon KB. Pharmacology of Compounds Targeting Cation-Chloride Cotransporter Physiology. Handb Exp Pharmacol 2024; 283:249-284. [PMID: 37563251 PMCID: PMC10823342 DOI: 10.1007/164_2023_692] [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] [Indexed: 08/12/2023]
Abstract
Transporters of the solute carrier family 12 (SLC12) carry inorganic cations such as Na+ and/or K+ alongside Cl across the plasma membrane of cells. These tightly coupled, electroneutral, transporters are expressed in almost all tissues/organs in the body where they fulfil many critical functions. The family includes two key transporters participating in salt reabsorption in the kidney: the Na-K-2Cl cotransporter-2 (NKCC2), expressed in the loop of Henle, and the Na-Cl cotransporter (NCC), expressed in the distal convoluted tubule. NCC and NKCC2 are the targets of thiazides and "loop" diuretics, respectively, drugs that are widely used in clinical medicine to treat hypertension and edema. Bumetanide, in addition to its effect as a loop diuretic, has recently received increasing attention as a possible therapeutic agent for neurodevelopmental disorders. This chapter also describes how over the past two decades, the pharmacology of Na+ independent transporters has expanded significantly to provide novel tools for research. This work has indeed led to the identification of compounds that are 100-fold to 1000-fold more potent than furosemide, the first described inhibitor of K-Cl cotransport, and identified compounds that possibly directly stimulate the function of the K-Cl cotransporter. Finally, the recent cryo-electron microscopy revolution has begun providing answers as to where and how pharmacological agents bind to and affect the function of the transporters.
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Affiliation(s)
- Eric Delpire
- Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN, USA.
| | - Andrew S Terker
- Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Kenneth B Gagnon
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
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3
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Lam P, Newland J, Faull RLM, Kwakowsky A. Cation-Chloride Cotransporters KCC2 and NKCC1 as Therapeutic Targets in Neurological and Neuropsychiatric Disorders. Molecules 2023; 28:1344. [PMID: 36771011 PMCID: PMC9920462 DOI: 10.3390/molecules28031344] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 01/21/2023] [Accepted: 01/25/2023] [Indexed: 02/04/2023] Open
Abstract
Neurological diseases including Alzheimer's, Huntington's disease, Parkinson's disease, Down syndrome and epilepsy, and neuropsychiatric disorders such as schizophrenia, are conditions that affect not only individuals but societies on a global scale. Current therapies offer a means for small symptomatic relief, but recently there has been increasing demand for therapeutic alternatives. The γ-aminobutyric acid (GABA)ergic signaling system has been investigated for developing new therapies as it has been noted that any dysfunction or changes to this system can contribute to disease progression. Expression of the K-Cl-2 (KCC2) and N-K-C1-1 (NKCC1) cation-chloride cotransporters (CCCs) has recently been linked to the disruption of GABAergic activity by affecting the polarity of GABAA receptor signaling. KCC2 and NKCC1 play a part in multiple neurological and neuropsychiatric disorders, making them a target of interest for potential therapies. This review explores current research suggesting the pathophysiological role and therapeutic importance of KCC2 and NKCC1 in neuropsychiatric and neurological disorders.
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Affiliation(s)
- Patricia Lam
- Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
| | - Julia Newland
- Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
| | - Richard L. M. Faull
- Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
| | - Andrea Kwakowsky
- Centre for Brain Research, Department of Anatomy and Medical Imaging, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand
- Pharmacology and Therapeutics, School of Medicine, Galway Neuroscience Centre, University of Galway, H91 W5P7 Galway, Ireland
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4
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Gharaylou Z, Shafaghi L, Pestehei SK, Hadjighassem M. Long-term bumetanide administration altered behavioral pattern in mosaic Down's Syndrome: A case report. APPLIED NEUROPSYCHOLOGY. CHILD 2023; 12:88-95. [PMID: 34860628 DOI: 10.1080/21622965.2021.2007481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
The behavioral phenotypes emerge from cognitive architecture comprising attention, executive functions, and primary communication skills that all have shown remarkable deficits in Down's Syndrome (DS). These states arise from the proper functional interactions of the contributing neurotransmission and neuromodulation systems and other coding platforms. Gamma-aminobutyric acid (GABA) is an integral part of the neural interaction and regulation networks that its reverse action leads to broad detrimental consequences. This inhibitory substance needs an appropriate balance of co-transporters that largely shape the ionic milieu. Bumetanide, a specific NKCC1 inhibitor used for an eighteen-month interval, showed promising effects in restoring some behavior deficits in a fourteen-year-old boy diagnosed with genetically confirmed mosaic Down's Syndrome.
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Affiliation(s)
- Zeinab Gharaylou
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Shefa Neuroscience Research Center, Tehran, Iran
| | - Lida Shafaghi
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mahmoudreza Hadjighassem
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
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5
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Zhang C, Dong N, Xu S, Ma H, Cheng M. Identification of hub genes and construction of diagnostic nomogram model in schizophrenia. Front Aging Neurosci 2022; 14:1032917. [PMID: 36313022 PMCID: PMC9614240 DOI: 10.3389/fnagi.2022.1032917] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 09/26/2022] [Indexed: 04/01/2024] Open
Abstract
Schizophrenia (SCZ), which is characterized by debilitating neuropsychiatric disorders with significant cognitive impairment, remains an etiological and therapeutic challenge. Using transcriptomic profile analysis, disease-related biomarkers linked with SCZ have been identified, and clinical outcomes can also be predicted. This study aimed to discover diagnostic hub genes and investigate their possible involvement in SCZ immunopathology. The Gene Expression Omnibus (GEO) database was utilized to get SCZ Gene expression data. Differentially expressed genes (DEGs) were identified and enriched by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and disease ontology (DO) analysis. The related gene modules were then examined using integrated weighted gene co-expression network analysis. Single-sample gene set enrichment (GSEA) was exploited to detect immune infiltration. SVM-REF, random forest, and least absolute shrinkage and selection operator (LASSO) algorithms were used to identify hub genes. A diagnostic model of nomogram was constructed for SCZ prediction based on the hub genes. The clinical utility of nomogram prediction was evaluated, and the diagnostic utility of hub genes was validated. mRNA levels of the candidate genes in SCZ rat model were determined. Finally, 24 DEGs were discovered, the majority of which were enriched in biological pathways and activities. Four hub genes (NEUROD6, NMU, PVALB, and NECAB1) were identified. A difference in immune infiltration was identified between SCZ and normal groups, and immune cells were shown to potentially interact with hub genes. The hub gene model for the two datasets was verified, showing good discrimination of the nomogram. Calibration curves demonstrated valid concordance between predicted and practical probabilities, and the nomogram was verified to be clinically useful. According to our research, NEUROD6, NMU, PVALB, and NECAB1 are prospective biomarkers in SCZ and that a reliable nomogram based on hub genes could be helpful for SCZ risk prediction.
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Affiliation(s)
- Chi Zhang
- Department of Anesthesiology, The First Hospital of Jilin University, Changchun, China
| | - Naifu Dong
- Department of Anesthesiology, The First Hospital of Jilin University, Changchun, China
| | - Shihan Xu
- College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Haichun Ma
- Department of Anesthesiology, The First Hospital of Jilin University, Changchun, China
| | - Min Cheng
- Department of Anesthesiology, The First Hospital of Jilin University, Changchun, China
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6
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Delpire E, Ben-Ari Y. A Wholistic View of How Bumetanide Attenuates Autism Spectrum Disorders. Cells 2022; 11:2419. [PMID: 35954263 PMCID: PMC9367773 DOI: 10.3390/cells11152419] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Revised: 07/22/2022] [Accepted: 08/03/2022] [Indexed: 01/27/2023] Open
Abstract
The specific NKCC1 cotransporter antagonist, bumetanide, attenuates the severity of Autism Spectrum Disorders (ASD), and many neurodevelopmental or neurodegenerative disorders in animal models and clinical trials. However, the pervasive expression of NKCC1 in many cell types throughout the body is thought to challenge the therapeutic efficacy of bumetanide. However, many peripheral functions, including intestinal, metabolic, or vascular, etc., are perturbed in brain disorders contributing to the neurological sequels. Alterations of these functions also increase the incidence of the disorder suggesting complex bidirectional links with the clinical manifestations. We suggest that a more holistic view of ASD and other disorders is warranted to account for the multiple sites impacted by the original intra-uterine insult. From this perspective, large-spectrum active repositioned drugs that act centrally and peripherally might constitute a useful approach to treating these disorders.
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Affiliation(s)
- Eric Delpire
- Departments of Anesthesiology and Molecular Physiology & Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA
| | - Yehezkel Ben-Ari
- NeuroChlore, Campus Scientifique de Luminy, 163 Route de Luminy, 13273 Marseilles, France
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7
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Carnovale C, Perrotta C, Baldelli S, Cattaneo D, Montrasio C, Barbieri SS, Pompilio G, Vantaggiato C, Clementi E, Pozzi M. Antihypertensive drugs and brain function: mechanisms underlying therapeutically beneficial and harmful neuropsychiatric effects. Cardiovasc Res 2022; 119:647-667. [PMID: 35895876 PMCID: PMC10153433 DOI: 10.1093/cvr/cvac110] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 06/15/2022] [Accepted: 06/21/2022] [Indexed: 11/14/2022] Open
Abstract
A bidirectional relationship exists between hypertension and psychiatric disorders, including unipolar and bipolar depression, anxiety, post-traumatic stress disorder (PTSD), psychosis, schizophrenia, mania, and dementia/cognitive decline. Repurposing of antihypertensive drugs to treat mental disorders is thus being explored. A systematic knowledge of the mechanisms of action and clinical consequences of the use of antihypertensive agents on neuropsychiatric functions has not been achieved yet. In this article, we review the putative role of antihypertensive agents in psychiatric disorders, discuss the targets and mechanisms of action, and examine how and to what extent specific drug classes/molecules may trigger, worsen, or mitigate psychiatric symptoms. In addition, we review pharmacokinetics (brain penetration of drugs) and pharmacogenetics data that add important information to assess risks and benefits of antihypertensive drugs in neuropsychiatric settings. The scientific literature shows robust evidence of a positive effect of α1 blockers on PTSD symptoms, nightmares and sleep quality, α2 agonists on core symptoms, executive function and quality of life in Attention-Deficit/Hyperactivity Disorder, PTSD, Tourette's syndrome, and β blockers on anxiety, aggression, working memory, and social communication. Renin-angiotensin system modulators exert protective effects on cognition, depression, and anxiety, and the loop diuretic bumetanide reduced the core symptoms of autism in a subset of patients. There is no evidence of clear benefits of calcium channel blockers in mood disorders in the scientific literature. These findings are mainly from preclinical studies; clinical data are still insufficient or of anecdotal nature, and seldom systematic. The information herewith provided can support a better therapeutic approach to hypertension, tailored to patients with, or with high susceptibility to, psychiatric illness. It may prompt clinical studies exploring the potential benefit of antihypertensive drugs in selected patients with neuropsychiatric comorbidities that include outcomes of neuropsychiatric interest and specifically assess undesirable effects or interactions.
