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Xu L, Zhang R, Xue R, Wang L, Ai Z, Li L, Wu W, Wang Z. Regional cerebral blood perfusion impairment in type 1 narcolepsy patients: An arterial spin labeling study. Sleep Med 2025; 129:122-130. [PMID: 40022862 DOI: 10.1016/j.sleep.2025.02.036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 02/09/2025] [Accepted: 02/24/2025] [Indexed: 03/04/2025]
Abstract
OBJECTIVE To investigate the pathophysiological characteristics of cerebral blood flow (CBF) in patients with narcolepsy type 1 (NT1) via the arterial spin labeling (ASL) technique. METHODS Thirty patients with diagnostic NT1 (PTs) and 34 age- and sex-matched healthy controls (HCs) were recruited for this study. Basic information was collected, and clinical evaluation and neuroimaging, including ASL and T1-3DBRAVO, was performed. The z-normalized CBF (zCBF) and spatial coefficient of variation (sCoV) were calculated, and the changes in NT1 were compared via analysis of covariate (ANCOVA). Furthermore, spearman's correlation analysis between impaired regional perfusion and clinical features was performed. Age, sex, and normalized grey matter volume were included as covariates. RESULTS Compared with that of HCs, the zCBF of PTs significantly differed in regions of fronto-temporal-occipital cortex, right insula and posterior insula, and left rostral/dorsal anterior cingulate gyrus (ACG) (P < 0.006). Moreover, the sCoV was significantly altered in the frontotemporal cortex, rostral ACG, right hippocampus, and posterior insula (P < 0.003). In PTs, positive correlations were identified between the zCBF of the right superior/middle frontal gyrus (SFG/MFG) and mean sleep latency, and between the zCBF of the left SFG of the frontal pole and sleep hallucination severity. Moreover, the sCoV of the right MFG/hippocampus were positively associated with Rapid Eye Movement efficiency and negatively associated with Hamilton Anxiety Scale score, respectively. CONCLUSION PTs exhibited abnormal regional perfusion in the frontal-temporal-occipital cortex and limbic system regions, which may serve as patient-specific imaging markers. Alterations in perfusion may lead to the clinical manifestations of underlying psychological and sleep disorders in PTs.
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Affiliation(s)
- Lin Xu
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
| | - Ruilin Zhang
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
| | - Rong Xue
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
| | - Linlin Wang
- Department of Neurology, Tianjin First Central Hospital, Tianjin, China
| | - Zhu Ai
- Department of Neurology, NHC Key Laboratory of Hormones and Development, Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, China
| | - Lili Li
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China
| | - Wei Wu
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China.
| | - Zuojun Wang
- Department of Diagnostic Radiology, University of Hong Kong, China.
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Chung AKK, Tse CY, Yeung GKY, Tang SW, Chan WM, Law JKC. Vortioxetine improves illness severity for cannabis users with anxiety and depressive symptoms in a 6-month randomized controlled study. JOURNAL OF SUBSTANCE USE AND ADDICTION TREATMENT 2025; 169:209607. [PMID: 39672338 DOI: 10.1016/j.josat.2024.209607] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 10/20/2024] [Accepted: 12/09/2024] [Indexed: 12/15/2024]
Abstract
INTRODUCTION Cannabis use and misuse have mental health implications, particularly affecting mood and anxiety symptoms. Vortioxetine, a potent serotonin partial agonist/antagonist reuptake inhibitor antidepressant, has well-established effects in treating depressive and anxiety disorders and may serve as a potential treatment for individuals with cannabis use disorder and comorbid mood symptoms. In the current study, we aimed to investigate the efficacy of vortioxetine for cannabis users with anxiety and depressive symptoms alongside their cannabis dependence. METHODS This 6-month prospective, randomized controlled interventional pilot study investigated if vortioxetine could improve cannabis dependence, comorbid anxiety and/or depressive symptoms, and cognitive and functional outcomes in individuals using cannabis. Participants were randomized to receive either vortioxetine (N = 11) or standard treatment (N = 19). RESULTS Participants taking vortioxetine (mean dose 10 mg/day) showed significant improvement on clinician-observed overall mood states over time (p < .05) but not on their self-reported anxiety or depressive symptoms. Cannabis users receiving standard treatment did not exhibit similar improvement. No significant differences were found on cannabis dependence, cognition and functional outcomes between the two groups otherwise. CONCLUSIONS The results suggest that the multimodal antidepressant vortioxetine may benefit cannabis users with depressive and anxiety symptoms in ameliorating their overall mood state.
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Affiliation(s)
- Albert Kar Kin Chung
- Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong.
| | - Cheuk Yin Tse
- Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Gladys Kwan Yin Yeung
- Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Sau Wan Tang
- Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Wing-Man Chan
- Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Johnson Kai Chun Law
- Department of Psychiatry, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
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Sampson E, Mills NT, Hori H, Cearns M, Schwarte K, Hohoff C, Oliver Schubert K, Fourrier C, Baune BT. Long-term characterisation of the relationship between change in depression severity and change in inflammatory markers following inflammation-stratified treatment with vortioxetine augmented with celecoxib or placebo. Brain Behav Immun 2025; 123:43-56. [PMID: 39243988 DOI: 10.1016/j.bbi.2024.09.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 08/08/2024] [Accepted: 09/03/2024] [Indexed: 09/09/2024] Open
Abstract
BACKGROUND Major depressive disorder (MDD) is a highly prevalent condition with a substantial incidence of relapse or treatment resistance. A subset of patients show evidence of low-grade inflammation, with these patients having a higher likelihood of more severe or difficult to treat courses of illness. Anti-inflammatory treatment of MDD has been investigated with mixed results, and no known studies have included assessments beyond cessation of the anti-inflammatory agent, meaning it remains unknown if any benefit from treatment persists. The objective of the present study was to investigate treatment outcomes up to 29 weeks post-cessation of celecoxib or placebo augmentation of an antidepressant, and how concentrations of selected inflammatory markers change over the same period. METHODS The PREDDICT parallel-group, randomised, double-blind, placebo-controlled trial (University of Adelaide, Australia) ran from December 2017 to April 2020. Participants with MDD were stratified into normal range or elevated inflammation strata according to screening concentrations of high sensitivity C-reactive protein (hsCRP). Participants were randomised to treatment with vortioxetine and celecoxib or vortioxetine and placebo for six weeks, and vortioxetine alone for an additional 29 weeks (35 total weeks). Following a previous publication of results from the six-week RCT phase, exploratory analyses were performed on Montgomery-Åsberg Depression Rating Scale (MADRS) scores, response and remission outcomes, and selected peripheral inflammatory markers across the entire study duration up to week 35. RESULTS Participants retained at each observation were baseline N=119, week 2 N=115, week 4 N=103, week 6 N=104, week 8 N=98, week 22 N=81, and week 35 N=60. Those in the elevated hsCRP celecoxib-augmented group had a statistically significantly greater reduction in MADRS score from baseline to week 35 compared to all other groups, demonstrating the greatest clinical improvement long-term, despite no group or strata differences at preceding time points. Response and remission outcomes did not differ by treatment group or hsCRP strata at any time point. Changes in hsCRP between baseline and week 35 and Tumour Necrosis Factor-α (TNF-α) concentrations between baseline and week 6 and baseline and week 35 were statistically significantly associated with MADRS scores observed at week 6 and week 35 respectively, with reducing TNF-α concentrations associated with reducing MADRS scores and vice versa in each case. A post-hoc stratification of the participant cohort by baseline TNF-α concentrations led to significant prediction by the derived strata on clinical response at weeks 6, 8 and 35, with participants with elevated baseline TNF-α less likely to achieve clinical response. INTERPRETATION The present analysis suggests for the first time a possible longer-term clinical benefit of celecoxib augmentation of vortioxetine in inflammation-associated MDD treatment. However, further research is needed to confirm the finding and to ascertain the reason for such a delayed effect. Furthermore, the trial suggests that TNF-α may have a stronger relationship with anti-inflammatory MDD treatment outcomes than hsCRP, and should be investigated further for potential predictive utility. CLINICAL TRIALS REGISTRATION Australian New Zealand Clinical Trials Registry (ANZCTR), ACTRN12617000527369p. Registered on 11 April 2017, http://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12617000527369p.
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Affiliation(s)
- Emma Sampson
- Discipline of Psychiatry, Adelaide Medical School, University of Adelaide, Adelaide, Australia
| | - Natalie T Mills
- Discipline of Psychiatry, Adelaide Medical School, University of Adelaide, Adelaide, Australia
| | - Hikaru Hori
- Department of Psychiatry, Faculty of Medicine, Fukuoka University, Fukuoka City, Japan
| | - Micah Cearns
- Discipline of Psychiatry, Adelaide Medical School, University of Adelaide, Adelaide, Australia
| | - Kathrin Schwarte
- Department of Psychiatry, University of Münster, Münster, Germany
| | - Christa Hohoff
- Department of Psychiatry, University of Münster, Münster, Germany
| | - K Oliver Schubert
- Discipline of Psychiatry, Adelaide Medical School, University of Adelaide, Adelaide, Australia; Northern Adelaide Mental Health Service, Salisbury, Australia
| | - Célia Fourrier
- Discipline of Psychiatry, Adelaide Medical School, University of Adelaide, Adelaide, Australia
| | - Bernhard T Baune
- Discipline of Psychiatry, Adelaide Medical School, University of Adelaide, Adelaide, Australia; Department of Psychiatry, University of Münster, Münster, Germany; Department of Psychiatry, Melbourne Medical School, The University of Melbourne, Melbourne, Australia; The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, VIC, Australia.
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Stanisavljević Ilić A, Filipović D. Mapping of c-Fos Expression in Rat Brain Sub/Regions Following Chronic Social Isolation: Effective Treatments of Olanzapine, Clozapine or Fluoxetine. Pharmaceuticals (Basel) 2024; 17:1527. [PMID: 39598437 PMCID: PMC11597560 DOI: 10.3390/ph17111527] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2024] [Revised: 11/07/2024] [Accepted: 11/12/2024] [Indexed: 11/29/2024] Open
Abstract
The c-Fos as a marker of cell activation is used to identify brain regions involved in stimuli processing. This review summarizes a pattern of c-Fos immunoreactivity and the overlapping brain sub/regions which may provide hints for the identification of neural circuits that underlie depressive- and anxiety-like behaviors of adult male rats following three and six weeks of chronic social isolation (CSIS), relative to controls, as well as the antipsychotic-like effects of olanzapine (Olz), and clozapine (Clz), and the antidepressant-like effect of fluoxetine (Flx) in CSIS relative to CSIS alone. Additionally, drug-treated controls relative to control rats were also characterized. The overlapping rat brain sub/regions with increased expression of c-Fos immunoreactivity following three or six weeks of CSIS were the retrosplenial granular cortex, c subregion, retrosplenial dysgranular cortex, dorsal dentate gyrus, paraventricular nucleus of the thalamus (posterior part, PVP), lateral/basolateral (LA/BL) complex of the amygdala, caudate putamen, and nucleus accumbens shell. Increased activity of the nucleus accumbens core following exposure of CSIS rats either to Olz, Clz, and Flx treatments was found, whereas these treatments in controls activated the LA/BL complex of the amygdala and PVP. We also outline sub/regions that might represent potential neuroanatomical targets for the aforementioned antipsychotics or antidepressant treatments.