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Affiliation(s)
- Carla Carnovale
- Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences (DIBIC), ASST Fatebenefratelli-Sacco University Hospital, Università degli Studi di Milano, 20157 Milano, Italy
| | - Cristiana Perrotta
- Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences (DIBIC), ASST Fatebenefratelli-Sacco University Hospital, Università degli Studi di Milano, 20157 Milano, Italy
| | - Sara Baldelli
- Unit of Clinical Pharmacology, ASST Fatebenefratelli-Sacco University Hospital, 20157 Milano, Italy
| | - Dario Cattaneo
- Unit of Clinical Pharmacology, ASST Fatebenefratelli-Sacco University Hospital, 20157 Milano, Italy
| | - Cristina Montrasio
- Unit of Clinical Pharmacology, ASST Fatebenefratelli-Sacco University Hospital, 20157 Milano, Italy
| | - Silvia S Barbieri
- Unit of Brain-Heart axis: cellular and molecular mechanisms - Centro Cardiologico Monzino IRCCS, 20138 Milano, Italy
| | - Giulio Pompilio
- Unit of Vascular Biology and Regenerative Medicine - Centro Cardiologico Monzino IRCCS, 20138, Milan, Italy.,Department of Biomedical, Surgical and Dental Sciences, Università degli Studi di Milano, Milan, Italy
| | | | - Emilio Clementi
- Unit of Clinical Pharmacology, Department of Biomedical and Clinical Sciences (DIBIC), ASST Fatebenefratelli-Sacco University Hospital, Università degli Studi di Milano, 20157 Milano, Italy.,Scientific Institute IRCCS Eugenio Medea, Bosisio Parini (LC), Italy
| | - Marco Pozzi
- Scientific Institute IRCCS Eugenio Medea, Bosisio Parini (LC), Italy
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8
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Hui KK, Chater TE, Goda Y, Tanaka M. How Staying Negative Is Good for the (Adult) Brain: Maintaining Chloride Homeostasis and the GABA-Shift in Neurological Disorders. Front Mol Neurosci 2022; 15:893111. [PMID: 35875665 PMCID: PMC9305173 DOI: 10.3389/fnmol.2022.893111] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 06/10/2022] [Indexed: 01/27/2023] Open
Abstract
Excitatory-inhibitory (E-I) imbalance has been shown to contribute to the pathogenesis of a wide range of neurodevelopmental disorders including autism spectrum disorders, epilepsy, and schizophrenia. GABA neurotransmission, the principal inhibitory signal in the mature brain, is critically coupled to proper regulation of chloride homeostasis. During brain maturation, changes in the transport of chloride ions across neuronal cell membranes act to gradually change the majority of GABA signaling from excitatory to inhibitory for neuronal activation, and dysregulation of this GABA-shift likely contributes to multiple neurodevelopmental abnormalities that are associated with circuit dysfunction. Whilst traditionally viewed as a phenomenon which occurs during brain development, recent evidence suggests that this GABA-shift may also be involved in neuropsychiatric disorders due to the "dematuration" of affected neurons. In this review, we will discuss the cell signaling and regulatory mechanisms underlying the GABA-shift phenomenon in the context of the latest findings in the field, in particular the role of chloride cotransporters NKCC1 and KCC2, and furthermore how these regulatory processes are altered in neurodevelopmental and neuropsychiatric disorders. We will also explore the interactions between GABAergic interneurons and other cell types in the developing brain that may influence the GABA-shift. Finally, with a greater understanding of how the GABA-shift is altered in pathological conditions, we will briefly outline recent progress on targeting NKCC1 and KCC2 as a therapeutic strategy against neurodevelopmental and neuropsychiatric disorders associated with improper chloride homeostasis and GABA-shift abnormalities.
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Affiliation(s)
- Kelvin K. Hui
- Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY, United States
- Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Thomas E. Chater
- Laboratory for Synaptic Plasticity and Connectivity, RIKEN Center for Brain Science, Wako, Japan
| | - Yukiko Goda
- Laboratory for Synaptic Plasticity and Connectivity, RIKEN Center for Brain Science, Wako, Japan
- Synapse Biology Unit, Okinawa Institute for Science and Technology Graduate University, Onna, Japan
| | - Motomasa Tanaka
- Laboratory for Protein Conformation Diseases, RIKEN Center for Brain Science, Wako, Japan
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9
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Atefimanash P, Pourhamzeh M, Susanabadi A, Arabi M, Jamali-Raeufy N, Mehrabi S. Hippocampal chloride transporter KCC2 contributes to excitatory GABA dysregulation in the developmental rat model of schizophrenia. J Chem Neuroanat 2021; 118:102040. [PMID: 34695562 DOI: 10.1016/j.jchemneu.2021.102040] [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: 08/12/2021] [Revised: 10/18/2021] [Accepted: 10/18/2021] [Indexed: 10/20/2022]
Abstract
Recent studies have revealed an altered expression of NKCC1 and KCC2 in prefrontal cortex (PFC) and hippocampus of schizophrenic patients. Despite extensive considerations, the alteration of NKCC1 and KCC2 co-transporters at different stages of development has not been fully studied. Therefore, we evaluated the expression of these transporters in PFC and hippocampus at time points of four, eight, and twelve weeks in post-weaning social isolation rearing rat model. For this purpose, 23-25 days-old rats were classified into social- or isolation-reared groups. The levels of NKCC1 and KCC2 mRNA expression were evaluated at hippocampus or PFC regions at the time-points of four, eight, and twelve weeks following housing. Post-weaning isolation rearing decreased the hippocampal KCC2 mRNA expression level, but does not affect the NKCC1 mRNA expression. However, no significant difference was observed in the PFC mRNA levels of NKCC1 and KCC2 in the isolation-reared group compared to the socially-reared group during the course of modeling. Further, we assessed the therapeutic effect of selective NKCC1 inhibitor bumetanide (10 mg/kg), on improvement of prepulse inhibition (PPI) test on twelve weeks isolation-reared rats. Intraperitoneal administration of bumetanide (10 mg/kg) did not exert beneficial effects on PPI deficit. Our findings show that isolation rearing reduces hippocampal KCC2 expression level and may underlie hippocampal GABA excitatory. In addition, 10 mg/kg bumetanide is not effective in improving the reduced PPI of twelve weeks isolation-reared rats. Collectively, our findings show that hippocampal chloride transporter KCC2 contributes to excitatory GABA dysregulation in the developmental rat model of schizophrenia.
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Affiliation(s)
- Pezhman Atefimanash
- Division of Neuroscience, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mahsa Pourhamzeh
- Division of Neuroscience, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Alireza Susanabadi
- Department of Anesthesia and pain medicine, Arak University of Medical Sciences, Arak, Iran
| | - Mehrnoosh Arabi
- Division of Neuroscience, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Radiology and Medical Physics, Faculty of Paramedicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Nida Jamali-Raeufy
- Department of Physiology, Faculty of Medicine, Iran University of Medical Science, Tehran, Iran
| | - Soraya Mehrabi
- Division of Neuroscience, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran; Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran; Department of Physiology, Faculty of Medicine, Iran University of Medical Science, Tehran, Iran.
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10
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Taubes A, Nova P, Zalocusky KA, Kosti I, Bicak M, Zilberter MY, Hao Y, Yoon SY, Oskotsky T, Pineda S, Chen B, Jones EAA, Choudhary K, Grone B, Balestra ME, Chaudhry F, Paranjpe I, De Freitas J, Koutsodendris N, Chen N, Wang C, Chang W, An A, Glicksberg BS, Sirota M, Huang Y. Experimental and real-world evidence supporting the computational repurposing of bumetanide for APOE4-related Alzheimer's disease. NATURE AGING 2021; 1:932-947. [PMID: 36172600 PMCID: PMC9514594 DOI: 10.1038/s43587-021-00122-7] [Citation(s) in RCA: 55] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/30/2023]
Abstract
The evident genetic, pathological, and clinical heterogeneity of Alzheimer's disease (AD) poses challenges for traditional drug development. We conducted a computational drug repurposing screen for drugs to treat apolipoprotein (apo) E4-related AD. We first established apoE-genotype-dependent transcriptomic signatures of AD by analyzing publicly-available human brain database. We then queried these signatures against the Connectivity Map database containing transcriptomic perturbations of >1300 drugs to identify those that best reverse apoE-genotype-specific AD signatures. Bumetanide was identified as a top drug for apoE4 AD. Bumetanide treatment of apoE4 mice without or with Aβ accumulation rescued electrophysiological, pathological, or cognitive deficits. Single-nucleus RNA-sequencing revealed transcriptomic reversal of AD signatures in specific cell types in these mice, a finding confirmed in apoE4-iPSC-derived neurons. In humans, bumetanide exposure was associated with a significantly lower AD prevalence in individuals over the age of 65 in two electronic health record databases, suggesting effectiveness of bumetanide in preventing AD.
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Affiliation(s)
- Alice Taubes
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA
- Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA
| | - Phil Nova
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA
- Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA
| | - Kelly A. Zalocusky
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA
- Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA 94158, USA
- Department of Neurology, University of California, San Francisco, CA 94143, USA
| | - Idit Kosti
- Bakar Computational Health Sciences Institute, University of California, San Francisco, CA 94158, USA
- Department of Pediatrics, University of California, San Francisco, CA 94158, USA, USA
| | - Mesude Bicak
- Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY 10065, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10065, USA
| | - Misha Y. Zilberter
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA
- Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA 94158, USA
| | - Yanxia Hao
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA
| | - Seo Yeon Yoon
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA
| | - Tomiko Oskotsky
- Bakar Computational Health Sciences Institute, University of California, San Francisco, CA 94158, USA
- Department of Pediatrics, University of California, San Francisco, CA 94158, USA, USA
| | - Silvia Pineda
- Bakar Computational Health Sciences Institute, University of California, San Francisco, CA 94158, USA
- Department of Surgery, University of California, San Francisco, CA 94143, USA
| | - Bin Chen
- Bakar Computational Health Sciences Institute, University of California, San Francisco, CA 94158, USA
| | - Emily A. Aery Jones
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA
- Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA
| | - Krishna Choudhary
- Gladstone Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, CA 94158, USA
| | - Brian Grone
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA
- Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA 94158, USA
- Department of Neurology, University of California, San Francisco, CA 94143, USA
| | - Maureen E. Balestra
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA
| | - Fayzan Chaudhry
- Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY 10065, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10065, USA
| | - Ishan Paranjpe
- Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY 10065, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10065, USA
| | - Jessica De Freitas
- Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY 10065, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10065, USA
| | - Nicole Koutsodendris
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA
- Development and Stem Cell Biology Graduate Program, University of California, San Francisco, CA 94143, USA
| | - Nuo Chen
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA
| | - Celine Wang
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA
| | - William Chang
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA
| | - Alice An
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA
| | - Benjamin S. Glicksberg
- Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, NY 10065, USA
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10065, USA
| | - Marina Sirota
- Bakar Computational Health Sciences Institute, University of California, San Francisco, CA 94158, USA
- Department of Pediatrics, University of California, San Francisco, CA 94158, USA, USA
- Correspondence: Yadong Huang () or Marina Sirota ()
| | - Yadong Huang
- Gladstone Institute of Neurological Disease, Gladstone Institutes, San Francisco, CA 94158, USA
- Biomedical Sciences Graduate Program, University of California, San Francisco, CA 94143, USA
- Gladstone Center for Translational Advancement, Gladstone Institutes, San Francisco, CA 94158, USA
- Department of Neurology, University of California, San Francisco, CA 94143, USA
- Department of Pathology, University of California, San Francisco, CA 94143, USA
- Correspondence: Yadong Huang () or Marina Sirota ()
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11
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Matsumoto D, Ushio S, Wada Y, Noda Y, Esumi S, Izushi Y, Kitamura Y, Sendo T. Bumetanide prevents diazepam-modified anxiety-like behavior in lipopolysaccharide-treated mice. Eur J Pharmacol 2021; 904:174195. [PMID: 34004209 DOI: 10.1016/j.ejphar.2021.174195] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/27/2021] [Accepted: 05/12/2021] [Indexed: 10/21/2022]
Abstract
Benzodiazepine receptor agonists are widely prescribed therapeutic agents that alter gamma-aminobutyric acid (GABA)A receptor activity and have anxiolytic effects. Post-operative use of benzodiazepines is a risk factor of delirium. Inflammatory conditions alter the anxiolytic effects of benzodiazepine. We investigated the effect of diazepam, a typical benzodiazepine anxiolytic, on changes in the emotional behavior of mice in a hole-board test after lipopolysaccharide (LPS) treatment. Diazepam dose-dependently increased the number of head-dips at doses that did not alter locomotor activity; however, diazepam dose-dependently significantly decreased the number of head-dips at doses that did not alter locomotor activity in LPS-treated mice. Flumazenil, a benzodiazepine receptor antagonist, normalized the decrease in head-dipping behavior caused by diazepam treatment in normal and LPS-treated mice. The decrease of the head-dipping effect caused by diazepam was attenuated by minocycline in LPS-treated mice. We further found that the decrease in head-dipping behavior caused by diazepam was blocked by bumetanide, a Na+-K+-2Cl- cotransporter isoform 1 (NKCC1) antagonist, in LPS-treated mice. These findings suggest that diazepam induces the anxiety-like behavior under inflammation conditions, and may cause the GABAA receptor dysfunction associated with the chloride plasticity mediated by NKCC1, which contributes to benzodiazepine-induced delirium after surgery.
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Affiliation(s)
- Daiki Matsumoto
- Department of Clinical Pharmacy, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan
| | - Soichiro Ushio
- Department of Pharmacy, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Yudai Wada
- Department of Clinical Pharmacy, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan
| | - Yukiko Noda
- Department of Clinical Pharmacy, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan
| | - Satoru Esumi
- Department of Pharmacy, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
| | - Yasuhisa Izushi
- Department of Pharmacotherapy, School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama, 703-8516, Japan
| | - Yoshihisa Kitamura
- Department of Pharmacy, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan; Department of Pharmacotherapy, School of Pharmacy, Shujitsu University, 1-6-1 Nishigawara, Naka-ku, Okayama, 703-8516, Japan.
| | - Toshiaki Sendo
- Department of Clinical Pharmacy, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Okayama, 700-8558, Japan; Department of Pharmacy, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, 700-8558, Japan
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12
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Borgogno M, Savardi A, Manigrasso J, Turci A, Portioli C, Ottonello G, Bertozzi SM, Armirotti A, Contestabile A, Cancedda L, De Vivo M. Design, Synthesis, In Vitro and In Vivo Characterization of Selective NKCC1 Inhibitors for the Treatment of Core Symptoms in Down Syndrome. J Med Chem 2021; 64:10203-10229. [PMID: 34137257 PMCID: PMC8311653 DOI: 10.1021/acs.jmedchem.1c00603] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Intracellular chloride concentration [Cl-]i is defective in several neurological disorders. In neurons, [Cl-]i is mainly regulated by the action of the Na+-K+-Cl- importer NKCC1 and the K+-Cl- exporter KCC2. Recently, we have reported the discovery of ARN23746 as the lead candidate of a novel class of selective inhibitors of NKCC1. Importantly, ARN23746 is able to rescue core symptoms of Down syndrome (DS) and autism in mouse models. Here, we describe the discovery and extensive characterization of this chemical class of selective NKCC1 inhibitors, with focus on ARN23746 and other promising derivatives. In particular, we present compound 40 (ARN24092) as a backup/follow-up lead with in vivo efficacy in a mouse model of DS. These results further strengthen the potential of this new class of compounds for the treatment of core symptoms of brain disorders characterized by the defective NKCC1/KCC2 expression ratio.
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Affiliation(s)
- Marco Borgogno
- Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Annalisa Savardi
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.,Dulbecco Telethon Institute, 38123 Rome, Italy
| | - Jacopo Manigrasso
- Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Alessandra Turci
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.,Università degli Studi di Genova, via Balbi, 5, 16126 Genoa, Italy
| | - Corinne Portioli
- Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.,Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Giuliana Ottonello
- Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Sine Mandrup Bertozzi
- Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Andrea Armirotti
- Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Andrea Contestabile
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Laura Cancedda
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy.,Dulbecco Telethon Institute, 38123 Rome, Italy
| | - Marco De Vivo
- Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
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13
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Ben-Ari Y, Delpire E. Phenobarbital, midazolam, bumetanide, and neonatal seizures: The devil is in the details. Epilepsia 2021; 62:935-940. [PMID: 33534145 PMCID: PMC8035263 DOI: 10.1111/epi.16830] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 01/11/2021] [Indexed: 12/21/2022]
Abstract
Kaila, Löscher, and colleagues report that phenobarbital (PHB) and midazolam (MDZ) attenuate neonatal seizures following birth asphyxia, but the former only when applied before asphyxia and the latter before or after the triggering insult. In contrast, the NKCC1 chloride importer antagonist bumetanide (BUM) had no effect whether applied alone or with PHB. The observations are compelling and in accord with earlier studies. However, there are several general issues that deserve discussion. What is the clinical relevance of these data and the validity of animal models of encephalopathic seizures? Why is it that although they act on similar targets, these agents have different efficacy? Are both PHB and MDZ actions restricted to γ-aminobutyric acidergic (GABAergic) mechanisms? Why is BUM inefficient in attenuating seizures but capable of reducing the severity of other brain disorders? We suggest that the relative failure of antiepileptic drugs (AEDs) to treat this severe life-threatening condition is in part explicable by the recurrent seizures that shift the polarity of GABA, thereby counteracting their effects on their target. AEDs might be efficient after a few seizures but not recurrent ones. In addition, PHB and MDZ actions are not limited to GABA signals. BUM efficiently attenuates autism symptomatology notably in patients with tuberous sclerosis but does not reduce the recurrent seizures, illustrating the uniqueness of epilepsies. Therefore, the efficacy of AEDs to treat babies with encephalopathic seizures will depend on the history and severity of the seizures prior to their administration, challenging a universal common underlying mechanism.
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Affiliation(s)
- Yehezkel Ben-Ari
- Neurochlore, Fundamental Research Department, Ben-Ari Institute of Neuroarcheology (IBEN), Marseille, France.,Correspondence should be addressed to Dr. Yehezkel Ben-Ari, , Address: Neurochlore, Parc Scientifique et Technologique de Luminy, Bâtiment Beret-Delaage, Zone Luminy Biotech Entreprises, Case 922, 163 avenue de Luminy, 13288 Marseille Cedex 9. Phone number: +33 (0)4 86 94 85 02
| | - Eric Delpire
- Department of Anesthesiology, Vanderbilt University Medical School, Nashville, TN 37232, USA
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14
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Kim HR, Rajagopal L, Meltzer HY, Martina M. Depolarizing GABA A current in the prefrontal cortex is linked with cognitive impairment in a mouse model relevant for schizophrenia. SCIENCE ADVANCES 2021; 7:eaba5032. [PMID: 33789887 PMCID: PMC8011979 DOI: 10.1126/sciadv.aba5032] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 02/12/2021] [Indexed: 05/06/2023]
Abstract
Cognitive impairment in schizophrenia (CIAS) is the most critical predictor of functional outcome. Limited understanding of the cellular mechanisms of CIAS hampers development of more effective treatments. We found that in subchronic phencyclidine (scPCP)-treated mice, an animal model that mimics CIAS, the reversal potential of GABAA currents in pyramidal neurons of the infralimbic prefrontal cortex (ILC) shifts from hyperpolarizing to depolarizing, the result of increased expression of the chloride transporter NKCC1. Further, we found that in scPCP mice, the NKCC1 antagonist bumetanide normalizes GABAA current polarity ex vivo and improves performance in multiple cognitive tasks in vivo. This behavioral effect was mimicked by selective, bilateral, NKCC1 knockdown in the ILC. Thus, we show that depolarizing GABAA currents in the ILC contributes to cognitive impairments in scPCP mice and suggest that bumetanide, an FDA-approved drug, has potential to treat or prevent CIAS and other components of the schizophrenia syndrome.
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Affiliation(s)
- Haram R Kim
- Department of Physiology, Feinberg School of Medicine, Northwestern University, 300 E. Chicago Avenue, Chicago, IL 60611, USA
| | - Lakshmi Rajagopal
- Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, 300 E. Chicago Avenue, Chicago, IL 60611, USA
| | - Herbert Y Meltzer
- Department of Physiology, Feinberg School of Medicine, Northwestern University, 300 E. Chicago Avenue, Chicago, IL 60611, USA.
- Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, 300 E. Chicago Avenue, Chicago, IL 60611, USA
| | - Marco Martina
- Department of Physiology, Feinberg School of Medicine, Northwestern University, 300 E. Chicago Avenue, Chicago, IL 60611, USA.
- Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, 300 E. Chicago Avenue, Chicago, IL 60611, USA
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15
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Pergakis M, Badjatia N, Simard JM. An update on the pharmacological management and prevention of cerebral edema: current therapeutic strategies. Expert Opin Pharmacother 2021; 22:1025-1037. [PMID: 33467932 DOI: 10.1080/14656566.2021.1876663] [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: 10/22/2022]
Abstract
Introduction: Cerebral edema is a common complication of multiple neurological diseases and is a strong predictor of outcome, especially in traumatic brain injury and large hemispheric infarction.Areas Covered: Traditional and current treatments of cerebral edema include treatment with osmotherapy or decompressive craniectomy at the time of clinical deterioration. The authors discuss preclinical and clinical models of a variety of neurological disease states that have identified receptors, ion transporters, and channels involved in the development of cerebral edema as well as modulation of these receptors with promising agents.Expert opinion: Further study is needed on the safety and efficacy of the agents discussed. IV glibenclamide has shown promise in preclinical and clinical trials of cerebral edema in large hemispheric infarct and traumatic brain injury. Consideration of underlying pathophysiology and pharmacodynamics is vital, as the synergistic use of agents has the potential to drastically mitigate cerebral edema and secondary brain injury thusly transforming our treatment paradigms.
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Affiliation(s)
- Melissa Pergakis
- Program in Trauma Department of Neurology University of Maryland School of Medicine,Baltimore MD USA
| | - Neeraj Badjatia
- Program in Trauma Department of Neurology University of Maryland School of Medicine,Baltimore MD USA
| | - J Marc Simard
- Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD, USA
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16
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Josiah SS, Meor Azlan NF, Zhang J. Targeting the WNK-SPAK/OSR1 Pathway and Cation-Chloride Cotransporters for the Therapy of Stroke. Int J Mol Sci 2021; 22:1232. [PMID: 33513812 PMCID: PMC7865768 DOI: 10.3390/ijms22031232] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/22/2021] [Accepted: 01/24/2021] [Indexed: 02/05/2023] Open
Abstract
Stroke is one of the major culprits responsible for morbidity and mortality worldwide, and the currently available pharmacological strategies to combat this global disease are scanty. Cation-chloride cotransporters (CCCs) are expressed in several tissues (including neurons) and extensively contribute to the maintenance of numerous physiological functions including chloride homeostasis. Previous studies have implicated two CCCs, the Na+-K+-Cl- and K+-Cl- cotransporters (NKCCs and KCCs) in stroke episodes along with their upstream regulators, the with-no-lysine kinase (WNKs) family and STE20/SPS1-related proline/alanine rich kinase (SPAK) or oxidative stress response kinase (OSR1) via a signaling pathway. As the WNK-SPAK/OSR1 pathway reciprocally regulates NKCC and KCC, a growing body of evidence implicates over-activation and altered expression of NKCC1 in stroke pathology whilst stimulation of KCC3 during and even after a stroke event is neuroprotective. Both inhibition of NKCC1 and activation of KCC3 exert neuroprotection through reduction in intracellular chloride levels and thus could be a novel therapeutic strategy. Hence, this review summarizes the current understanding of functional regulations of the CCCs implicated in stroke with particular focus on NKCC1, KCC3, and WNK-SPAK/OSR1 signaling and discusses the current and potential pharmacological treatments for stroke.
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Affiliation(s)
| | | | - Jinwei Zhang
- Hatherly Laboratories, Institute of Biomedical and Clinical Sciences, Medical School, College of Medicine and Health, University of Exeter, Exeter EX4 4PS, UK; (S.S.J.); (N.F.M.A.)
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17
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Murillo-de-Ozores AR, Chávez-Canales M, de los Heros P, Gamba G, Castañeda-Bueno M. Physiological Processes Modulated by the Chloride-Sensitive WNK-SPAK/OSR1 Kinase Signaling Pathway and the Cation-Coupled Chloride Cotransporters. Front Physiol 2020; 11:585907. [PMID: 33192599 PMCID: PMC7606576 DOI: 10.3389/fphys.2020.585907] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 09/29/2020] [Indexed: 12/15/2022] Open
Abstract
The role of Cl- as an intracellular signaling ion has been increasingly recognized in recent years. One of the currently best described roles of Cl- in signaling is the modulation of the With-No-Lysine (K) (WNK) - STE20-Proline Alanine rich Kinase (SPAK)/Oxidative Stress Responsive Kinase 1 (OSR1) - Cation-Coupled Cl- Cotransporters (CCCs) cascade. Binding of a Cl- anion to the active site of WNK kinases directly modulates their activity, promoting their inhibition. WNK activation due to Cl- release from the binding site leads to phosphorylation and activation of SPAK/OSR1, which in turn phosphorylate the CCCs. Phosphorylation by WNKs-SPAK/OSR1 of the Na+-driven CCCs (mediating ions influx) promote their activation, whereas that of the K+-driven CCCs (mediating ions efflux) promote their inhibition. This results in net Cl- influx and feedback inhibition of WNK kinases. A wide variety of alterations to this pathway have been recognized as the cause of several human diseases, with manifestations in different systems. The understanding of WNK kinases as Cl- sensitive proteins has allowed us to better understand the mechanistic details of regulatory processes involved in diverse physiological phenomena that are reviewed here. These include cell volume regulation, potassium sensing and intracellular signaling in the renal distal convoluted tubule, and regulation of the neuronal response to the neurotransmitter GABA.
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Affiliation(s)
- Adrián Rafael Murillo-de-Ozores
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
- Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - María Chávez-Canales
- Unidad de Investigación UNAM-INC, Instituto Nacional de Cardiología Ignacio Chávez and Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Paola de los Heros
- Unidad de Investigación UNAM-INC, Research Division, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - Gerardo Gamba
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
- Molecular Physiology Unit, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico City, Mexico
| | - María Castañeda-Bueno
- Department of Nephrology and Mineral Metabolism, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico
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18
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Savardi A, Borgogno M, Narducci R, La Sala G, Ortega JA, Summa M, Armirotti A, Bertorelli R, Contestabile A, De Vivo M, Cancedda L. Discovery of a Small Molecule Drug Candidate for Selective NKCC1 Inhibition in Brain Disorders. Chem 2020; 6:2073-2096. [PMID: 32818158 PMCID: PMC7427514 DOI: 10.1016/j.chempr.2020.06.017] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 04/14/2020] [Accepted: 06/11/2020] [Indexed: 02/06/2023]
Abstract
Aberrant expression ratio of Cl− transporters, NKCC1 and KCC2, is implicated in several brain conditions. NKCC1 inhibition by the FDA-approved diuretic drug, bumetanide, rescues core symptoms in rodent models and/or clinical trials with patients. However, bumetanide has a strong diuretic effect due to inhibition of the kidney Cl− transporter NKCC2, creating critical drug compliance issues and health concerns. Here, we report the discovery of a new chemical class of selective NKCC1 inhibitors and the lead drug candidate ARN23746. ARN23746 restores the physiological intracellular Cl− in murine Down syndrome neuronal cultures, has excellent solubility and metabolic stability, and displays no issues with off-target activity in vitro. ARN23746 recovers core symptoms in mouse models of Down syndrome and autism, with no diuretic effect, nor overt toxicity upon chronic treatment in adulthood. ARN23746 is ready for advanced preclinical/manufacturing studies toward the first sustainable therapeutics for the neurological conditions characterized by impaired Cl− homeostasis.
NKCC1 is a promising target for the treatment of brain disorders The newly discovered ARN23746 presents selective NKCC1 versus NKCC2 and KCC2 inhibition ARN23746 restores altered neuronal chloride homeostasis in vitro ARN23746 rescues core behaviors in DS and ASD mice with no diuretic effect or toxicity In the last few decades, drug development for brain disorders has struggled to deliver effective small molecules as novel breakthrough classes of drugs. Discovery of effective chemical compounds for brain disorders has been greatly hampered by the fact that the few currently clinically used drugs were identified by serendipity, and these drugs’ mechanism of action is often poorly understood. Here, by leveraging drug repurposing as a means to quickly and safely evaluate the new pharmacological target NKCC1 and its implications in brain disorders in animal models and patients, we report an integrated strategy for the rational design and discovery of a novel, selective, and safe NKCC1 inhibitor, active in vivo. This compound has the potential to become a clinical drug candidate to treat several neurological conditions in patients. Eventually, this integrated drug-discovery strategy has the prospective to revive the appeal of drug-discovery programs in the challenging field of neuroscience.
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Affiliation(s)
- Annalisa Savardi
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
- Università degli Studi di Genova, Via Balbi, 5, 16126 Genoa, Italy
| | - Marco Borgogno
- Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Roberto Narducci
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Giuseppina La Sala
- Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Jose Antonio Ortega
- Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Maria Summa
- In Vivo Pharmacology Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Andrea Armirotti
- Analytical Chemistry Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Rosalia Bertorelli
- In Vivo Pharmacology Facility, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Andrea Contestabile
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
| | - Marco De Vivo
- Molecular Modeling and Drug Discovery Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
- Corresponding author
| | - Laura Cancedda
- Brain Development and Disease Laboratory, Istituto Italiano di Tecnologia, via Morego, 30, 16163 Genoa, Italy
- Dulbecco Telethon Institute, Via Orus 2, 35129 Padova, Italy
- Corresponding author
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19
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Interleukin-18 from neurons and microglia mediates depressive behaviors in mice with post-stroke depression. Brain Behav Immun 2020; 88:411-420. [PMID: 32272223 DOI: 10.1016/j.bbi.2020.04.004] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2020] [Revised: 03/23/2020] [Accepted: 04/04/2020] [Indexed: 02/07/2023] Open
Abstract
Post-stroke depression (PSD) is a common and serious complication that is affecting one thirds of stroke patients which leaves them with a poor quality of life, high mortality rate, high recurrent rate, and slow recovery. Recent studies showed that serum interleukin-18 (IL-18) level is a biomarker for patients with PSD. However, the role of IL-18 in the pathology of PSD is still unclear. In this study, we demonstrated that the IL-18 level in the ischemic brain significantly increased in mice with depression-like behaviors that were caused by the combined use of chronic spatial restraint stress and middle cerebral artery occlusion. Interestingly, IL-18 expression was mainly found in neurons at early phase and in microglia at a later phase. Injection of the exogenous IL-18 into the amygdala, but not the hippocampus or the striatum caused severe depression-like behaviors. On the contrary, the blockage of endogenous IL-18 by IL-18 binding protein, a specific antagonist of IL-18, repressed depressive phenotypes in SIR mice. IL-18 KO mice exhibited the resistance to spatial restraint stress and cerebral ischemia injury. Finally, we found that IL-18 mediated depressive behaviors by the interaction of IL-18 receptor and NKCC1, a sodium-potassium chloride co-transporter that is related to GABAergic inhibition. Administration of NKCC1 antagonist bumetanide exerted a therapeutic effect on the in IL-18-induced depressive mice. In conclusion, we demonstrated that increased IL-18 in the brain causes depression-like behaviors by promoting the IL-18 receptor/NKCC1 signaling pathway. Targeting IL-18 and its downstream pathway is a promising strategy for the prevention and treatment of PSD.