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Affiliation(s)
| | - Dragana Filipović
- Department of Molecular Biology and Endocrinology, “VINČA” Institute of Nuclear Sciences, National Institute of the Republic of Serbia, University of Belgrade, 11000 Belgrade, Serbia;
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Akotkar L, Aswar U, Ganeshpurkar A, Rathod K, Bagad P, Gurav S. Phytoconstituents Targeting the Serotonin 5-HT 3 Receptor: Promising Therapeutic Strategies for Neurological Disorders. ACS Pharmacol Transl Sci 2024; 7:1694-1710. [PMID: 38898946 PMCID: PMC11184608 DOI: 10.1021/acsptsci.4c00084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 05/17/2024] [Accepted: 05/21/2024] [Indexed: 06/21/2024]
Abstract
The 5-hydroxytryptamine-3 receptor (5-HT3R), a subtype of serotonin receptor, is a ligand-gated ion channel crucial in mediating fast synaptic transmission in the central and peripheral nervous systems. This receptor significantly influences various neurological activities, encompassing neurotransmission, mood regulation, and cognitive processing; hence, it may serve as an innovative target for neurological disorders. Multiple studies have revealed promising results regarding the beneficial effects of these phytoconstituents and extracts on conditions such as nausea, vomiting, neuropathic pain depression, anxiety, Alzheimer's disease, cognition, epilepsy, sleep, and dyskinesia via modulation of 5-HT3R in the pathophysiology of neurological disorder. The review delves into a detailed exploration of in silico, in vitro, and in vivo studies and clinical studies that discussed phytoconstituents acting on 5-HT3R and attenuates difficulties in neurological diseases. The diverse mechanisms by which plant-derived phytoconstituents influence 5-HT3R activity offer exciting avenues for developing innovative therapeutic interventions. Besides producing an agonistic or antagonistic effect, some phytoconstituents exert modulatory effects on 5-HT3R activity through multifaceted mechanisms. These include γ-aminobutyric acid and cholinergic neuronal pathways, interactions with neurokinin (NK)-1, NK2, serotonergic, and γ-aminobutyric acid(GABA)ergic systems, dopaminergic influences, and mediation of calcium ions release and inflammatory cascades. Notably, the phytoconstituent's capacity to reduce oxidative stress has also emerged as a significant factor contributing to their modulatory role. Despite the promising implications, there is currently a dearth of exploration needed to understand the effect of phytochemicals on the 5-HT3R. Comprehensive preclinical and clinical research is of the utmost importance to broaden our knowledge of the potential therapeutic benefits associated with these substances.
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Affiliation(s)
- Likhit Akotkar
- Department
of Pharmacology, Poona College of Pharmacy,
Bharati Vidyapeeth (Deemed to be University), Pune 411038, India
| | - Urmila Aswar
- Department
of Pharmacology, Poona College of Pharmacy,
Bharati Vidyapeeth (Deemed to be University), Pune 411038, India
| | - Ankit Ganeshpurkar
- Department
of Pharmaceutical Chemistry, Poona College
of Pharmacy, Bharati Vidyapeeth (Deemed to be University), Pune411038, India
| | - Kundlik Rathod
- Department
of Pharmacology, Poona College of Pharmacy,
Bharati Vidyapeeth (Deemed to be University), Pune 411038, India
| | - Pradnya Bagad
- Department
of Pharmacology, Poona College of Pharmacy,
Bharati Vidyapeeth (Deemed to be University), Pune 411038, India
| | - Shailendra Gurav
- Department
of Pharmacognosy, Goa College of Pharmacy, Goa University, Goa 403001, India
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Al-Kachak A, Di Salvo G, Fulton SL, Chan JC, Farrelly LA, Lepack AE, Bastle RM, Kong L, Cathomas F, Newman EL, Menard C, Ramakrishnan A, Safovich P, Lyu Y, Covington HE, Shen L, Gleason K, Tamminga CA, Russo SJ, Maze I. Histone serotonylation in dorsal raphe nucleus contributes to stress- and antidepressant-mediated gene expression and behavior. Nat Commun 2024; 15:5042. [PMID: 38871707 PMCID: PMC11176395 DOI: 10.1038/s41467-024-49336-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Accepted: 05/28/2024] [Indexed: 06/15/2024] Open
Abstract
Mood disorders are an enigmatic class of debilitating illnesses that affect millions of individuals worldwide. While chronic stress clearly increases incidence levels of mood disorders, including major depressive disorder (MDD), stress-mediated disruptions in brain function that precipitate these illnesses remain largely elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with depressive symptoms, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding direct roles for serotonin in the precipitation and treatment of affective disorders. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this non-canonical phenomenon has not yet been explored following stress and/or AD exposures. Here, we employed a combination of genome-wide and biochemical analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress, as well as in DRN of human MDD patients, to examine the impact of stress exposures/MDD diagnosis on H3K4me3Q5ser dynamics, as well as associations between the mark and depression-related gene expression. We additionally assessed stress-induced/MDD-associated regulation of H3K4me3Q5ser following AD exposures, and employed viral-mediated gene therapy in mice to reduce H3K4me3Q5ser levels in DRN and examine its impact on stress-associated gene expression and behavior. We found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity. Chronically stressed mice displayed dysregulated H3K4me3Q5ser dynamics in DRN, with both AD- and viral-mediated disruption of these dynamics proving sufficient to attenuate stress-mediated gene expression and behavior. Corresponding patterns of H3K4me3Q5ser regulation were observed in MDD subjects on vs. off ADs at their time of death. These findings thus establish a neurotransmission-independent role for serotonin in stress-/AD-associated transcriptional and behavioral plasticity, observations of which may be of clinical relevance to human MDD and its treatment.
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Affiliation(s)
- Amni Al-Kachak
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Giuseppina Di Salvo
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
- Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNs), Maastricht University, Maastricht, The Netherlands
| | - Sasha L Fulton
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Jennifer C Chan
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Lorna A Farrelly
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Ashley E Lepack
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Ryan M Bastle
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Lingchun Kong
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Flurin Cathomas
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Emily L Newman
- Department of Psychiatry, McLean Hospital and Harvard Medical School, Belmont, MA, 02478, USA
| | - Caroline Menard
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Aarthi Ramakrishnan
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Polina Safovich
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Yang Lyu
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Herbert E Covington
- Department of Psychology, Empire State College, State University of New York, Saratoga Springs, NY, 12866, USA
| | - Li Shen
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Kelly Gleason
- Department of Psychiatry, University of Texas Southwestern Medical School, Dallas, TX, 75390, USA
| | - Carol A Tamminga
- Department of Psychiatry, University of Texas Southwestern Medical School, Dallas, TX, 75390, USA
| | - Scott J Russo
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA
| | - Ian Maze
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
- Howard Hughes Medical Institute, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.
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Orimaye SO, Schmidtke KA. Combining artificial neural networks and a marginal structural model to predict the progression from depression to Alzheimer's disease. FRONTIERS IN DEMENTIA 2024; 3:1362230. [PMID: 39081615 PMCID: PMC11285640 DOI: 10.3389/frdem.2024.1362230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2023] [Accepted: 03/21/2024] [Indexed: 08/02/2024]
Abstract
Introduction Decades of research in population health have established depression as a likely precursor to Alzheimer's disease. A combination of causal estimates and machine learning methods in artificial intelligence could identify internal and external mediating mechanisms that contribute to the likelihood of progression from depression to Alzheimer's disease. Methods We developed an integrated predictive model, combining the marginal structural model and an artificial intelligence predictive model, distinguishing between patients likely to progress from depressive states to Alzheimer's disease better than each model alone. Results The integrated predictive model achieved substantial clinical relevance when using the area under the curve measure. It performed better than the traditional statistical method or a single artificial intelligence method alone. Discussion The integrated predictive model could form a part of a clinical screening tool that identifies patients who are likely to progress from depression to Alzheimer's disease for early behavioral health interventions. Given the high costs of treating Alzheimer's disease, our model could serve as a cost-effective intervention for the early detection of depression before it progresses to Alzheimer's disease.
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Affiliation(s)
- Sylvester O. Orimaye
- College of Global Population Health, University of Health Sciences and Pharmacy, St. Louis, MO, United States
| | - Kelly A. Schmidtke
- College of Arts and Sciences, University of Health Sciences and Pharmacy, St. Louis, MO, United States
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Adeoluwa OA, Eduviere AT, Adeoluwa GO, Otomewo LO, Adeniyi FR. The monoaminergic pathways are involved in the antidepressant-like effect of quercetin. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2024; 397:2497-2506. [PMID: 37851059 DOI: 10.1007/s00210-023-02789-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Accepted: 10/12/2023] [Indexed: 10/19/2023]
Abstract
Quercetin, a plant-derived flavonoid, is an antioxidant and has demonstrated antidepressant and anti-inflammatory activities in several animal models. However, there is scanty information on the underlying mechanisms of its antidepressant property. This present study aimed at assessing the involvement of monoaminergic systems in the antidepressant-like activity of quercetin in experimental animals. Mice received varying doses of quercetin (25, 50 &100 mg/kg daily) and were then subjected to open field test (OPF), despair tests, the reserpine test, and the yohimbine lethality test (YLT). In addition, monoaminergic involvement was investigated by combining quercetin (100 mg/kg) with dopaminergic antagonists (haloperidol and sulpiride), adrenergic blockers (prazosin, propranolol and yohimbine), and serotonergic blockers/inhibitors (metergoline). The results showed that quercetin produced significant anti-immobility effects in the forced swim test (FST) and tail suspension test (TST), suggesting antidepressant activity. In addition, the potentiation of yohimbine lethality by quercetin further indicates its antidepressant-like property. This antidepressant action demonstrated was, however, blocked when quercetin was co-administered with dopaminergic, adrenergic and serotonergic antagonists, suggesting involvement of the monoaminergic system in the antidepressant action of quercetin. Nevertheless, quercetin did not significantly alter the locomotor activity of mice, which implies lack of stimulant effect. Taken together, these outcomes suggest that monoaminergic systems are likely involved in the anti-depressant effect of quercetin in mice.
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Affiliation(s)
- Olusegun Adebayo Adeoluwa
- Department of Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria.
| | - Anthony Taghogho Eduviere
- Department of Pharmacology, Faculty of Basic Medical Sciences, Delta State University, Abraka, Delta State, Nigeria
| | - Gladys Onyinye Adeoluwa
- Department of Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria
| | - Lily Oghenevovwero Otomewo
- Department of Pharmacology and Therapeutics, Faculty of Basic Clinical Sciences, College of Medicine and Health Sciences, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria
| | - Funmilayo Racheal Adeniyi
- Department of Pharmacology and Toxicology, College of Pharmacy, Afe Babalola University, Ado-Ekiti, Ekiti State, Nigeria
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9
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Obermanns J, Meiser H, Hoberg S, Vesterager CS, Schulz F, Juckel G, Emons B. Genetic variation of the 5-HT1A rs6295, 5-HT2A rs6311, and CNR1 rs1049353 and an altered endocannabinoid system in depressed patients. Brain Behav 2023; 13:e3323. [PMID: 37984468 PMCID: PMC10726863 DOI: 10.1002/brb3.3323] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 10/16/2023] [Accepted: 10/31/2023] [Indexed: 11/22/2023] Open
Abstract
BACKGROUND The reasons for developing depression are not fully understood. However, it is known that the serotonergic system plays a role in the etiology, but the endocannabinoid system receives attention. METHOD In this study, 161 patients with a depressive disorder and 161 healthy participants were examined for the distribution of the CNR1 rs4940353, 5-HT2A rs6311, and 5-HT1A rs6295 by high-resolution melting genotyping. The concentration of arachidonoyl ethanolamide (AEA) and 2-arachidonoylglycerol (2-AG) in the blood was measured by liquid chromatography-tandem mass spectrometry. Additionally, depression and anxiety symptoms were evaluated based on self-questionnaires. Fifty-nine patients participated in a second appointment to measure the concentration of AEA, 2-AG, and symptoms of depression and anxiety. RESULTS We observed higher AEA and decreased 2-AG concentrations in patients with depression compared to healthy participants. During the treatment, the concentrations of AEA and 2-AG did not change significantly. In patients higher symptoms of anxiety correlated with lower concentrations of 2-AG. Gender differences were found concerning increased 2-AG concentration in male patients and increased anxiety symptoms in female patients. Genotypic variations of 5-HT1A rs6295 and 5-HT2A rs6311 are associated with altered serotonergic activity and serotonin content in patients. CONCLUSION In conclusion, it seems that the endocannabinoid system, especially the endocannabinoids 2-AG and AEA, and genetic variations of the 5-HT1A and 5-HT2A could play a role in patients with depression and may be involved in a depressive disorder.