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20
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Martynyuk AE, Ju LS, Morey TE, Zhang JQ. Neuroendocrine, epigenetic, and intergenerational effects of general anesthetics. World J Psychiatry 2020; 10:81-94. [PMID: 32477904 PMCID: PMC7243620 DOI: 10.5498/wjp.v10.i5.81] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2019] [Revised: 03/18/2020] [Accepted: 03/26/2020] [Indexed: 02/05/2023] Open
Abstract
The progress of modern medicine would be impossible without the use of general anesthetics (GAs). Despite advancements in refining anesthesia approaches, the effects of GAs are not fully reversible upon GA withdrawal. Neurocognitive deficiencies attributed to GA exposure may persist in neonates or endure for weeks to years in the elderly. Human studies on the mechanisms of the long-term adverse effects of GAs are needed to improve the safety of general anesthesia but they are hampered not only by ethical limitations specific to human research, but also by a lack of specific biological markers that can be used in human studies to safely and objectively study such effects. The latter can primarily be attributed to an insufficient understanding of the full range of the biological effects induced by GAs and the molecular mechanisms mediating such effects even in rodents, which are far more extensively studied than any other species. Our most recent experimental findings in rodents suggest that GAs may adversely affect many more people than is currently anticipated. Specifically, we have shown that anesthesia with the commonly used GA sevoflurane induces in exposed animals not only neuroendocrine abnormalities (somatic effects), but also epigenetic reprogramming of germ cells (germ cell effects). The latter may pass the neurobehavioral effects of parental sevoflurane exposure to the offspring, who may be affected even at levels of anesthesia that are not harmful to the exposed parents. The large number of patients who require general anesthesia, the even larger number of their future unexposed offspring whose health may be affected, and a growing number of neurodevelopmental disorders of unknown etiology underscore the translational importance of investigating the intergenerational effects of GAs. In this mini review, we discuss emerging experimental findings on neuroendocrine, epigenetic, and intergenerational effects of GAs.
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Affiliation(s)
- Anatoly E Martynyuk
- Department of Anesthesiology and the McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL 32610, United States
| | - Jia-Qiang Zhang
- Department of Anesthesiology and Perioperative Medicine, Henan Provincial People’s Hospital, People's Hospital of Zhengzhou University, Zhengzhou 450003, Henan Province, China
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21
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Maguire JL. Get With the (Developmental) Program. Epilepsy Curr 2020; 20:102-104. [PMID: 32313506 PMCID: PMC7160877 DOI: 10.1177/1535759720901606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Impaired Regulation of KCC2 Phosphorylation Leads to Neuronal Network Dysfunction and Neurodevelopmental Pathology Pisella LI, Gaiarsa JL, Diabira D, et al. Sci Signal. 2019:12(603):eaay0300. doi:10.1126/scisignal.aay0300. KCC2 is a vital neuronal K+/Cl− cotransporter that is implicated in the etiology of numerous neurological diseases. In normal cells, KCC2 undergoes developmental dephosphorylation at Thr906 and Thr1007. We engineered mice with heterozygous phosphomimetic mutations T906E and T1007E (KCC2E/+) to prevent the normal developmental dephosphorylation of these sites. Immature (postnatal day 15) but not juvenile (postnatal day 30) KCC2E/+ mice exhibited altered GABAergic inhibition, an increased glutamate/GABA synaptic ratio, and greater susceptibility to seizure. KCC2E/+ mice also had abnormal ultrasonic vocalizations at postnatal days 10 to 12 and impaired social behavior at postnatal day 60. Postnatal bumetanide treatment restored network activity by postnatal day 15 but failed to restore social behavior by postnatal day 60. Our data indicate that posttranslational KCC2 regulation controls the GABAergic developmental sequence in vivo, indicating that deregulation of KCC2 could be a risk factor for the emergence of neurological pathology. Developmental Regulation of KCC2 Phosphorylation Has Long-Term Impacts on Cognitive Function Moore YE, Conway LC, Wobst HJ, et al. Front Mol Neurosci. 2019;12:173. doi:10.3389/fnmol.2019.00173. The GABAA receptor-mediated currents shift from excitatory to inhibitory during postnatal brain development in rodents. A postnatal increase in KCC2 protein expression is considered to be the sole mechanism controlling the developmental onset of hyperpolarizing synaptic transmission, but here we identify a key role for KCC2 phosphorylation in the developmental EGABA shift. Preventing phosphorylation of KCC2 in vivo at either residue serine 940 (S940), or at residues threonine 906 and threonine 1007 (T906/T1007), delayed or accelerated the postnatal onset of KCC2 function, respectively. Several models of neurodevelopmental disorders including Rett syndrome, Fragile × and Down syndrome exhibit delayed postnatal onset of hyperpolarizing GABAergic inhibition, but whether the timing of the onset of hyperpolarizing synaptic inhibition during development plays a role in establishing adulthood cognitive function is unknown; we have used the distinct KCC2-S940A and KCC2-T906A/T1007A knock-in mouse models to address this issue. Altering KCC2 function resulted in long-term abnormalities in social behavior and memory retention. Tight regulation of KCC2 phosphorylation is therefore required for the typical timing of the developmental onset of hyperpolarizing synaptic inhibition, and it plays a fundamental role in the regulation of adulthood cognitive function.
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22
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Waddington JL, Zhen X, O'Tuathaigh CMP. Developmental Genes and Regulatory Proteins, Domains of Cognitive Impairment in Schizophrenia Spectrum Psychosis and Implications for Antipsychotic Drug Discovery: The Example of Dysbindin-1 Isoforms and Beyond. Front Pharmacol 2020; 10:1638. [PMID: 32063853 PMCID: PMC7000454 DOI: 10.3389/fphar.2019.01638] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2019] [Accepted: 12/16/2019] [Indexed: 12/19/2022] Open
Abstract
Alongside positive and negative symptomatology, deficits in working memory, attention, selective learning processes, and executive function have been widely documented in schizophrenia spectrum psychosis. These cognitive abnormalities are strongly associated with impairment across multiple function domains and are generally treatment-resistant. The DTNBP1 (dystrobrevin-binding protein-1) gene, encoding dysbindin, is considered a risk factor for schizophrenia and is associated with variation in cognitive function in both clinical and nonclinical samples. Downregulation of DTNBP1 expression in dorsolateral prefrontal cortex and hippocampal formation of patients with schizophrenia has been suggested to serve as a primary pathophysiological process. Described as a "hub," dysbindin is an important regulatory protein that is linked with multiple complexes in the brain and is involved in a wide variety of functions implicated in neurodevelopment and neuroplasticity. The expression pattern of the various dysbindin isoforms (-1A, -1B, -1C) changes depending upon stage of brain development, tissue areas and subcellular localizations, and can involve interaction with different protein partners. We review evidence describing how sequence variation in DTNBP1 isoforms has been differentially associated with schizophrenia-associated symptoms. We discuss results linking these isoform proteins, and their interacting molecular partners, with cognitive dysfunction in schizophrenia, including evidence from drosophila through to genetic mouse models of dysbindin function. Finally, we discuss preclinical evidence investigating the antipsychotic potential of molecules that influence dysbindin expression and functionality. These studies, and other recent work that has extended this approach to other developmental regulators, may facilitate identification of novel molecular pathways leading to improved antipsychotic treatments.
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Affiliation(s)
- John L Waddington
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.,Jiangsu Key Laboratory of Translational Research & Therapy for Neuro-Psychiatric Disorders and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Xuechu Zhen
- Jiangsu Key Laboratory of Translational Research & Therapy for Neuro-Psychiatric Disorders and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Colm M P O'Tuathaigh
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.,Medical Education Unit, School of Medicine, Brookfield Health Sciences Complex, University College Cork, Cork, Ireland
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23
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Tang BL. The Expanding Therapeutic Potential of Neuronal KCC2. Cells 2020; 9:E240. [PMID: 31963584 PMCID: PMC7016893 DOI: 10.3390/cells9010240] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 01/09/2020] [Accepted: 01/16/2020] [Indexed: 02/06/2023] Open
Abstract
Dysfunctions in GABAergic inhibitory neural transmission occur in neuronal injuries and neurological disorders. The potassium-chloride cotransporter 2 (KCC2, SLC12A5) is a key modulator of inhibitory GABAergic inputs in healthy adult neurons, as its chloride (Cl-) extruding activity underlies the hyperpolarizing reversal potential for GABAA receptor Cl- currents (EGABA). Manipulation of KCC2 levels or activity improve symptoms associated with epilepsy and neuropathy. Recent works have now indicated that pharmacological enhancement of KCC2 function could reactivate dormant relay circuits in an injured mouse's spinal cord, leading to functional recovery and the attenuation of neuronal abnormality and disease phenotype associated with a mouse model of Rett syndrome (RTT). KCC2 interacts with Huntingtin and is downregulated in Huntington's disease (HD), which contributed to GABAergic excitation and memory deficits in the R6/2 mouse HD model. Here, these recent advances are highlighted, which attest to KCC2's growing potential as a therapeutic target for neuropathological conditions resulting from dysfunctional inhibitory input.
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Affiliation(s)
- Bor Luen Tang
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117596, Singapore; ; Tel.: +65-6516-1040
- NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore 119077, Singapore
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24
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Kang E, Song J, Lin Y, Park J, Lee JH, Hussani Q, Gu Y, Ge S, Li W, Hsu KS, Berninger B, Christian KM, Song H, Ming GL. Interplay between a Mental Disorder Risk Gene and Developmental Polarity Switch of GABA Action Leads to Excitation-Inhibition Imbalance. Cell Rep 2019; 28:1419-1428.e3. [PMID: 31390557 PMCID: PMC6690484 DOI: 10.1016/j.celrep.2019.07.024] [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: 06/19/2018] [Revised: 05/29/2019] [Accepted: 07/10/2019] [Indexed: 12/17/2022] Open
Abstract
Excitation-inhibition (E-I) imbalance is considered a hallmark of various neurodevelopmental disorders, including schizophrenia and autism. How genetic risk factors disrupt coordinated glutamatergic and GABAergic synapse formation to cause an E-I imbalance is not well understood. Here, we show that knockdown of Disrupted-in-schizophrenia 1 (DISC1), a risk gene for major mental disorders, leads to E-I imbalance in mature dentate granule neurons. We found that excessive GABAergic inputs from parvalbumin-, but not somatostatin-, expressing interneurons enhance the formation of both glutamatergic and GABAergic synapses in immature mutant neurons. Following the switch in GABAergic signaling polarity from depolarizing to hyperpolarizing during neuronal maturation, heightened inhibition from excessive parvalbumin+ GABAergic inputs causes loss of excitatory glutamatergic synapses in mature mutant neurons, resulting in an E-I imbalance. Our findings provide insights into the developmental role of depolarizing GABA in establishing E-I balance and how it can be influenced by genetic risk factors for mental disorders.
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Affiliation(s)
- Eunchai Kang
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Juan Song
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA; Neuroscience Center, School of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA
| | - Yuting Lin
- Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan City 701, Taiwan
| | - Jaesuk Park
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Jennifer H Lee
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Qassim Hussani
- Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA
| | - Yan Gu
- Department of Neurobiology and Behavior, State University of New York at Stony Brook, Stony Brook, NY 11794, USA
| | - Shaoyu Ge
- Department of Neurobiology and Behavior, State University of New York at Stony Brook, Stony Brook, NY 11794, USA
| | - Weidong Li
- Bio-X Institute, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Shanghai Jiao Tong University, Shanghai, China
| | - Kuei-Sen Hsu
- Department of Pharmacology, College of Medicine, National Cheng Kung University, No. 1, University Road, Tainan City 701, Taiwan
| | - Benedikt Berninger
- Center for Developmental Neurobiology, King's College London, London SE1UL, UK
| | - Kimberly M Christian
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Hongjun Song
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; The Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Guo-Li Ming
- Department of Neuroscience and Mahoney Institute for Neurosciences, Perelman School for Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Cell and Developmental Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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25
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Hede V, Devillé C. Treating psychiatric symptoms and disorders with non-psychotropic medications. DIALOGUES IN CLINICAL NEUROSCIENCE 2019. [PMID: 31636493 PMCID: PMC6787535 DOI: 10.31887/dcns.2019.21.2/vhede] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
A few drugs prescribed in internal medicine, ie, non-psychotropic drugs, can be used
to treat certain neuropsychiatric disorders. For most of these situations, the level
of evidence remains low. But when sufficient data becomes available, these molecules
are then included in official guidelines for the treatment of neuropsychiatric
disorders. In this article we review interesting drugs which may be relevant from an
evidence-based medicine point of view, and could become part of psychiatric practice
in the future.
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Affiliation(s)
- Vincent Hede
- Author affiliations: Liaison Psychiatry Unit (Vincent Hede); Young Adult Psychiatry Unit (Cédric Devillé); Department of Psychiatry, Geneva University Hospitals, Geneva, Switzerland. Address for correspondence: Dr Vincent Hede, Hôpitaux Universitaires de Genève, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland. (e-mail: )
| | - Cédric Devillé
- Author affiliations: Liaison Psychiatry Unit (Vincent Hede); Young Adult Psychiatry Unit (Cédric Devillé); Department of Psychiatry, Geneva University Hospitals, Geneva, Switzerland. Address for correspondence: Dr Vincent Hede, Hôpitaux Universitaires de Genève, Rue Gabrielle-Perret-Gentil 4, 1205 Geneva, Switzerland. (e-mail: )
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26
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Gharaylou Z, Shafaghi L, Oghabian MA, Yoonessi A, Tafakhori A, Shahsavand Ananloo E, Hadjighassem M. Longitudinal Effects of Bumetanide on Neuro-Cognitive Functioning in Drug-Resistant Epilepsy. Front Neurol 2019; 10:483. [PMID: 31133976 PMCID: PMC6517515 DOI: 10.3389/fneur.2019.00483] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Accepted: 04/23/2019] [Indexed: 12/25/2022] Open
Abstract
Antiepileptic drugs (AEDs) have repeatedly shown inconsistent and almost contradictory effects on the neurocognitive system, from substantial impairments in processing speed to the noticeable improvement in working memory and executive functioning. Previous studies have provided a novel insight into the cognitive improvement by bumetanide as a potential antiepileptic drug. Through the current investigation, we evaluated the longitudinal effects of bumetanide, an NKCC1 co-transporter antagonist, on the brain microstructural organization as a probable underlying component for cognitive performance. Microstructure assessment was completed using SPM for the whole brain assay and Freesurfer/TRACULA for the automatic probabilistic tractography analysis. Primary cognitive operations including selective attention and processing speed, working memory capacity and spatial memory were evaluated in 12 patients with a confirmed diagnosis of refractory epilepsy. Participants treated with bumetanide (2 mg/ day) in two divided doses as an adjuvant therapy to their regular AEDs for 6 months, which followed by the re-assessment of their cognitive functions and microstructural organizations. Seizure frequency reduced in eight patients which accompanied by white matter reconstruction; fractional anisotropy (FA) increased in the cingulum-cingulate gyrus (CCG), anterior thalamic radiation (ATR), and temporal part of the superior longitudinal fasciculus (SLFt) in correlation with the clinical response. The voxel-based analysis in responder patients revealed increased FA in the left hippocampus, right cerebellum, and right medial temporal lobe, while mean diffusivity (MD) values reduced in the right occipital lobe and cerebellum. Microstructural changes in SLFt and ATR accompanied by a reduction in the error rate in the spatial memory test. These primary results have provided preliminary evidence for the effect of bumetanide on cognitive functioning through microstructural changes in patients with drug-resistant epilepsy.
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Affiliation(s)
- Zeinab Gharaylou
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Lida Shafaghi
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Ali Oghabian
- Neuroimaging and Analysis Group, Imam Khomeini Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Yoonessi
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Abbas Tafakhori
- Imam Khomeini Hospital, Iranian Center of Neurological Research, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Mahmoudreza Hadjighassem
- Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.,Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
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27
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Kharod SC, Kang SK, Kadam SD. Off-Label Use of Bumetanide for Brain Disorders: An Overview. Front Neurosci 2019; 13:310. [PMID: 31068771 PMCID: PMC6491514 DOI: 10.3389/fnins.2019.00310] [Citation(s) in RCA: 73] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Accepted: 03/19/2019] [Indexed: 01/17/2023] Open
Abstract
Bumetanide (BTN or BUM) is a FDA-approved potent loop diuretic (LD) that acts by antagonizing sodium-potassium-chloride (Na-K-Cl) cotransporters, NKCC1 (SLc12a2) and NKCC2. While NKCC1 is expressed both in the CNS and in systemic organs, NKCC2 is kidney-specific. The off-label use of BTN to modulate neuronal transmembrane Cl− gradients by blocking NKCC1 in the CNS has now been tested as an anti-seizure agent and as an intervention for neurological disorders in pre-clinical studies with varying results. BTN safety and efficacy for its off-label use has also been tested in several clinical trials for neonates, children, adolescents, and adults. It failed to meet efficacy criteria for hypoxic-ischemic encephalopathy (HIE) neonatal seizures. In contrast, positive outcomes in temporal lobe epilepsy (TLE), autism, and schizophrenia trials have been attributed to BTN in studies evaluating its off-label use. NKCC1 is an electroneutral neuronal Cl− importer and the dominance of NKCC1 function has been proposed as the common pathology for HIE seizures, TLE, autism, and schizophrenia. Therefore, the use of BTN to antagonize neuronal NKCC1 with the goal to lower internal Cl− levels and promote GABAergic mediated hyperpolarization has been proposed. In this review, we summarize the data and results for pre-clinical and clinical studies that have tested off-label BTN interventions and report variable outcomes. We also compare the data underlying the developmental expression profile of NKCC1 and KCC2, highlight the limitations of BTN’s brain-availability and consider its actions on non-neuronal cells.
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Affiliation(s)
- Shivani C Kharod
- Neuroscience Laboratory, Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, United States
| | - Seok Kyu Kang
- Neuroscience Laboratory, Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, United States
| | - Shilpa D Kadam
- Neuroscience Laboratory, Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, MD, United States.,Department of Neurology and Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, MD, United States
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28
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Goubert E, Altvater M, Rovira MN, Khalilov I, Mazzarino M, Sebastiani A, Schaefer MKE, Rivera C, Pellegrino C. Bumetanide Prevents Brain Trauma-Induced Depressive-Like Behavior. Front Mol Neurosci 2019; 12:12. [PMID: 30804751 PMCID: PMC6370740 DOI: 10.3389/fnmol.2019.00012] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 01/14/2019] [Indexed: 01/24/2023] Open
Abstract
Brain trauma triggers a cascade of deleterious events leading to enhanced incidence of drug resistant epilepsies, depression, and cognitive dysfunctions. The underlying mechanisms leading to these alterations are poorly understood and treatment that attenuates those sequels are not available. Using controlled-cortical impact as an experimental model of brain trauma in adult mice, we found a strong suppressive effect of the sodium-potassium-chloride importer (NKCC1) specific antagonist bumetanide on the appearance of depressive-like behavior. We demonstrate that this alteration in behavior is associated with an impairment of post-traumatic secondary neurogenesis within the dentate gyrus of the hippocampus. The mechanism mediating the effect of bumetanide involves early transient changes in the expression of chloride regulatory proteins and qualitative changes in GABA(A) mediated transmission from hyperpolarizing to depolarizing after brain trauma. This work opens new perspectives in the early treatment of human post-traumatic induced depression. Our results strongly suggest that bumetanide might constitute an efficient prophylactic treatment to reduce neurological and psychiatric consequences of brain trauma.