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Affiliation(s)
- Jasmin Obermanns
- LWL University HospitalDepartment of PsychiatryPsychotherapy and Preventive MedicineRuhr University BochumBochumGermany
| | - Hanna Meiser
- LWL University HospitalDepartment of PsychiatryPsychotherapy and Preventive MedicineRuhr University BochumBochumGermany
| | - Saskia Hoberg
- LWL University HospitalDepartment of PsychiatryPsychotherapy and Preventive MedicineRuhr University BochumBochumGermany
| | | | - Frank Schulz
- Chemistry and Biochemistry of Natural ProductsRuhr University BochumBochumGermany
| | - Georg Juckel
- LWL University HospitalDepartment of PsychiatryPsychotherapy and Preventive MedicineRuhr University BochumBochumGermany
| | - Barbara Emons
- LWL University HospitalDepartment of PsychiatryPsychotherapy and Preventive MedicineRuhr University BochumBochumGermany
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Zhao Y, Wang S, Pan J, Ma K. Verbascoside: A neuroprotective phenylethanoid glycosides with anti-depressive properties. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 120:155027. [PMID: 37657207 DOI: 10.1016/j.phymed.2023.155027] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 07/31/2023] [Accepted: 08/14/2023] [Indexed: 09/03/2023]
Abstract
BACKGROUND Verbascoside is a natural and water-soluble phenylethanoid glycoside found in several medicinal plants. It has extensive pharmacological effects, including antioxidative and antineoplastic actions, and a wide range of therapeutic effects against depression. PURPOSE In this review, we appraised preclinical and limited clinical evidence to fully discuss the anti-depression capacity of verbascoside and its holistic characteristics that can contribute to better management of depression in vivo and in vitro models, as well as, its toxicities and medicinal value. METHODS This review was prepared according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A systematic review of 32 preclinical trials published up to April 2023, combined with a comprehensive bioinformatics analysis of network pharmacology and molecular docking, was conducted to elucidate the antidepressant mechanism of action of verbascoside. Studies included in the systematic review were obtained from 7 electronic databases: PubMed, Scopus, Web of Science, Cochrane, ResearchGate, ScienceDirect, and Google Scholar. RESULTS Studies on the antidepressant effects of verbascoside showed that various pharmacological mechanisms and pathways, such as modulating the levels of monoamine neurotransmitters, inhibiting hypothalamic-pituitary-adrenal (HPA) axis hyperfunction and promoting neuroprotection may be involved in the process of its action against depression. Verbascoside promotes dopamine (DA) biosynthesis by promoting the expression of tyrosine hydroxylase mRNA and protein, upregulates the expression of 5-hydroxytryptamine receptor 1B (5-HT1B), prominence protein, microtubule-associated protein 2 (MAP2), hemeoxygenase-1 (HO-1), SQSTM1, Recombinant Autophagy Related Protein 5 (ATG5) and Beclin-1, and decreases the expression of caspase-3 and a-synuclein, thus exerting antidepressant effects. We identified seven targets (CCL2, FOS, GABARAPL1, CA9, TYR, CA12, and SQSTM1) and three signaling pathways (glutathione metabolism, metabolism of xenobiotics by cytochrome P450, fluid shear stress and atherosclerosis) as potential molecular biological sites for verbascoside. CONCLUSIONS These findings provide strong evidence that verbascoside exerts its antidepressant effects through various pharmacological mechanisms. However, further multicentre clinical case-control and molecularly targeted fishing studies are required to confirm the clinical efficacy of verbascoside and its underlying direct targets.
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Affiliation(s)
- Yi Zhao
- Shandong Co-Innovation Center of Classic TCM Formula, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Sijia Wang
- Shandong Co-Innovation Center of Classic TCM Formula, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Jin Pan
- Shandong Co-Innovation Center of Classic TCM Formula, Shandong University of Traditional Chinese Medicine, Jinan 250355, China
| | - Ke Ma
- Shandong Co-Innovation Center of Classic TCM Formula, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
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11
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Piao J, Wang Y, Zhang T, Zhao J, Lv Q, Ruan M, Yu Q, Li B. Antidepressant-like Effects of Representative Types of Food and Their Possible Mechanisms. Molecules 2023; 28:6992. [PMID: 37836833 PMCID: PMC10574116 DOI: 10.3390/molecules28196992] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 09/22/2023] [Accepted: 09/30/2023] [Indexed: 10/15/2023] Open
Abstract
Depression is a mental disorder characterized by low mood, lack of motivation, negative cognitive outlook, and sleep problems. Suicide may occur in severe cases, although suicidal thoughts are not seen in all cases. Globally, an estimated 350 million individuals grapple with depression, as reported by the World Health Organization. At present, drug and psychological treatments are the main treatments, but they produce insufficient responses in many patients and fail to work at all in many others. Consequently, treating depression has long been an important topic in society. Given the escalating prevalence of depression, a comprehensive strategy for managing its symptoms and impacts has garnered significant attention. In this context, nutritional psychiatry emerges as a promising avenue. Extensive research has underscored the potential benefits of a well-rounded diet rich in fruits, vegetables, fish, and meat in alleviating depressive symptoms. However, the intricate mechanisms linking dietary interventions to brain function alterations remain largely unexplored. This review delves into the intricate relationship between dietary patterns and depression, while exploring the plausible mechanisms underlying the impact of dietary interventions on depression management. As we endeavor to unveil the pathways through which nutrition influences mental well-being, a holistic perspective that encompasses multidisciplinary strategies gains prominence, potentially reshaping how we approach and address depression.
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Affiliation(s)
- Jingjing Piao
- Jilin Provincial Key Laboratory for Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun 130041, China; (J.P.); (T.Z.); (J.Z.); (Q.L.); (M.R.); (Q.Y.)
- Engineering Laboratory for Screening of Antidepressant Drugs, Jilin Province Development and Reform Commission, Changchun 130041, China
| | - Yingwei Wang
- Changchun Zhuoyi Biological Co., Ltd., Changchun 130616, China;
| | - Tianqi Zhang
- Jilin Provincial Key Laboratory for Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun 130041, China; (J.P.); (T.Z.); (J.Z.); (Q.L.); (M.R.); (Q.Y.)
- Engineering Laboratory for Screening of Antidepressant Drugs, Jilin Province Development and Reform Commission, Changchun 130041, China
| | - Jiayu Zhao
- Jilin Provincial Key Laboratory for Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun 130041, China; (J.P.); (T.Z.); (J.Z.); (Q.L.); (M.R.); (Q.Y.)
- Engineering Laboratory for Screening of Antidepressant Drugs, Jilin Province Development and Reform Commission, Changchun 130041, China
| | - Qianyu Lv
- Jilin Provincial Key Laboratory for Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun 130041, China; (J.P.); (T.Z.); (J.Z.); (Q.L.); (M.R.); (Q.Y.)
- Engineering Laboratory for Screening of Antidepressant Drugs, Jilin Province Development and Reform Commission, Changchun 130041, China
| | - Mengyu Ruan
- Jilin Provincial Key Laboratory for Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun 130041, China; (J.P.); (T.Z.); (J.Z.); (Q.L.); (M.R.); (Q.Y.)
- Engineering Laboratory for Screening of Antidepressant Drugs, Jilin Province Development and Reform Commission, Changchun 130041, China
| | - Qin Yu
- Jilin Provincial Key Laboratory for Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun 130041, China; (J.P.); (T.Z.); (J.Z.); (Q.L.); (M.R.); (Q.Y.)
- Engineering Laboratory for Screening of Antidepressant Drugs, Jilin Province Development and Reform Commission, Changchun 130041, China
| | - Bingjin Li
- Jilin Provincial Key Laboratory for Molecular and Chemical Genetics, The Second Hospital of Jilin University, Changchun 130041, China; (J.P.); (T.Z.); (J.Z.); (Q.L.); (M.R.); (Q.Y.)
- Engineering Laboratory for Screening of Antidepressant Drugs, Jilin Province Development and Reform Commission, Changchun 130041, China
- Jilin Provincial Key Laboratory on Target of Traditional Chinese Medicine with Anti-Depressive Effect, Changchun 130041, China
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12
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Kim S, Doukmak EJ, Shanguhyia M, Gray DJ, Steinhardt RC. Photoactivatable Agonist-Antagonist Pair as a Tool for Precise Spatiotemporal Control of Serotonin Receptor 2C Signaling. ACS Chem Neurosci 2023; 14:3665-3673. [PMID: 37721710 PMCID: PMC10557072 DOI: 10.1021/acschemneuro.3c00290] [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: 05/02/2023] [Accepted: 09/01/2023] [Indexed: 09/19/2023] Open
Abstract
Orthogonal recreation of the signaling profile of a chemical synapse is a current challenge in neuroscience. This is due in part to the kinetics of synaptic signaling, where neurotransmitters are rapidly released and quickly cleared by active reuptake machinery. One strategy to produce a rapid rise in an orthogonally controlled signal is via photocaged compounds. In this work, photocaged compounds are employed to recreate both the rapid rise and equally rapid fall in activation at a chemical synapse. Specifically, a complementary pair of photocages based on BODIPY were conjugated to a 5-HT2C subtype-selective agonist, WAY-161503, and antagonist, N-desmethylclozapine, to generate "caged" versions of these drugs. These conjugates release the bioactive drug upon illumination with green light (agonist) or red light (antagonist). We report on the synthesis, characterization, and bioactivity testing of the conjugates against the 5-HT2C receptor. We then characterize the kinetics of photolysis quantitatively using HPLC and qualitatively in cell culture conditions stimulating live cells. The compounds are shown to be stable in the dark for 48 h at room temperature, yet photolyze rapidly when irradiated with visible light. In live cells expressing the 5-HT2C receptor, precise spatiotemporal control of the degree and length of calcium signaling is demonstrated. By loading both compounds in tandem and leveraging spectral multiplexing as a noninvasive method to control local small-molecule drug availability, we can reproducibly initiate and suppress intracellular calcium flux on a timescale not possible by traditional methods of drug dosing. These tools enable a greater spatiotemporal control of 5-HT2C modulation and will allow for more detailed studies of the receptors' signaling, interactions with other proteins, and native physiology.
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Affiliation(s)
- Spencer
T. Kim
- Syracuse University, Syracuse, New York 13244, United States
| | - Emma J. Doukmak
- Syracuse University, Syracuse, New York 13244, United States
| | | | - Dylan J. Gray
- Syracuse University, Syracuse, New York 13244, United States
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Al-Kachak A, Fulton SL, Di Salvo G, Chan JC, Farrelly LA, Lepack AE, Bastle RM, Kong L, Cathomas F, Newman EL, Menard C, Ramakrishnan A, Safovich P, Lyu Y, Covington HE, Shen L, Gleason K, Tamminga CA, Russo SJ, Maze I. Histone H3 serotonylation dynamics in dorsal raphe nucleus contribute to stress- and antidepressant-mediated gene expression and behavior. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.05.04.539464. [PMID: 37205414 PMCID: PMC10187276 DOI: 10.1101/2023.05.04.539464] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/21/2023]
Abstract
Background Major depressive disorder (MDD), along with related mood disorders, is a debilitating illness that affects millions of individuals worldwide. While chronic stress increases incidence levels of mood disorders, stress-mediated disruptions in brain function that precipitate these illnesses remain elusive. Serotonin-associated antidepressants (ADs) remain the first line of therapy for many with depressive symptoms, yet low remission rates and delays between treatment and symptomatic alleviation have prompted skepticism regarding precise roles for serotonin in the precipitation of mood disorders. Our group recently demonstrated that serotonin epigenetically modifies histone proteins (H3K4me3Q5ser) to regulate transcriptional permissiveness in brain. However, this phenomenon has not yet been explored following stress and/or AD exposures. Methods We employed a combination of genome-wide and biochemical analyses in dorsal raphe nucleus (DRN) of male and female mice exposed to chronic social defeat stress to examine the impact of stress exposures on H3K4me3Q5ser dynamics, as well as associations between the mark and stress-induced gene expression. We additionally assessed stress-induced regulation of H3K4me3Q5ser following AD exposures, and employed viral-mediated gene therapy to reduce H3K4me3Q5ser levels in DRN and examine the impact on stress-associated gene expression and behavior. Results We found that H3K4me3Q5ser plays important roles in stress-mediated transcriptional plasticity. Chronically stressed mice displayed dysregulated H3K4me3Q5ser dynamics in DRN, with both AD- and viral-mediated disruption of these dynamics proving sufficient to rescue stress-mediated gene expression and behavior. Conclusions These findings establish a neurotransmission-independent role for serotonin in stress-/AD-associated transcriptional and behavioral plasticity in DRN.
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Affiliation(s)
- Amni Al-Kachak
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Sasha L. Fulton
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Giuseppina Di Salvo
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Jennifer C Chan
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Lorna A. Farrelly
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Ashley E. Lepack
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Ryan M. Bastle
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Lingchun Kong
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Flurin Cathomas
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Emily L. Newman
- Department of Psychiatry, McLean Hospital and Harvard Medical School, Belmont, MA 02478, USA
| | - Caroline Menard
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Aarthi Ramakrishnan
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Polina Safovich
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Yang Lyu
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Herbert E. Covington
- Department of Psychology, Empire State College, State University of New York, Saratoga Springs, NY 12866
| | - Li Shen
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Kelly Gleason
- Department of Psychiatry, University of Texas Southwestern Medical School, Dallas, TX, 75390, USA
| | - Carol A. Tamminga
- Department of Psychiatry, University of Texas Southwestern Medical School, Dallas, TX, 75390, USA
| | - Scott J. Russo
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
| | - Ian Maze
- Nash Family Department of Neuroscience, Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
- Howard Hughes Medical Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA
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Cao M, Xu T, Zhang H, Wei S, Wang H, Song Y, Guo X, Chen D, Yin D. BDE-47 Causes Depression-like Effects in Zebrafish Larvae via a Non-Image-Forming Visual Mechanism. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2023. [PMID: 37354122 DOI: 10.1021/acs.est.3c01716] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/26/2023]
Abstract
Depression is a high-incidence mood disorder that is frequently accompanied by sleep disturbances, which can be triggered by the non-image-forming (NIF) visual system. Therefore, we hypothesize that polybrominated diphenyl ethers are known to induce visual impairment that could promote depression by disrupting the NIF visual pathway. In this study, zebrafish larvae were exposed to BDE-47 at environmentally relevant concentrations (2.5 and 25 μg/L). BDE-47 caused melanopsin genes that dominate the NIF visual system that fell at night (p < 0.05) but rose in the morning (p < 0.05). Such bidirectional difference transmitted to clock genes and neuropeptides in the suprachiasmatic nucleus and impacted the adjacent serotonin system. However, indicative factors of depression, including serta, htr1aa, and aanat2, were unidirectionally increased 1.3- to 1.6-fold (p < 0.05). They were consistent with the increase in nighttime thigmotaxis (p < 0.05) and circadian hypoactivity (p < 0.05). The results of melanopsin antagonism also indicated that these consequences were possibly due to the combination of direct photoentrainment by melanopsin and circadian disruption originating from melanopsin. Collectively, our findings revealed that BDE-47 exposure disrupted the NIF visual pathway and resulted in depression-like effects, which may further exert profound health effects like mood disorders.
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Affiliation(s)
- Miao Cao
- Key Laboratory of Yangtze River Water Environment, Ministry of Education, College of Environmental Science and Engineering, Tongji University, Shanghai 200092, China
| | - Ting Xu
- Key Laboratory of Yangtze River Water Environment, Ministry of Education, College of Environmental Science and Engineering, Tongji University, Shanghai 200092, China
- Shanghai Institute of Pollution Control and Ecological Security, Shanghai 200092, China
| | - Hongchang Zhang
- Shanghai Academy of Environmental Sciences, Shanghai 200233, China
| | - Sheng Wei
- Key Laboratory of Yangtze River Water Environment, Ministry of Education, College of Environmental Science and Engineering, Tongji University, Shanghai 200092, China
| | - Huan Wang
- Key Laboratory of Yangtze River Water Environment, Ministry of Education, College of Environmental Science and Engineering, Tongji University, Shanghai 200092, China
| | - Yiqun Song
- Key Laboratory of Yangtze River Water Environment, Ministry of Education, College of Environmental Science and Engineering, Tongji University, Shanghai 200092, China
| | - Xueping Guo
- Key Laboratory of Yangtze River Water Environment, Ministry of Education, College of Environmental Science and Engineering, Tongji University, Shanghai 200092, China
- Shanghai Institute of Pollution Control and Ecological Security, Shanghai 200092, China
| | - Da Chen
- School of Environment and Guangdong Key Laboratory of Environmental Pollution and Health, Jinan University, Guangzhou 510632, China
| | - Daqiang Yin
- Key Laboratory of Yangtze River Water Environment, Ministry of Education, College of Environmental Science and Engineering, Tongji University, Shanghai 200092, China
- Shanghai Institute of Pollution Control and Ecological Security, Shanghai 200092, China
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15
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Vasiliu O. Efficacy, Tolerability, and Safety of Toludesvenlafaxine for the Treatment of Major Depressive Disorder-A Narrative Review. Pharmaceuticals (Basel) 2023; 16:411. [PMID: 36986510 PMCID: PMC10051807 DOI: 10.3390/ph16030411] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 03/05/2023] [Accepted: 03/06/2023] [Indexed: 03/12/2023] Open
Abstract
The estimated rate of treatment-resistant major depressive disorder (TRD) remains higher than 30%, even after the discovery of multiple classes of antidepressants in the last 7 decades. Toludesvenlafaxine (ansofaxine, LY03005, or LPM570065) is a first-in-class triple monoaminergic reuptake inhibitor (TRI) that has reached clinical use. The objective of this narrative review was to summarize clinical and preclinical evidence about the efficacy, tolerability, and safety of toludesvenlafaxine. Based on the results of 17 reports retrieved in the literature, the safety and tolerability profiles of toludesvenlafaxine were good in all clinical trials, and the pharmacokinetic parameters were well described in the phase 1 trials. The efficacy of toludesvenlafaxine was demonstrated in one phase 2 and one phase 3 trial, both on primary and secondary outcomes. In conclusion, this review highlights the favorable clinical results of toludesvenlafaxine in only two short-term trials that enrolled patients with major depressive disorder (MDD) (efficacy and tolerability were good for up to eight weeks), indicating the need for more good quality, larger-sample, and longer-term trials. Exploring new antidepressants, such as TRI, can be considered a priority for clinical research due to the high rates of TRD, but also due to the significant percentages of relapse in patients with MDD.
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Affiliation(s)
- Octavian Vasiliu
- Department of Psychiatry, Dr. Carol Davila University Emergency Central Military Hospital, 010825 Bucharest, Romania
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16
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Dorsal raphe serotonergic neurons preferentially reactivate dorsal dentate gyrus cell ensembles associated with positive experience. Cell Rep 2023; 42:112149. [PMID: 36821440 DOI: 10.1016/j.celrep.2023.112149] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 11/24/2022] [Accepted: 02/06/2023] [Indexed: 02/24/2023] Open
Abstract
Major depressive disorder (MDD) is among the most common mental illnesses. Serotonergic (5-HT) neurons are central to the pathophysiology and treatment of MDD. Repeatedly recalling positive episodes is effective for MDD. Stimulating 5-HT neurons of the dorsal raphe nucleus (DRN) or neuronal ensembles in the dorsal dentate gyrus (dDG) associated with positive memories reverses the stress-induced behavioral abnormalities. Despite this phenotypic similarity, their causal relationship is unclear. This study revealed that the DRN 5-HT neurons activate dDG neurons; surprisingly, this activation was specifically observed in positive memory ensembles rather than neutral or negative ensembles. Furthermore, we revealed that dopaminergic signaling induced by activation of DRN 5-HT neurons projecting to the ventral tegmental area mediates an increase in active coping behavior and positive dDG ensemble reactivation. Our study identifies a role of DRN 5-HT neurons as specific reactivators of positive memories and provides insights into how serotonin elicits antidepressive effects.
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da Rocha MJ, Pires CS, Presa MH, Besckow EM, Nunes GD, Gomes CS, Penteado F, Lenardão EJ, Bortolatto CF, Brüning CA. Involvement of the serotonergic system in the antidepressant-like effect of 1-(phenylselanyl)-2-(p-tolyl)indolizine in mice. Psychopharmacology (Berl) 2023; 240:373-389. [PMID: 36645465 DOI: 10.1007/s00213-023-06313-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 01/05/2023] [Indexed: 01/17/2023]
Abstract
RATIONALE Depression is a mental disorder that affects approximately 280 million people worldwide. In the search for new treatments for mood disorders, compounds containing selenium and indolizine derivatives show promising results. OBJECTIVES AND METHODS To evaluate the antidepressant-like effect of 1-(phenylselanyl)-2-(p-tolyl)indolizine (MeSeI) (0.5-50 mg/kg, intragastric-i.g.) on the tail suspension test (TST) and the forced swim test (FST) in adult male Swiss mice and to elucidate the role of the serotonergic system in this effect through pharmacological and in silico approaches, as well to evaluate acute oral toxicity at a high dose (300 mg/kg). RESULTS MeSeI administered 30 min before the FST and the TST reduced immobility time at doses from 1 mg/kg and at 50 mg/kg and increased the latency time for the first episode of immobility, demonstrating an antidepressant-like effect. In the open field test (OFT), MeSeI did not change the locomotor activity. The antidepressant-like effect of MeSeI (50 mg/kg, i.g.) was prevented by the pre-treatment with p-chlorophenylalanine (p-CPA), a selective tryptophan hydroxylase inhibitor (100 mg/kg, intraperitoneally-i.p. for 4 days), with ketanserin, a 5-HT2A/2C receptor antagonist (1 mg/kg, i.p.), and with GR113808, a 5-HT4 receptor antagonist (0.1 mg/kg, i.p.), but not with WAY100635, a selective 5-HT1A receptor antagonist (0.1 mg/kg, subcutaneous-s.c.) and ondansetron, a 5-HT3 receptor antagonist (1 mg/kg, i.p.). MeSeI showed a binding affinity with 5-HT2A, 5 -HT2C, and 5-HT4 receptors by molecular docking. MeSeI (300 mg/kg, i.g.) demonstrated low potential to cause acute toxicity in adult female Swiss mice. CONCLUSION In summary, MeSeI exhibits an antidepressant-like effect mediated by the serotonergic system and could be considered for the development of new treatment strategies for depression.
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Affiliation(s)
- Marcia Juciele da Rocha
- Laboratory of Biochemistry and Molecular Neuropharmacology (LABIONEM), Postgraduate Program in Biochemistry and Bioprospecting (PPGBBio), Center of Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas (UFPel), Capão Do Leão Campus, Pelotas, RS, 96010-900, Brazil
| | - Camila Simões Pires
- Laboratory of Biochemistry and Molecular Neuropharmacology (LABIONEM), Postgraduate Program in Biochemistry and Bioprospecting (PPGBBio), Center of Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas (UFPel), Capão Do Leão Campus, Pelotas, RS, 96010-900, Brazil
| | - Marcelo Heinemann Presa
- Laboratory of Biochemistry and Molecular Neuropharmacology (LABIONEM), Postgraduate Program in Biochemistry and Bioprospecting (PPGBBio), Center of Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas (UFPel), Capão Do Leão Campus, Pelotas, RS, 96010-900, Brazil
| | - Evelyn Mianes Besckow
- Laboratory of Biochemistry and Molecular Neuropharmacology (LABIONEM), Postgraduate Program in Biochemistry and Bioprospecting (PPGBBio), Center of Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas (UFPel), Capão Do Leão Campus, Pelotas, RS, 96010-900, Brazil
| | - Gustavo D'Avila Nunes
- Laboratory of Biochemistry and Molecular Neuropharmacology (LABIONEM), Postgraduate Program in Biochemistry and Bioprospecting (PPGBBio), Center of Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas (UFPel), Capão Do Leão Campus, Pelotas, RS, 96010-900, Brazil
| | - Caroline Signorini Gomes
- Clean Organic Synthesis Laboratory (LASOL), Postgraduate Program in Chemistry (PPGQ), Center of Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas (UFPel), Capão Do Leão Campus, Pelotas, RS, 96010-900, Brazil
| | - Filipe Penteado
- Clean Organic Synthesis Laboratory (LASOL), Postgraduate Program in Chemistry (PPGQ), Center of Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas (UFPel), Capão Do Leão Campus, Pelotas, RS, 96010-900, Brazil
| | - Eder João Lenardão
- Clean Organic Synthesis Laboratory (LASOL), Postgraduate Program in Chemistry (PPGQ), Center of Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas (UFPel), Capão Do Leão Campus, Pelotas, RS, 96010-900, Brazil
| | - Cristiani Folharini Bortolatto
- Laboratory of Biochemistry and Molecular Neuropharmacology (LABIONEM), Postgraduate Program in Biochemistry and Bioprospecting (PPGBBio), Center of Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas (UFPel), Capão Do Leão Campus, Pelotas, RS, 96010-900, Brazil.
| | - César Augusto Brüning
- Laboratory of Biochemistry and Molecular Neuropharmacology (LABIONEM), Postgraduate Program in Biochemistry and Bioprospecting (PPGBBio), Center of Chemical, Pharmaceutical and Food Sciences (CCQFA), Federal University of Pelotas (UFPel), Capão Do Leão Campus, Pelotas, RS, 96010-900, Brazil.