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Affiliation(s)
- Emmanuelle Goubert
- INSERM, Institute of Mediterranean Neurobiology, Aix-Marseille University, Marseille, France
| | - Marc Altvater
- Department of Anesthesiology and Research Center Translational Neurosciences, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Marie-Noelle Rovira
- INSERM, Institute of Mediterranean Neurobiology, Aix-Marseille University, Marseille, France
| | - Ilgam Khalilov
- INSERM, Institute of Mediterranean Neurobiology, Aix-Marseille University, Marseille, France.,Laboratory of Neurobiology, Kazan Federal University, Kazan, Russia
| | - Morgane Mazzarino
- INSERM, Institute of Mediterranean Neurobiology, Aix-Marseille University, Marseille, France
| | - Anne Sebastiani
- Department of Anesthesiology and Research Center Translational Neurosciences, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Michael K E Schaefer
- Department of Anesthesiology and Research Center Translational Neurosciences, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
| | - Claudio Rivera
- INSERM, Institute of Mediterranean Neurobiology, Aix-Marseille University, Marseille, France.,Neuroscience Center, University of Helsinki, Helsinki, Finland
| | - Christophe Pellegrino
- INSERM, Institute of Mediterranean Neurobiology, Aix-Marseille University, Marseille, France
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29
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Schulte JT, Wierenga CJ, Bruining H. Chloride transporters and GABA polarity in developmental, neurological and psychiatric conditions. Neurosci Biobehav Rev 2018; 90:260-271. [PMID: 29729285 DOI: 10.1016/j.neubiorev.2018.05.001] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 03/20/2018] [Accepted: 05/01/2018] [Indexed: 12/22/2022]
Abstract
Neuronal chloride regulation is a determinant factor for the dynamic tuning of GABAergic inhibition during and beyond brain development. This regulation is mainly dependent on the two co-transporters K+/Cl- co-transporter KCC2 and Na+/K+/Cl- co-transporter NKCC1, whose activity can decrease or increase neuronal chloride concentrations respectively. Altered expression and/or activity of either of these co-transporters has been associated with a wide variety of brain disorders including developmental disorders, epilepsy, schizophrenia and stroke. Here, we review current knowledge on chloride transporter expression and activity regulation and highlight the intriguing potential for existing and future interventions to support chloride homeostasis across a wide range of mental disorders and neurological conditions.
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Affiliation(s)
- Joran T Schulte
- Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center, Heidelberglaan 100, 3508 GA Utrecht The Netherlands
| | - Corette J Wierenga
- Division of Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH, Utrecht, The Netherlands
| | - Hilgo Bruining
- Department of Psychiatry, Brain Center Rudolf Magnus, University Medical Center, Heidelberglaan 100, 3508 GA Utrecht The Netherlands.
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30
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Dargaei Z, Bang JY, Mahadevan V, Khademullah CS, Bedard S, Parfitt GM, Kim JC, Woodin MA. Restoring GABAergic inhibition rescues memory deficits in a Huntington's disease mouse model. Proc Natl Acad Sci U S A 2018; 115:E1618-E1626. [PMID: 29382760 PMCID: PMC5816181 DOI: 10.1073/pnas.1716871115] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Huntington's disease (HD) is classically characterized as a movement disorder, however cognitive impairments precede the motor symptoms by ∼15 y. Based on proteomic and bioinformatic data linking the Huntingtin protein (Htt) and KCC2, which is required for hyperpolarizing GABAergic inhibition, and the important role of inhibition in learning and memory, we hypothesized that aberrant KCC2 function contributes to the hippocampal-associated learning and memory deficits in HD. We discovered that Htt and KCC2 interact in the hippocampi of wild-type and R6/2-HD mice, with a decrease in KCC2 expression in the hippocampus of R6/2 and YAC128 mice. The reduced expression of the Cl--extruding cotransporter KCC2 is accompanied by an increase in the Cl--importing cotransporter NKCC1, which together result in excitatory GABA in the hippocampi of HD mice. NKCC1 inhibition by the FDA-approved NKCC1 inhibitor bumetanide abolished the excitatory action of GABA and rescued the performance of R6/2 mice on hippocampal-associated behavioral tests.
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Affiliation(s)
- Zahra Dargaei
- Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada
| | - Jee Yoon Bang
- Department of Psychology, University of Toronto, Toronto, ON M5S 3G3, Canada
| | - Vivek Mahadevan
- Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada
| | - C Sahara Khademullah
- Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada
| | - Simon Bedard
- Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada
| | - Gustavo Morrone Parfitt
- Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada
- Department of Psychology, University of Toronto, Toronto, ON M5S 3G3, Canada
| | - Jun Chul Kim
- Department of Psychology, University of Toronto, Toronto, ON M5S 3G3, Canada
| | - Melanie A Woodin
- Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada;
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31
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Zeidler S, de Boer H, Hukema RK, Willemsen R. Combination Therapy in Fragile X Syndrome; Possibilities and Pitfalls Illustrated by Targeting the mGluR5 and GABA Pathway Simultaneously. Front Mol Neurosci 2017; 10:368. [PMID: 29163043 PMCID: PMC5681991 DOI: 10.3389/fnmol.2017.00368] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Accepted: 10/24/2017] [Indexed: 11/13/2022] Open
Abstract
Fragile X syndrome (FXS) is the most common monogenetic cause of intellectual disability and autism. The disorder is characterized by altered synaptic plasticity in the brain. Synaptic plasticity is tightly regulated by a complex balance of different synaptic pathways. In FXS, various synaptic pathways are disrupted, including the excitatory metabotropic glutamate receptor 5 (mGluR5) and the inhibitory γ-aminobutyric acid (GABA) pathways. Targeting each of these pathways individually, has demonstrated beneficial effects in animal models, but not in patients with FXS. This lack of translation might be due to oversimplification of the disease mechanisms when targeting only one affected pathway, in spite of the complexity of the many pathways implicated in FXS. In this report we outline the hypothesis that targeting more than one pathway simultaneously, a combination therapy, might improve treatment effects in FXS. In addition, we present a glance of the first results of chronic combination therapy on social behavior in Fmr1 KO mice. In contrast to what we expected, targeting both the mGluR5 and the GABAergic pathways simultaneously did not result in a synergistic effect, but in a slight worsening of the social behavior phenotype. This does implicate that both pathways are interconnected and important for social behavior. Our results underline the tremendous fine-tuning that is needed to reach the excitatory-inhibitory balance in the synapse in relation to social behavior. We believe that alternative strategies focused on combination therapy should be further explored, including targeting pathways in different cellular compartments or cell-types.
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Affiliation(s)
- Shimriet Zeidler
- Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Helen de Boer
- Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Renate K Hukema
- Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Rob Willemsen
- Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, Netherlands
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32
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Yang J, Ju L, Jia M, Zhang H, Sun X, Ji M, Yang J, Martynyuk AE. Subsequent maternal separation exacerbates neurobehavioral abnormalities in rats neonatally exposed to sevoflurane anesthesia. Neurosci Lett 2017; 661:137-142. [PMID: 28982596 DOI: 10.1016/j.neulet.2017.09.063] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Revised: 09/24/2017] [Accepted: 09/29/2017] [Indexed: 12/16/2022]
Abstract
Several recent studies suggest that in the human population, a routine, short anesthetic in otherwise healthy infants is void of neurodevelopmental insult. On the other hand, many human retrospective epidemiological studies report evidence of cognitive abnormalities in children after testing those who had different anesthesia-requiring procedures in early childhood. We tested in a rat model whether post-anesthesia stressful environmental factors can contribute to developmental abnormalities that were initiated by a relatively short exposure to sevoflurane, the most widely used anesthetic in pediatric anesthesia, whose polyvalent actions include enhancement of gamma-aminobutyric acid type A receptor (GABAAR) activity. Postnatal day 6 (P6) male Sprague-Dawley rats were anesthetized with sevoflurane for 60min. To simulate subsequent stress, the animals were subjected to a single maternal separation for 180min at P10. To study the role of GABAAR-mediated depolarization, subgroups of P6 rats received a single injection of the Na+-K+-2Cl- (NKCC1) inhibitor, bumetanide, prior to initiation of anesthesia with sevoflurane. Rats that were exposed to sevoflurane had decreased hypothalamic K+-2Cl- (KCC2) mRNA level (F(2,13)=3.839, P=0.049), increased NKCC1/KCC2 mRNA ratio (F(2,13)=5.043, P=0.024) and increased corticotropin-releasing hormone (CRH) mRNA level (F(2,12)=9.450, P=0.003) at P10, the age at which maternal separation was imposed. Adult rats, neonatally exposed to a combination of sevoflurane and maternal separation, exhibited increases in the escape latencies greater than animals exposed to sevoflurane only (P=0.012), and only rats in the sevoflurane plus maternal separation group spent significantly less time in the target quadrant during the Morris water maze test (F(4,55)=4.856, P=0.002). Bumetanide ameliorated abnormalities induced by sevoflurane and a combination of sevoflurane plus maternal separation. Neonatal exposure to sevoflurane may sensitize to stressors later in life, and post-exposure stress may exacerbate neurodevelopmental abnormalities even after a relatively short exposure to sevoflurane in rodents. The NKCC1 downregulation prior to exposure to the anesthetic may be therapeutic.
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Affiliation(s)
- Jiaojiao Yang
- Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Lingsha Ju
- Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Min Jia
- Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Hui Zhang
- Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Xiaoru Sun
- Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Muhuo Ji
- Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Jianjun Yang
- Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; Department of Anesthesiology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China.
| | - Anatoly E Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; McKnight Brain Institute, University of FL College of Medicine, Gainesville, FL, United States.
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Follow-up Case Report: Bumetanide Can Control Seizural Activity in Temporal Lobe Epilepsy Patient. ARCHIVES OF NEUROSCIENCE 2017. [DOI: 10.5812/archneurosci.58681] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Hu D, Yu ZL, Zhang Y, Han Y, Zhang W, Lu L, Shi J. Bumetanide treatment during early development rescues maternal separation-induced susceptibility to stress. Sci Rep 2017; 7:11878. [PMID: 28928398 PMCID: PMC5605528 DOI: 10.1038/s41598-017-12183-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2017] [Accepted: 09/05/2017] [Indexed: 12/17/2022] Open
Abstract
Stress is a major risk factor for psychiatric disorders, such as depression, posttraumatic stress disorder, and schizophrenia. Early life stress, such as maternal separation, can have long-term effects on the development of the central nervous system and pathogenesis of psychiatric disorders. In the present study, we found that maternal separation increased the susceptibility to stress in adolescent rats, increased the expression of Na+/K+/2Cl- cotransporter 1 (NKCC1) on postnatal day 14, and increased the expression of K+/2Cl- cotransporter 2 (KCC2) and γ-aminobutyric acid A (GABAA) receptor subunits on postnatal day 40 in the hippocampus. NKCC1 inhibition by the U.S. Food and Drug Administration-approved drug bumetanide during the first two postnatal weeks rescued the depressive- and anxiety-like behavior that was induced by maternal separation and decreased the expression of NKCC1, KCC2 and GABAA receptor α1 and β2,3 subunits in the hippocampus. Bumetanide treatment during early development did not adversely affect body weight or normal behaviors in naive rats, or affect serum osmolality in adult rats. These results suggest that bumetanide treatment during early development may prevent the maternal separation-induced susceptibility to stress and impairments in GABAergic transmission in the hippocampus.