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Turner D, Briken P, Grubbs J, Malandain L, Mestre-Bach G, Potenza MN, Thibaut F. The World Federation of Societies of Biological Psychiatry guidelines on the assessment and pharmacological treatment of compulsive sexual behaviour disorder. DIALOGUES IN CLINICAL NEUROSCIENCE 2022; 24:10-69. [PMID: 37522807 PMCID: PMC10408697 DOI: 10.1080/19585969.2022.2134739] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 09/18/2022] [Accepted: 10/03/2022] [Indexed: 11/18/2022]
Abstract
OBJECTIVES The current guidelines aim to evaluate the role of pharmacological agents in the treatment of patients with compulsive sexual behaviour disorder (CSBD). They are intended for use in clinical practice by clinicians who treat patients with CSBD. METHODS An extensive literature search was conducted using the English-language-literature indexed on PubMed and Google Scholar without time limit, supplemented by other sources, including published reviews. RESULTS Each treatment recommendation was evaluated with respect to the strength of evidence for its efficacy, safety, tolerability, and feasibility. Psychoeducation and psychotherapy are first-choice treatments and should always be conducted. The type of medication recommended depended mainly on the intensity of CSBD and comorbid sexual and psychiatric disorders. There are few randomised controlled trials. Although no medications carry formal indications for CSBD, selective-serotonin-reuptake-inhibitors and naltrexone currently constitute the most relevant pharmacological treatments for the treatment of CSBD. In cases of CSBD with comorbid paraphilic disorders, hormonal agents may be indicated, and one should refer to previously published guidelines on the treatment of adults with paraphilic disorders. Specific recommendations are also proposed in case of chemsex behaviour associated with CSBD. CONCLUSIONS An algorithm is proposed with different levels of treatment for different categories of patients with CSBD.
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Affiliation(s)
- Daniel Turner
- Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Mainz, Germany
| | - Peer Briken
- Institute for Sex Research, Sexual Medicine, and Forensic Psychiatry, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Joshua Grubbs
- Department of Psychology, Bowling Green State University, Bowling Green, OH, USA
| | - Leo Malandain
- Department of Psychiatry and Addictive Disorders, University Hospital Cochin (site Tarnier) AP-HP, Paris, France
| | - Gemma Mestre-Bach
- Facultad de Ciencias de la Salud, Universidad Internacional de La Rioja, La Rioja, Spain
| | - Marc N. Potenza
- Departments of Psychiatry and Neuroscience and Child Study Center, Yale School of Medicine, New Haven, CT, USA
- Connecticut Mental Health Center, New Haven, CT, USA
- Connecticut Council on Problem Gambling, Wethersfield, CT, USA
- Wu Tsai Institute, Yale University, New Haven, CT, USA
| | - Florence Thibaut
- Department of Psychiatry and Addictive Disorders, University Hospital Cochin (site Tarnier) AP-HP, Paris, France
- INSERM U1266, Institute of Psychiatry and Neurosciences, University of Paris Cité, Paris, France
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Perić M, Bečeheli I, Čičin-Šain L, Desoye G, Štefulj J. Serotonin system in the human placenta - the knowns and unknowns. Front Endocrinol (Lausanne) 2022; 13:1061317. [PMID: 36531448 PMCID: PMC9751904 DOI: 10.3389/fendo.2022.1061317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 11/10/2022] [Indexed: 12/02/2022] Open
Abstract
The biogenic monoamine serotonin (5-hydroxytryptamine, 5-HT) is a chemical messenger widely distributed in the brain and various other organs. Its homeostasis is maintained by the coordinated activity of a variety of proteins, including enzymes of serotonin metabolism, transmembrane transporters of serotonin, and serotonin receptors. The serotonin system has been identified also in the placenta in rodent models as a key component of placental physiology. However, serotonin pathways in the human placenta are far from well understood. Their alterations may have long-lasting consequences for the fetus that can manifest later in life. In this review, we summarize information on the location of the components of the serotonin system in the human placenta, their regulation, function, and alterations in pathological pregnancies. We highlight current controversies and discuss important topics for future research.
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Affiliation(s)
- Maja Perić
- Laboratory of Neurochemistry and Molecular Neurobiology, Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia
| | - Ivona Bečeheli
- Laboratory of Neurochemistry and Molecular Neurobiology, Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia
| | - Lipa Čičin-Šain
- Laboratory of Neurochemistry and Molecular Neurobiology, Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia
| | - Gernot Desoye
- Department of Obstetrics and Gynecology, Medical University of Graz, Graz, Austria
| | - Jasminka Štefulj
- Laboratory of Neurochemistry and Molecular Neurobiology, Division of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia
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20
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Exploring the Mechanism of Action of Trachelospermi Caulis et Folium for Depression Based on Experiments: Combining Network Pharmacology and Molecular Docking. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2022; 2022:3945063. [PMID: 36506595 PMCID: PMC9729047 DOI: 10.1155/2022/3945063] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 11/04/2022] [Accepted: 11/16/2022] [Indexed: 12/02/2022]
Abstract
Objective To reveal the safety, efficacy, and mechanism of action of Trachelospermi Caulis et Folium (TCEF) for treating depression. Methods The maximum dose method was employed to evaluate the safety of TCEF, and its antidepressant activity was assessed using the tail suspension and sugar water depletion tests. The main components of TCEF were determined using ultrahigh performance liquid chromatography coupled with quadrupole exactive orbitrap mass spectrometer (UHPLC-Q-EOMS). The active ingredients and their action targets were obtained using network pharmacology with SwissADME and SwissTargetPrediction screening, and the targets of depression were obtained using GeneCards, DrugBank, etc. The drug and depression-related targets were intersected and analyzed via PPI network, GO, and KEGG. Subsequently, the binding ability of the core components of TCEF to the core targets was validated via molecular docking and simulation. Results No statistically significant difference was observed between the normal and TCEF groups in terms of body weight, visceral index, and biochemical parameters (P > 0.05). Compared with the model group, all dose groups of TCEF had reduced the immobility time of tail suspension (P < 0.05) and increased the rate of sugar water consumption (P < 0.05). UHPLC-Q-EOMS was employed to identify 59 major components of TCEF, and network pharmacology analysis was used to screen 48 active components of TCEF for treating depression, corresponding to 139 relevant targets, including ALB, AKT1, TNF, ESR1, and CTNNB1. The involved pathways include neuroactive ligand-receptor interaction. The molecular docking results indicated that the core components have a good binding activity to the core targets. Conclusions TCEF is a relatively safe antidepressant medicine that exerts therapeutic effects through multiple components, targets, and pathways, providing a new idea and theoretical basis for future use of TCEF to treat depression.
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Li ZH, Yang GH, Wang F. Molecular mechanisms of Baihedihuang decoction as a treatment for breast cancer related anxiety: A network pharmacology and molecular docking study. World J Clin Cases 2022; 10:12104-12115. [PMID: 36483797 PMCID: PMC9724542 DOI: 10.12998/wjcc.v10.i33.12104] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 09/04/2022] [Accepted: 10/12/2022] [Indexed: 11/23/2022] Open
Abstract
BACKGROUND The therapeutic effects of a combination of Chinese medicines called Baihedihuang decoction (BD) have been clinically verified, although its molecular targets in breast cancer related anxiety remain unknown.
AIM To explore the molecular mechanisms of BD for breast cancer related anxiety treatment.
METHODS We used the Traditional Chinese Medicine Systems Pharmacology database to screen the active ingredients and potential targets of BD, and constructed the "drug-ingredient-target" network map with the help of Cytoscape 3.8 software. Also, we used the Online Mendelian Inheritance in Man, DrugBank, and Gencards databases to collect the disease targets of breast cancer related anxiety, and used the STRING platform to perform protein interaction analysis and construct the protein-protein interaction network. Metascape platform was used for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis of key targets. Molecular docking technology was used to verify the drug component/target disease network.
RESULTS We screened 16 active ingredients of BD for breast cancer related anxiety, with 113 target proteins. There are 931 disease targets of breast cancer related anxiety, and finally, 43 key targets and 305 Kyoto Encyclopedia of Genes and Genomes pathways were generated. The main active ingredients of BD for breast cancer related anxiety are verbascoside, β-sitosterol, stigmasterol, catalpol, etc. CDK2, TP53, HTR2A, ESR1, etc. are its key targets, and the main involved signaling pathways may include neuroactive ligand-receptor interaction pathway, 5-hydroxytryptaminergic synapse, P53 signaling pathway, cGMP-PKG signaling pathway, the cAMP signaling pathway, etc. Finally, molecular docking was performed with Vina software to validate the key active ingredients in BD with the selected key action targets. The molecular docking results showed that verbascoside, β-sitosterol, stigmasterol and CDK2 could stably bind and interact through amino acid residues SER249, ARG260, PRO228, ALA282, SER276, LYS273, ASN272, etc.
CONCLUSION The therapeutic effect of BD for breast cancer related anxiety is multi-level, multi-target, and multi-pathway. The findings of this study provide ideas and basis for further research.
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Affiliation(s)
- Zhong-Hui Li
- Department of Oncology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China
| | - Guo-Hua Yang
- Department of Oncology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China
| | - Fang Wang
- Department of Oncology, Wangjing Hospital, China Academy of Chinese Medical Sciences, Beijing 100102, China
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22
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Yu W, Liang Z, Li Q, Liu Y, Liu X, Jiang L, Liu C, Zhang Y, Kang C, Yan J. The pharmacological validation of the Xiao-Jian-Zhong formula against ulcerative colitis by network pharmacology integrated with metabolomics. JOURNAL OF ETHNOPHARMACOLOGY 2022; 298:115647. [PMID: 35987415 DOI: 10.1016/j.jep.2022.115647] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/01/2022] [Revised: 08/08/2022] [Accepted: 08/13/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Inflammatory bowel disease (IBD) is pathologically characterized by an immune response accommodative insufficiency and dysbiosis accompanied by persistent epithelial barrier dysfunction, and is divided into ulcerative colitis (UC) and Crohn's disease (CD). Its progression increases the susceptibility to colitis-associated cancer (CAC), as well as other complications. The Xiao-Jian-Zhong (XJZ) formula has a historical application in the clinic to combat gastrointestinal disorders. AIM OF THE STUDY The investigation aimed to explore the molecular and cellular mechanisms of XJZ. MATERIALS AND METHODS Dextran sodium sulfate (DSS) was diluted in drinking water and given to mice for a week to establish murine models of experimental colitis, and the XJZ solution was administered for two weeks. Network pharmacology analysis and weighted gene co-expression network analysis (WGCNA) were utilized to predict the therapeutic role of XJZ against UC and CAC. 16S rRNA sequencing and untargeted metabolomics were conducted utilizing murine feces to examine the changes in the microbiome profile. Biochemical experiments were conducted to confirm the predicted functions. RESULTS XJZ treatment markedly attenuated DSS-induced experimental colitis progression, and the targets were enriched in inflammation, infection, and tumorigenesis, predicted by network pharmacology analysis. Based on The Cancer Genome Atlas (TCGA) database, the XJZ-targets were related to the survival probability in patients with colorectal cancer, underlying a potential therapeutic value in cancer intervention. Moreover, the XJZ therapy successfully rescued the decreased richness and diversity of microbiota, suppressed the potentially pathogenic phenotype of the gut microorganisms, and reversed the declined linoleic acid metabolism and increased cytochrome P450 activity in murine colitis models. Our in-vitro experiments confirmed that the XJZ treatment suppressed Caspase1-dependent pyroptosis and increased peroxisome proliferators-activated receptor-γ(PPAR-γ) expression in the colon, facilitated the alternative activation of macrophages (Mφs), inhibited tumor necrosis factor-α (TNFα)-induced reactive oxygen species (ROS) level in intestinal organoids (IOs), thereby favoring the mucosal healing. CONCLUSION The XJZ formula is efficacious for colitis by a prompt resolution of inflammation and dysbiosis, and by re-establishing a microbiome profile that favors re-epithelization, and prevents carcinogenesis.
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Affiliation(s)
- Wei Yu
- Department of Physiology, Jining Medical University, Jining City, Shandong province, China.
| | - Zhenghao Liang
- Department of Physiology, Jining Medical University, Jining City, Shandong province, China.
| | - Qi Li
- Department of Physiology, Jining Medical University, Jining City, Shandong province, China.
| | - Yanzhi Liu
- Department of Physiology, Jining Medical University, Jining City, Shandong province, China.
| | - Xincheng Liu
- Department of Physiology, Jining Medical University, Jining City, Shandong province, China.
| | - Lu Jiang
- Department of Physiology, Jining Medical University, Jining City, Shandong province, China.
| | - Chen Liu
- Department of Physiology, Jining Medical University, Jining City, Shandong province, China.
| | - Yijia Zhang
- Department of Physiology, Jining Medical University, Jining City, Shandong province, China.
| | - Cai Kang
- Department of Physiology, Jining Medical University, Jining City, Shandong province, China.
| | - Jing Yan
- Department of Physiology, Jining Medical University, Jining City, Shandong province, China.
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Lu J, Huang C, Lu Q, Lu X. Therapeutic and Prophylactic Effects of Amphotericin B Liposomes on Chronic Social Defeat Stress-Induced Behavioral Abnormalities in Mice. Front Pharmacol 2022; 13:918177. [PMID: 35910388 PMCID: PMC9335357 DOI: 10.3389/fphar.2022.918177] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 05/30/2022] [Indexed: 11/13/2022] Open
Abstract
Recently, innate immune system stimulants, such as lipopolysaccharide (LPS) and macrophage-colony stimulating factor (M-CSF), were reported to prevent and reverse chronic stress-induced behavioral abnormalities, suggesting that innate immune stimulation could be a potential strategy for the treatment and prevention of mental disorders. Amphotericin B liposome is a clinically available antifungal medication that can stimulate macrophages and microglia. We hypothesize that amphotericin B liposome may be used to prevent and reverse behavioral abnormalities triggered by chronic stress. As expected, our results showed that a single injection of amphotericin B liposome (1 mg/kg) immediately after stress cessation reversed the decrease in time spent in the interaction zone in the social interaction test (SIT) and the increase in immobility time in the tail suspension test (TST) and forced swimming test (FST) in mice caused by chronic social defeat stress (CSDS). In addition, a single injection of amphotericin B liposomes (1 mg/kg) 1 day before stress exposure was found to prevent the CSDS-induced decrease in time spent in the interaction zone in the SIT and the increase in immobility time in the TST and FST in mice. Pretreatment with minocycline to inhibit the innate immune response was able to abolish the reversal effect of post-stress injection of amphotericin B liposomes on CSDS-induced behavioral abnormalities and the prophylactic effect of pre-stress injection of amphotericin B liposomes on CSDS-induced behavioral abnormalities. These results demonstrate that amphotericin B liposomes have both therapeutic and prophylactic effects on chronic stress-induced behavioral abnormalities in mice by mobilizing the innate immune response.
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Affiliation(s)
- Jiashu Lu
- Department of Pharmacy, The People’s Hospital of Taizhou, The Fifth Affiliated Hospital of Nantong University, Taizhou, China
- *Correspondence: Jiashu Lu,
| | - Chao Huang
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, China
| | - Qun Lu
- Department of Pharmacy, Nantong Third Hospital Affiliated to Nantong University, Nantong, China
| | - Xu Lu
- Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, China
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Burtscher J, Niedermeier M, Hüfner K, van den Burg E, Kopp M, Stoop R, Burtscher M, Gatterer H, Millet GP. The interplay of hypoxic and mental stress: Implications for anxiety and depressive disorders. Neurosci Biobehav Rev 2022; 138:104718. [PMID: 35661753 DOI: 10.1016/j.neubiorev.2022.104718] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2022] [Revised: 05/26/2022] [Accepted: 05/27/2022] [Indexed: 12/14/2022]
Abstract
Adequate oxygen supply is essential for the human brain to meet its high energy demands. Therefore, elaborate molecular and systemic mechanism are in place to enable adaptation to low oxygen availability. Anxiety and depressive disorders are characterized by alterations in brain oxygen metabolism and of its components, such as mitochondria or hypoxia inducible factor (HIF)-pathways. Conversely, sensitivity and tolerance to hypoxia may depend on parameters of mental stress and the severity of anxiety and depressive disorders. Here we discuss relevant mechanisms of adaptations to hypoxia, as well as their involvement in mental stress and the etiopathogenesis of anxiety and depressive disorders. We suggest that mechanisms of adaptations to hypoxia (including metabolic responses, inflammation, and the activation of chemosensitive brain regions) modulate and are modulated by stress-related pathways and associated psychiatric diseases. While severe chronic hypoxia or dysfunctional hypoxia adaptations can contribute to the pathogenesis of anxiety and depressive disorders, harnessing controlled responses to hypoxia to increase cellular and psychological resilience emerges as a novel treatment strategy for these diseases.
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Affiliation(s)
- Johannes Burtscher
- Institute of Sport Sciences, University of Lausanne, Lausanne, Switzerland; Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland.
| | - Martin Niedermeier
- Department of Sport Science, University of Innsbruck, Innsbruck, Austria
| | - Katharina Hüfner
- Department of Psychiatry, Psychotherapy, Psychosomatics and Medical Psychology, University Clinic for Psychiatry II, Innsbruck Medical University, Innsbruck, Austria
| | - Erwin van den Burg
- Department of Psychiatry, Center of Psychiatric Neuroscience (CNP), University Hospital of Lausanne (CHUV), Prilly, Lausanne, Switzerland
| | - Martin Kopp
- Department of Sport Science, University of Innsbruck, Innsbruck, Austria
| | - Ron Stoop
- Department of Psychiatry, Center of Psychiatric Neuroscience (CNP), University Hospital of Lausanne (CHUV), Prilly, Lausanne, Switzerland
| | - Martin Burtscher
- Department of Sport Science, University of Innsbruck, Innsbruck, Austria
| | - Hannes Gatterer
- Institute of Mountain Emergency Medicine, Eurac Research, Bolzano, Italy
| | - Grégoire P Millet
- Institute of Sport Sciences, University of Lausanne, Lausanne, Switzerland; Department of Biomedical Sciences, University of Lausanne, Lausanne, Switzerland
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25
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Neis VB, Werle I, Moretti M, Rosa PB, Camargo A, de O Dalsenter Y, Platt N, Rosado AF, Engel WD, de Almeida GRL, Selhorst I, Dafre AL, Rodrigues ALS. Involvement of serotonergic neurotransmission in the antidepressant-like effect elicited by cholecalciferol in the chronic unpredictable stress model in mice. Metab Brain Dis 2022; 37:1597-1608. [PMID: 35435610 DOI: 10.1007/s11011-022-00979-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Accepted: 04/04/2022] [Indexed: 12/12/2022]
Abstract
Cholecalciferol deficiency has been associated with stress-related psychiatric disorders, particularly depression. Therefore, the present study investigated the antidepressant-like effect of cholecalciferol in female mice and the possible role of the serotonergic system in this response. The ability of cholecalciferol to elicit an antidepressant-like effect and to modulate serotonin levels in the hippocampus and prefrontal cortex of mice subjected to chronic unpredictable stress (CUS) was also investigated. The administration of cholecalciferol (2.5, 7.5, and 25 µg/kg, p.o.) for 7 days, similar to fluoxetine (10 mg/kg, p.o., serotonin reuptake inhibitor), reduced the immobility time in the tail suspension test, without altering the locomotor performance in the open-field test. Moreover, the administration of p-chlorophenylalanine methyl ester (PCPA - 100 mg/kg, i.p., for 4 days, a selective inhibitor of tryptophan hydroxylase, involved in the serotonin synthesis) abolished the antidepressant-like effect of cholecalciferol and fluoxetine in the tail suspension test, demonstrating the involvement of serotonergic system. Additionally, CUS protocol (21 days) induced depressive-like behavior in the tail suspension test and decreased serotonin levels in the prefrontal cortex and hippocampus of mice. Conversely, the administration of cholecalciferol and fluoxetine in the last 7 days of CUS protocol completely abolished the stress-induced depressive-like phenotype. Cholecalciferol was also effective to abrogate CUS-induced reduction on serotonin levels in the prefrontal cortex, but not in the hippocampus. Our results indicate that cholecalciferol has an antidepressant-like effect in mice by modulating the serotonergic system and support the assumption that cholecalciferol may have beneficial effects for the management of depression.
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Affiliation(s)
- Vivian B Neis
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-900, Brazil
| | - Isabel Werle
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-900, Brazil
| | - Morgana Moretti
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-900, Brazil
| | - Priscila B Rosa
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-900, Brazil
| | - Anderson Camargo
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-900, Brazil
| | - Yasmim de O Dalsenter
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-900, Brazil
| | - Nicolle Platt
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-900, Brazil
| | - Axel F Rosado
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-900, Brazil
| | - William D Engel
- Educational Society of Santa Catarina - Unisociesc, Jaraguá do Sul, Santa Catarina, 89251-970, Brazil
| | - Gudrian Ricardo L de Almeida
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-900, Brazil
| | - Ingrid Selhorst
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-900, Brazil
| | - Alcir Luiz Dafre
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-900, Brazil
| | - Ana Lúcia S Rodrigues
- Department of Biochemistry, Center of Biological Sciences, Universidade Federal de Santa Catarina, Florianópolis, Santa Catarina, 88040-900, Brazil.
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Yao C, Niu L, Fu Y, Zhu X, Yang J, Zhao P, Sun X, Ma Y, Li S, Li J. Cognition, motor symptoms, and glycolipid metabolism in Parkinson's disease with depressive symptoms. J Neural Transm (Vienna) 2022; 129:563-573. [PMID: 34837534 DOI: 10.1007/s00702-021-02437-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 10/29/2021] [Indexed: 12/29/2022]
Abstract
Depressive symptoms and abnormal glycolipid metabolisms are common in patients with Parkinson's disease (PD), but their relationship has not been fully reported. It is not clear whether glycolipid impairments lead to poor cognitive and motor function, and aggravate depressive symptoms. Therefore, we aimed to explore the relationships between glycolipid variables, cognition, motor and depressive symptoms in PD patients cross-sectionally. Two hundred ten PD patients were recruited. Glycolipid parameters and Uric acid (UA) were measured. Depressive symptoms, cognitive function and motor symptoms were assessed using the Hamilton Depression Rating Scale-17 (HAMD-17), the Montreal Cognitive Assessment (MOCA) and the Movement Disorder Society Unified Parkinson's Disease Rating Scale Part-III (UPDRS-III). Depressive PD patients had significantly worse motor symptoms and higher levels of fasting plasma glucose (FPG) than those in non-depressive patients (F = 24.145, P < 0.001). Further, logistic regression analysis indicated that UPDRS-III (OR = 1.039, 95% CI 1.019-1.057, P = 0.044), FPG (OR = 1.447, 95% CI 1.050-1.994, P = 0.024) were independently associated with depression. In PD patients without depression, UA (β = - 0.068, t = - 2.913, P = 0.005) and cholesterol (CHOL) (β = - 3.941, t = - 2.518, P = 0.014) were independent predictors of the UPDRS-III score; in addition, UPDRS-III score was negatively associated with MOCA score (β = - 0.092, t = - 2.791, P = 0.007). FPG levels and motor symptoms were related to depressive symptoms in PD patients. Further, in non-depressive PD patients, UA and CHOL showed putative biomarkers of motor symptoms.
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Affiliation(s)
- Cong Yao
- Laboratory of Biological Psychiatry, Institute of Mental Health, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, 13 Liulin Road, Hexi District, 300222, Tianjin, China
| | - Lichao Niu
- Laboratory of Biological Psychiatry, Institute of Mental Health, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, 13 Liulin Road, Hexi District, 300222, Tianjin, China
| | - Yun Fu
- Department of Genetics, College of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
| | - Xu Zhu
- Department of Genetics, College of Basic Medical Sciences, Tianjin Medical University, Tianjin, 300070, China
- Department of Psychiatry and Psychology, College of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Roads, Heping District, Tianjin, 300070, China
| | - Junfeng Yang
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Peng Zhao
- Department of Neurology, Tianjin Medical University General Hospital, Tianjin, 300052, China
| | - Xiaoxiao Sun
- Laboratory of Biological Psychiatry, Institute of Mental Health, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, 13 Liulin Road, Hexi District, 300222, Tianjin, China
| | - Yanyan Ma
- Laboratory of Biological Psychiatry, Institute of Mental Health, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, 13 Liulin Road, Hexi District, 300222, Tianjin, China
| | - Shen Li
- Laboratory of Biological Psychiatry, Institute of Mental Health, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, 13 Liulin Road, Hexi District, 300222, Tianjin, China.