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Affiliation(s)
- Die Hu
- National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, 100191, China
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Zhou-Long Yu
- National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, 100191, China
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Yan Zhang
- National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, 100191, China
- Department of Pharmacology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China
| | - Ying Han
- National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, 100191, China
| | - Wen Zhang
- National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, 100191, China
| | - Lin Lu
- National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, 100191, China
- Institute of Mental Health, National Clinical Research Center for Mental Disorders, Key Laboratory of Mental Health and Peking University Sixth Hospital, Peking University, Beijing, 100191, China
- Peking-Tsinghua Center for Life Sciences and PKU-IDG/McGovern Institute for Brain Research, Beijing, 100191, China
| | - Jie Shi
- National Institute on Drug Dependence and Beijing Key Laboratory of Drug Dependence, Peking University, Beijing, 100191, China.
- State Key Laboratory of Natural and Biomimetic Drugs, Beijing, 100191, China.
- Key Laboratory for Neuroscience of the Ministry of Education and Ministry of Public Healthy, Beijing, 100191, China.
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Katsarou A, Moshé SL, Galanopoulou AS. INTERNEURONOPATHIES AND THEIR ROLE IN EARLY LIFE EPILEPSIES AND NEURODEVELOPMENTAL DISORDERS. Epilepsia Open 2017; 2:284-306. [PMID: 29062978 PMCID: PMC5650248 DOI: 10.1002/epi4.12062] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/03/2017] [Indexed: 12/22/2022] Open
Abstract
GABAergic interneurons control the neural circuitry and network activity in the brain. The advances in genetics have identified genes that control the development, maturation and integration of GABAergic interneurons and implicated them in the pathogenesis of epileptic encephalopathies or neurodevelopmental disorders. For example, mutations of the Aristaless-Related homeobox X-linked gene (ARX) may result in defective GABAergic interneuronal migration in infants with epileptic encephalopathies like West syndrome (WS), Ohtahara syndrome or X-linked lissencephaly with abnormal genitalia (XLAG). The concept of "interneuronopathy", i.e. impaired development, migration or function of interneurons, has emerged as a possible etiopathogenic mechanism for epileptic encephalopathies. Treatments that enhance GABA levels, may help seizure control but do not necessarily show disease modifying effect. On the other hand, interneuronopathies can be seen in other conditions in which epilepsy may not be the primary manifestation, such as autism. In this review, we plan to outline briefly the current state of knowledge on the origin, development, and migration and integration of GABAergic interneurons, present neurodevelopmental conditions, with or without epilepsy, that have been associated with interneuronopathies and discuss the evidence linking certain types of interneuronal dysfunction with epilepsy and/or cognitive or behavioral deficits.
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Affiliation(s)
- Anna‐Maria Katsarou
- Laboratory of Developmental EpilepsySaul R. Korey Department of NeurologyAlbert Einstein College of MedicineBronxNew YorkU.S.A.
| | - Solomon L. Moshé
- Laboratory of Developmental EpilepsySaul R. Korey Department of NeurologyAlbert Einstein College of MedicineBronxNew YorkU.S.A.
- Dominick P. Purpura Department of NeuroscienceMontefiore/Einstein Epilepsy CenterAlbert Einstein College of MedicineBronxNew YorkU.S.A.
- Department of PediatricsAlbert Einstein College of MedicineBronxNew YorkU.S.A.
| | - Aristea S. Galanopoulou
- Laboratory of Developmental EpilepsySaul R. Korey Department of NeurologyAlbert Einstein College of MedicineBronxNew YorkU.S.A.
- Dominick P. Purpura Department of NeuroscienceMontefiore/Einstein Epilepsy CenterAlbert Einstein College of MedicineBronxNew YorkU.S.A.
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Ben-Ari Y. NKCC1 Chloride Importer Antagonists Attenuate Many Neurological and Psychiatric Disorders. Trends Neurosci 2017; 40:536-554. [PMID: 28818303 DOI: 10.1016/j.tins.2017.07.001] [Citation(s) in RCA: 136] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Revised: 07/03/2017] [Accepted: 07/10/2017] [Indexed: 12/23/2022]
Abstract
In physiological conditions, adult neurons have low intracellular Cl- [(Cl-)I] levels underlying the γ-aminobutyric acid (GABA)ergic inhibitory drive. In contrast, neurons have high (Cl-)I levels and excitatory GABA actions in a wide range of pathological conditions including spinal cord lesions, chronic pain, brain trauma, cerebrovascular infarcts, autism, Rett and Down syndrome, various types of epilepsies, and other genetic or environmental insults. The diuretic highly specific NKCC1 chloride importer antagonist bumetanide (PubChem CID: 2461) efficiently restores low (Cl-)I levels and attenuates many disorders in experimental conditions and in some clinical trials. Here, I review the mechanisms of action, therapeutic effects, promises, and pitfalls of bumetanide.
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Affiliation(s)
- Yehezkel Ben-Ari
- New INMED, Aix-Marseille University, Campus Scientifique de Luminy, Marseilles, France.
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Bumetanide Treatment for Psychiatric Disorders and the Modulation of Central Nitric Oxide Metabolism. Clin Neuropharmacol 2017; 40:192-193. [PMID: 28704252 DOI: 10.1097/wnf.0000000000000228] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Ju LS, Yang JJ, Gravenstein N, Seubert CN, Morey TE, Sumners C, Vasilopoulos T, Yang JJ, Martynyuk AE. Role of environmental stressors in determining the developmental outcome of neonatal anesthesia. Psychoneuroendocrinology 2017; 81:96-104. [PMID: 28433802 PMCID: PMC5492971 DOI: 10.1016/j.psyneuen.2017.04.001] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Revised: 03/28/2017] [Accepted: 04/04/2017] [Indexed: 12/17/2022]
Abstract
BACKGROUND The majority of studies evaluating neurocognition in humans who had procedures under anesthesia early in life found long-term deficits even though the typical anesthesia duration normalized to the human life span is much shorter than that shown to induce developmental abnormalities in rodents. Therefore, we studied whether subsequent environmental stressors contribute to deficiencies programmed by a brief neonatal etomidate exposure. METHODS Postnatal days (P) 4, 5, or 6, Sprague-Dawley rats, pretreated with vehicle or the Na+-K+-2Cl- (NKCC1) inhibitor, bumetanide, received two injections of etomidate resulting in anesthesia for 2h. To simulate stress after anesthesia, the animals were exposed to a single maternal separation for 3h at P10. 3-7days after exposure to etomidate the rats had increased hypothalamic NKCC1 mRNA and corticotropin releasing hormone (CRH) mRNA and decreased K+-2Cl- (KCC2) mRNA levels with greater changes in males. In rats neonatally exposed to both etomidate and maternal separation, these abnormalities persisted into adulthood. These animals also exhibited extended corticosterone responses to restraint stress with increases in total plasma corticosterone more robust in males, as well as behavioral abnormalities. Pretreatment with the NKCC1 inhibitor ameliorated most of these effects. CONCLUSIONS Post-anesthesia stressors may exacerbate/unmask neurodevelopmental abnormalities even after a relatively short anesthetic with etomidate, leading to dysregulated stress response systems and neurobehavioral deficiencies in adulthood. Amelioration by bumetanide suggests a mechanistic role for etomidate-enhanced gamma-aminobutyric acid type A receptor-mediated depolarization in initiating long-lasting alterations in gene expression that are further potentiated by subsequent maternal separation.
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Affiliation(s)
- Ling-Sha Ju
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Jiao-Jiao Yang
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Nikolaus Gravenstein
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States
| | - Christoph N Seubert
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Timothy E Morey
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Colin Sumners
- The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States; Department of Physiology and Functional Genomics, University of Florida College of Medicine, Gainesville, FL, United States
| | - Terrie Vasilopoulos
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States
| | - Jian-Jun Yang
- Department of Anesthesiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
| | - Anatoly E Martynyuk
- Department of Anesthesiology, University of Florida College of Medicine, Gainesville, FL, United States; The McKnight Brain Institute, University of Florida College of Medicine, Gainesville, FL, United States.
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Rahmanzadeh R, Eftekhari S, Shahbazi A, Khodaei Ardakani MR, Rahmanzade R, Mehrabi S, Barati M, Joghataei MT. Effect of bumetanide, a selective NKCC1 inhibitor, on hallucinations of schizophrenic patients; a double-blind randomized clinical trial. Schizophr Res 2017; 184:145-146. [PMID: 27956008 DOI: 10.1016/j.schres.2016.12.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 11/28/2016] [Accepted: 12/04/2016] [Indexed: 11/20/2022]
Affiliation(s)
- Reza Rahmanzadeh
- Division of Neuroscience, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Sanaz Eftekhari
- Faculty of Advanced Technologies in Medicine, Department of Neuroscience, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Shahbazi
- Faculty of Advanced Technologies in Medicine, Department of Neuroscience, Iran University of Medical Sciences, Tehran, Iran
| | | | - Ramin Rahmanzade
- Division of Neuroscience, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Soraya Mehrabi
- Division of Neuroscience, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mahmood Barati
- Division of Neuroscience, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Taghi Joghataei
- Division of Neuroscience, Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran.
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40
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Is insulin growth factor-1 the future for treating autism spectrum disorder and/or schizophrenia? Med Hypotheses 2017; 99:23-25. [DOI: 10.1016/j.mehy.2016.12.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2016] [Revised: 12/05/2016] [Accepted: 12/10/2016] [Indexed: 12/14/2022]
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Ben-Ari Y, Damier P, Lemonnier E. Failure of the Nemo Trial: Bumetanide Is a Promising Agent to Treat Many Brain Disorders but Not Newborn Seizures. Front Cell Neurosci 2016; 10:90. [PMID: 27147965 PMCID: PMC4830840 DOI: 10.3389/fncel.2016.00090] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 03/21/2016] [Indexed: 11/13/2022] Open
Abstract
The diuretic bumetanide failed to treat acute seizures due to hypoxic ischemic encephalopathy (HIE) in newborn babies and was associated with hearing loss (NEMO trial, Pressler et al., 2015). On the other hand, clinical and experimental observations suggest that the diuretic might provide novel therapy for many brain disorders including Autism Spectrum Disorders (ASD), schizophrenia, Rett syndrome, and Parkinson disease. Here, we discuss the differences between the pathophysiology of severe recurrent seizures in the neonates and neurological and psychiatric disorders stressing the uniqueness of severe seizures in newborn in comparison to other disorders.
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Affiliation(s)
- Yehezkel Ben-Ari
- INMED - Institut National de la Santé et de la Recherche Médicale U901, Aix-Marseille University Marseilles, France
| | - Philippe Damier
- Institut National de la Santé et de la Recherche Médicale, Centre d'Investigation Clinique 0004 Nantes, France
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