- Department of Psychiatry and Psychology, College of Basic Medical Sciences, Tianjin Medical University, 22 Qixiangtai Roads, Heping District, Tianjin, 300070, China.
| | - Jie Li
- Laboratory of Biological Psychiatry, Institute of Mental Health, Tianjin Anding Hospital, Mental Health Center of Tianjin Medical University, 13 Liulin Road, Hexi District, 300222, Tianjin, China.
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C Curtin A, Johnston CS. Vitamin B6 Supplementation Reduces Symptoms of Depression in College Women Taking Oral Contraceptives: A Randomized, Double-Blind Crossover Trial. J Diet Suppl 2022:1-13. [PMID: 35109763 DOI: 10.1080/19390211.2022.2030843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Oral contraceptive (OC) users have a heightened risk of low plasma concentrations of vitamin B6, a cofactor in the tryptophan-serotonin pathway critical to mood regulation. The purpose of this crossover study was to determine whether vitamin B6 supplementation reduced symptoms of depression and improved mood states in college women using OC. Participants were healthy (aged 18-25 yrs), did not take dietary supplements, and used OC (estrogen with progestin) consistently for at least 1 year. During the 12-week, randomized, double-blind crossover trial (4-week treatment periods [100 mg vitamin B6 daily or placebo] separated by a 4-week washout) participants (n = 8) maintained normal exercise and eating patterns and recorded tablet consumption daily. The Beck Depression Inventory-II (BDI-II) and Profile of Mood States (POMS) were used to assess mental health before and after each 4-week treatment period. Average dietary vitamin B6 intakes did not vary during the trial (1.2-1.4 mg/d), whereas vitamin B6 status rose significantly following the B6 supplementation period compared to the other three time points. BDI-II scores were reduced 20% by vitamin B6 supplementation in comparison to an 11% rise with placebo ingestion (p = 0.046). POMS scores were not significantly impacted by vitamin B6 supplementation. These preliminary data support a growing literature suggesting the benefits of B6 supplementation for reducing symptoms of depression in young women using OC.
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Affiliation(s)
- Anne C Curtin
- College of Health Solutions, Arizona State University, Tempe, AZ, USA
| | - Carol S Johnston
- College of Health Solutions, Arizona State University, Tempe, AZ, USA
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Anti-depressive-like effect of monoterpene trans-anethole via monoaminergic pathways. Saudi J Biol Sci 2022; 29:3255-3261. [PMID: 35844399 PMCID: PMC9280236 DOI: 10.1016/j.sjbs.2022.01.060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 01/27/2022] [Accepted: 01/30/2022] [Indexed: 12/02/2022] Open
Abstract
Trans-anethole (ANE) is a monoterpene present in many aromatic plants, especially Pimpinella anisum (PA). In this regard, we previously reported the anti-depressant potential of PA. Here, we examined the anti-depressant activity of ANE and its possible mechanism in mice. In experiment 1, the animals received ANE (12.5–50 mg.kg -1) 60 min prior to forced swimming and open-field tests. In experiment 2, the animals received several receptor antagonists to assess the possible mechanism of ANE. The administration of ANE (25 and 50 mg.kg -1; p < 0.01 and p < 0.001, respectively) exhibited an anti-depressive-like effect in FST without any significant effect on animal locomotion(p > 0.05). Moreover, haloperidol(p < 0.001), SCH23390(p < 0.001), sulpiride(p < 0.001), ketanserin(p < 0.001), p-chlorophenylalanine(p < 0.001), WAY100135(p < 0.001), reserpine, (p < 0.001) prazosin(p < 0.001), and yohimbine(p < 0.001) inhibited the anti-depressive-like effect of ANE. Furthermore, co-treatment of a subeffective dose of ANE with imipramine or fluoxetine induced synergistic anti-depressant-like effects(p < 0.001). Our data mainly showed that the anti-depressive-like effect of ANE, which can be attributed to the contribution of the monoaminergic system.
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Castañeda R, Cáceres A, Velásquez D, Rodríguez C, Morales D, Castillo A. Medicinal plants used in traditional Mayan medicine for the treatment of central nervous system disorders: An overview. JOURNAL OF ETHNOPHARMACOLOGY 2022; 283:114746. [PMID: 34656668 DOI: 10.1016/j.jep.2021.114746] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 09/22/2021] [Accepted: 10/11/2021] [Indexed: 06/13/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE For thousands of years, different cultural groups have used and transformed natural resources for medicinal purposes focused on psychological or neurological conditions. Some of these are recognized as central nervous system (CNS) disorders and diseases, whereas other ethnopsychiatric interpretations are explained in culture-specific terms. In traditional Mayan medicine, several herbs have been part of treatments and rituals focused on cultural and ethnomedical concepts. AIM OF REVIEW This study aims to provide a comprehensive overview of the medicinal plants used in Mesoamerica by traditional healers and Mayan groups to CNS disorders and associate the traditional use with demonstrated pharmacological evidence to establish a solid foundation for directing future research. METHODS A systematic search for primary sources of plant use reports for traditional CNS-related remedies of Mesoamerica were obtained from library catalogs, thesis and scientific databases (PubMed, Scopus, Google Scholar; and Science Direct), and entered in a database with data analyzed in terms of the usage frequency, use by ethnic groups, plant endemism, and pharmacological investigation. RESULTS A total of 155 plants used for ethnopsychiatric conditions in Mesoamerica by Mayan groups were found, encompassing 127 native species. Of these, only 49 native species have reported in vitro or in vivo pharmacological analyses. The most commonly reported ethnopsychiatric conditions are related to anxiety, depression, memory loss, epilepsy, and insomnia. The extent of the scientific evidence available to understand the pharmacological application for their use against CNS disorders varied between different plant species, with the most prominent evidence shown by Annona cherimola, Justicia pectoralis, J. spicigera, Mimosa pudica, Persea americana, Petiveria alliacea, Piper amalago, Psidium guajava, Tagetes erecta and T. lucida. CONCLUSION Available pharmacological data suggest that different plant species used in traditional Mayan medicine may target the CNS, mainly related to GABA, serotonin, acetylcholine, or neuroprotective pathways. However, more research is required, given the limited data regarding mechanism of action at the preclinical in vivo level, identification of active compounds, scarce number of clinical studies, and the dearth of peer-reviewed studies.
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Affiliation(s)
- Rodrigo Castañeda
- School of Pharmacy, Faculty of Chemical Sciences and Pharmacy, University of San Carlos, Guatemala.
| | | | - Diana Velásquez
- School of Biology, Faculty of Chemical Sciences and Pharmacy, University of San Carlos, Guatemala.
| | - Cesar Rodríguez
- School of Pharmacy, Faculty of Chemical Sciences and Pharmacy, University of San Carlos, Guatemala.
| | - David Morales
- School of Pharmacy, Faculty of Chemical Sciences and Pharmacy, University of San Carlos, Guatemala.
| | - Andrea Castillo
- School of Pharmacy, Faculty of Chemical Sciences and Pharmacy, University of San Carlos, Guatemala.
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Anguita-Ruiz A, Zarza-Rebollo JA, Pérez-Gutiérrez AM, Molina E, Gutiérrez B, Bellón JÁ, Moreno-Peral P, Conejo-Cerón S, Aiarzagüena JM, Ballesta-Rodríguez MI, Fernández A, Fernández-Alonso C, Martín-Pérez C, Montón-Franco C, Rodríguez-Bayón A, Torres-Martos Á, López-Isac E, Cervilla J, Rivera M. Body mass index interacts with a genetic-risk score for depression increasing the risk of the disease in high-susceptibility individuals. Transl Psychiatry 2022; 12:30. [PMID: 35075110 PMCID: PMC8786870 DOI: 10.1038/s41398-022-01783-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 11/24/2021] [Accepted: 01/04/2022] [Indexed: 11/22/2022] Open
Abstract
Depression is strongly associated with obesity among other chronic physical diseases. The latest mega- and meta-analysis of genome-wide association studies have identified multiple risk loci robustly associated with depression. In this study, we aimed to investigate whether a genetic-risk score (GRS) combining multiple depression risk single nucleotide polymorphisms (SNPs) might have utility in the prediction of this disorder in individuals with obesity. A total of 30 depression-associated SNPs were included in a GRS to predict the risk of depression in a large case-control sample from the Spanish PredictD-CCRT study, a national multicentre, randomized controlled trial, which included 104 cases of depression and 1546 controls. An unweighted GRS was calculated as a summation of the number of risk alleles for depression and incorporated into several logistic regression models with depression status as the main outcome. Constructed models were trained and evaluated in the whole recruited sample. Non-genetic-risk factors were combined with the GRS in several ways across the five predictive models in order to improve predictive ability. An enrichment functional analysis was finally conducted with the aim of providing a general understanding of the biological pathways mapped by analyzed SNPs. We found that an unweighted GRS based on 30 risk loci was significantly associated with a higher risk of depression. Although the GRS itself explained a small amount of variance of depression, we found a significant improvement in the prediction of depression after including some non-genetic-risk factors into the models. The highest predictive ability for depression was achieved when the model included an interaction term between the GRS and the body mass index (BMI), apart from the inclusion of classical demographic information as marginal terms (AUC = 0.71, 95% CI = [0.65, 0.76]). Functional analyses on the 30 SNPs composing the GRS revealed an over-representation of the mapped genes in signaling pathways involved in processes such as extracellular remodeling, proinflammatory regulatory mechanisms, and circadian rhythm alterations. Although the GRS on its own explained a small amount of variance of depression, a significant novel feature of this study is that including non-genetic-risk factors such as BMI together with a GRS came close to the conventional threshold for clinical utility used in ROC analysis and improves the prediction of depression. In this study, the highest predictive ability was achieved by the model combining the GRS and the BMI under an interaction term. Particularly, BMI was identified as a trigger-like risk factor for depression acting in a concerted way with the GRS component. This is an interesting finding since it suggests the existence of a risk overlap between both diseases, and the need for individual depression genetics-risk evaluation in subjects with obesity. This research has therefore potential clinical implications and set the basis for future research directions in exploring the link between depression and obesity-associated disorders. While it is likely that future genome-wide studies with large samples will detect novel genetic variants associated with depression, it seems clear that a combination of genetics and non-genetic information (such is the case of obesity status and other depression comorbidities) will still be needed for the optimization prediction of depression in high-susceptibility individuals.
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Affiliation(s)
- Augusto Anguita-Ruiz
- grid.4489.10000000121678994Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain ,grid.4489.10000000121678994Institute of Nutrition and Food Technology “José Mataix”, Biomedical Research Center (CIBM), University of Granada, Granada, Spain ,grid.507088.2Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain ,grid.413448.e0000 0000 9314 1427CIBEROBN (Physiopathology of Obesity and Nutrition CB12/03/30038), Institute of Health Carlos III (ISCIII), Madrid, Spain
| | - Juan Antonio Zarza-Rebollo
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain. .,Institute of Neurosciences 'Federico Olóriz', Biomedical Research Center (CIBM), University of Granada, Granada, Spain.
| | - Ana M Pérez-Gutiérrez
- grid.4489.10000000121678994Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain ,grid.4489.10000000121678994Institute of Neurosciences ‘Federico Olóriz’, Biomedical Research Center (CIBM), University of Granada, Granada, Spain
| | - Esther Molina
- grid.507088.2Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain ,grid.4489.10000000121678994Institute of Neurosciences ‘Federico Olóriz’, Biomedical Research Center (CIBM), University of Granada, Granada, Spain ,grid.4489.10000000121678994Department of Nursing, Faculty of Health Sciences, University of Granada, Granada, Spain
| | - Blanca Gutiérrez
- grid.507088.2Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain ,grid.4489.10000000121678994Institute of Neurosciences ‘Federico Olóriz’, Biomedical Research Center (CIBM), University of Granada, Granada, Spain ,grid.4489.10000000121678994Department of Psychiatry, Faculty of Medicine, University of Granada, Granada, Spain
| | - Juan Ángel Bellón
- grid.452525.1Primary Care District of Málaga-Guadalhorce, Biomedical Research Institute of Málaga (IBIMA), Primary Care Prevention and Health Promotion Network (redIAPP), Málaga, Spain ,grid.10215.370000 0001 2298 7828Department of Public Health and Psychiatry, Faculty of Medicine, University of Málaga, Málaga, Spain
| | - Patricia Moreno-Peral
- grid.452525.1Primary Care District of Málaga-Guadalhorce, Biomedical Research Institute of Málaga (IBIMA), Primary Care Prevention and Health Promotion Network (redIAPP), Málaga, Spain
| | - Sonia Conejo-Cerón
- grid.452525.1Primary Care District of Málaga-Guadalhorce, Biomedical Research Institute of Málaga (IBIMA), Primary Care Prevention and Health Promotion Network (redIAPP), Málaga, Spain
| | | | | | - Anna Fernández
- grid.428876.7Parc Sanitari Sant Joan de Déu, Fundació Sant Joan de Déu, Barcelona, Spain ,grid.466571.70000 0004 1756 6246CIBERESP, Centro de Investigacion Biomedica en Red de Epidemiologia y Salud Publica, Madrid, Spain
| | | | - Carlos Martín-Pérez
- grid.418355.eMarquesado Health Centre, Servicio Andaluz de Salud, Granada, Spain
| | - Carmen Montón-Franco
- grid.488737.70000000463436020Casablanca Health Centre, Aragonese Institute of Health Sciences, IIS Aragón, Zaragoza, Spain ,grid.11205.370000 0001 2152 8769Department of Medicine and Psychiatry, University of Zaragoza, Zaragoza, Spain
| | | | - Álvaro Torres-Martos
- grid.4489.10000000121678994Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain
| | - Elena López-Isac
- grid.4489.10000000121678994Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain ,grid.4489.10000000121678994Institute of Neurosciences ‘Federico Olóriz’, Biomedical Research Center (CIBM), University of Granada, Granada, Spain
| | - Jorge Cervilla
- grid.507088.2Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain ,grid.4489.10000000121678994Institute of Neurosciences ‘Federico Olóriz’, Biomedical Research Center (CIBM), University of Granada, Granada, Spain ,grid.4489.10000000121678994Department of Psychiatry, Faculty of Medicine, University of Granada, Granada, Spain
| | - Margarita Rivera
- grid.4489.10000000121678994Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, Granada, Spain ,grid.507088.2Instituto de Investigación Biosanitaria ibs.GRANADA, Granada, Spain ,grid.4489.10000000121678994Institute of Neurosciences ‘Federico Olóriz’, Biomedical Research Center (CIBM), University of Granada, Granada, Spain
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Wang H, Liu J, He J, Huang D, Xi Y, Xiao T, Ouyang Q, Zhang S, Wan S, Chen X. Potential mechanisms underlying the therapeutic roles of sinisan formula in depression: Based on network pharmacology and molecular docking study. Front Psychiatry 2022; 13:1063489. [PMID: 36440424 PMCID: PMC9681910 DOI: 10.3389/fpsyt.2022.1063489] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Accepted: 10/25/2022] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND The incidence of depression has been increasing globally, which has brought a serious burden to society. Sinisan Formula (SNSF), a well-known formula of traditional Chinese medicine (TCM), has been found to demonstrate an antidepressant effect. However, the therapeutic mechanism of this formula remains unclear. Thus, the present study aimed to explore the mechanism of SNSF in depression through network pharmacology combined with molecular docking methods. MATERIALS AND METHODS Bioactive compounds, potential targets of SNSF, and related genes of depression were obtained from public databases. Essential ingredients, potential targets, and signaling pathways were identified using bioinformatics analysis, including protein-protein interaction (PPI), the Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Subsequently, Autodock software was further performed for conducting molecular docking to verify the binding ability of active ingredients to targets. RESULTS A total of 91 active compounds were successfully identified in SNSF with the use of the comprehensive network pharmacology approach, and they were found to be closely connected to 112 depression-related targets, among which CREB1, NOS3, CASP3, TP53, ESR1, and SLC6A4 might be the main potential targets for the treatment of depression. GO analysis revealed 801 biological processes, 123 molecular functions, and 67 cellular components. KEGG pathway enrichment analysis indicated that neuroactive ligand-receptor interaction, serotonergic synapse pathways, dopaminergic synapse pathways, and GABAergic synapse pathways might have played a role in treating depression. Molecular docking suggested that beta-sitosterol, nobiletin, and 7-methoxy-2-methyl isoflavone bound well to the main potential targets. CONCLUSION This study comprehensively illuminated the active ingredients, potential targets, primary pharmacological effects, and relevant mechanism of the SNSF in the treatment of depression. SNSF might exert its antidepressant effects by regulating the signaling pathway of 5-hydroxytryptamine, dopamine, GABA, and neuroactive ligand receptor interactions. Still, more pharmacological experiments are needed for verification.
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Affiliation(s)
- Hui Wang
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China.,Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Jiaqin Liu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China.,Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Jinbiao He
- Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Dengxia Huang
- Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Yujiang Xi
- Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Ting Xiao
- The First Affiliated Hospital of Hunan University of Chinese Medicine, Changsha, China
| | - Qian Ouyang
- Hunan University of Chinese Medicine, Changsha, China
| | - Shiwei Zhang
- Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Siyan Wan
- Yunnan University of Traditional Chinese Medicine, Kunming, China
| | - Xudong Chen
- Department of Psychiatry, National Clinical Research Center for Mental Disorders, The Second Xiangya Hospital of Central South University, Changsha, China
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Yang X, Guo JY, Jiang YN, Liu MM, Li QY, Li JY, Wei XJ, Wan GH, Shi JL. Valeriana jatamansi Jones ex Roxb. Against Post-Traumatic Stress Disorder, Network Pharmacological Analysis, and In Vivo Evaluation. Front Pharmacol 2021; 12:764548. [PMID: 34950028 PMCID: PMC8688958 DOI: 10.3389/fphar.2021.764548] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Accepted: 11/11/2021] [Indexed: 12/31/2022] Open
Abstract
Zhi zhu xiang (ZZX) is the root and rhizome of Valeriana jatamansi Jones ex Roxb. Recent studies have shown that ZZX can exert antianxiety, antidepressant, and sedative effects. Because post-traumatic stress disorder (PTSD) is similar to depression and anxiety in terms of its etiology, pathogenesis, and clinical manifestations, it is possible that ZZX may also be useful for the prevention and treatment of PTSD. In this study, a mouse model of PTSD was established and used to study the pharmacological action of a 95% ethanol extract of ZZX on PTSD via a series of classic behavioral tests. We found that a 95% ethanol extract of ZZX was indeed effective for relieving the symptoms of PTSD in mice. Moreover, network pharmacology analysis was used to predict the potential active ingredients, targets, and possible pathways of ZZX in the treatment of PTSD. The neurotransmitter system, the hypothalamic-pituitary-adrenal (HPA) axis, and the endocannabinoid (eCB) system were identified to be the most likely pathways for anti-PTSD action in ZZX. Due to the lack of a falsification mechanism in network pharmacology, in vivo tests were carried out in mice, and the expression levels of neurotransmitters, hormones, and genes of key targets were detected by enzyme-linked immunosorbent assay and real-time PCR to further verify this inference. Analysis showed that the levels of norepinephrine, 5-hydroxytryptamine, and glutamic acid were increased in the hippocampus, prefrontal cortex, and amygdala of PTSD mice, while the levels of dopamine and γ-aminobutyric acid were decreased in these brain regions; furthermore, ZZX could restore the expression of these factors, at least to a certain extent. The levels of adrenocorticotropic hormone, corticosterone, and corticotropin-releasing hormone were increased in these different brain regions and the serum of PTSD mice; these effects could be reversed by ZZX to a certain extent. The expression levels of cannabinoid receptor 1 and diacylglycerol lipase α mRNA were decreased in PTSD mice, while the levels of fatty acid amide hydrolase and monoacylglycerol lipase mRNA were increased; these effects were restored by ZZX to a certain extent. In conclusion, our findings suggest that ZZX may provide new therapeutic pathways for treating PTSD by the regulation of neurotransmitters, the HPA, and expression levels of eCB-related genes in the brain.
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Affiliation(s)
- Xue Yang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jian-You Guo
- CAS Key Laboratory of Mental Health, Institute of Psychology, Chinese Academy of Sciences, Beijing, China
| | - Ya-Ni Jiang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Meng-Meng Liu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Qiu-Yu Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jia-Yuan Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xiao-Jia Wei
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Guo-Hui Wan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jin-Li Shi
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
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Evsiukova VS, Bazovkina D, Bazhenova E, Kulikova EA, Kulikov AV. Tryptophan Hydroxylase 2 Deficiency Modifies the Effects of Fluoxetine and Pargyline on the Behavior, 5-HT- and BDNF-Systems in the Brain of Zebrafish ( Danio rerio). Int J Mol Sci 2021; 22:ijms222312851. [PMID: 34884655 PMCID: PMC8657639 DOI: 10.3390/ijms222312851] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 11/17/2021] [Accepted: 11/25/2021] [Indexed: 11/24/2022] Open
Abstract
The mechanisms of resistance to antidepressant drugs is a key and still unresolved problem of psychopharmacology. Serotonin (5-HT) and brain-derived neurotrophic factor (BDNF) play a key role in the therapeutic effect of many antidepressants. Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in 5-HT synthesis in the brain. We used zebrafish (Danio rerio) as a promising model organism in order to elucidate the effect of TPH2 deficiency caused by p-chlorophenylalanine (pCPA) on the alterations in behavior and expression of 5-HT-related (Tph2, Slc6a4b, Mao, Htr1aa, Htr2aa) and BDNF-related (Creb, Bdnf, Ntrk2a, Ngfra) genes in the brain after prolonged treatment with two antidepressants, inhibitors of 5-HT reuptake (fluoxetine) and oxidation (pargyline). In one experiment, zebrafish were treated for 72 h with 0.2 mg/L fluoxetine, 2 mg/L pCPA, or the drugs combination. In another experiment, zebrafish were treated for 72 h with 0.5 mg/L pargyline, 2 mg/L pCPA, or the drugs combination. Behavior was studied in the novel tank diving test, mRNA levels were assayed by qPCR, 5-HT and its metabolite concentrations were measured by HPLC. The effects of interaction between pCPA and the drugs on zebrafish behavior were observed: pCPA attenuated “surface dwelling” induced by the drugs. Fluoxetine decreased mRNA levels of Tph2 and Htr2aa genes, while pargyline decreased mRNA levels of Slc6a4b and Htr1aa genes. Pargyline reduced Creb, Bdnf and Ntrk2a genes mRNA concentration only in the zebrafish treated with pCPA. The results show that the disruption of the TPH2 function can cause a refractory to antidepressant treatment.
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Affiliation(s)
- Valentina S. Evsiukova
- Department of Psychoneuropharmacology, Federal Research Center Institute of Cytology and Genetic Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia; (V.S.E.); (E.A.K.)
| | - Daria Bazovkina
- Department of Behavioral Neurogenomics, Federal Research Center Institute of Cytology and Genetic Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia;
| | - Ekaterina Bazhenova
- Department of Genetic Collections of Neural Disorders, Federal Research Center Institute of Cytology and Genetic Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia;
| | - Elizabeth A. Kulikova
- Department of Psychoneuropharmacology, Federal Research Center Institute of Cytology and Genetic Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia; (V.S.E.); (E.A.K.)
| | - Alexander V. Kulikov
- Department of Genetic Collections of Neural Disorders, Federal Research Center Institute of Cytology and Genetic Siberian Branch of Russian Academy of Sciences, 630090 Novosibirsk, Russia;
- Correspondence: ; Tel.: +7-3833636187
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Valenzuela-Iglesias MF, Ccama-Leiva JL, Urrunaga-Pastor D, Runzer-Colmenares FM, Parodi JF. Association between depressive symptoms and disability in older adults of 12 high Andean communities from Peru. Int J Geriatr Psychiatry 2021; 37. [PMID: 34520083 DOI: 10.1002/gps.5619] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2021] [Accepted: 08/23/2021] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Our objective was to evaluate the association between depressive symptoms and disability in older adults residing in 12 high Andean communities in Peru. MATERIAL AND METHODS We carried out a secondary data analysis of a cross-sectional study that included older adults (60 years or older) from 12 high Andean communities in Peru from 2013 to 2019. Depressive symptoms were defined as a score of two or more in the abbreviated Geriatric Depression Scale, while disability was defined as a score of less than 95 in the Barthel index. We also included sociodemographic characteristics, medical and personal history, and functional and performance-based tests. We used crude and adjusted Poisson regression models to evaluate the association of interest and estimated prevalence ratios (PR) with their respective 95% confidence intervals (95% CI). RESULTS We included 442 older adults with a mean age of 73 ± 6.9 in the analysis; 63.1% (n = 279) were women, and 79.9% (n = 353) had no education or incomplete primary school. 50.9% (n = 225) of the participants had depressive symptoms, and 49.8% (n = 220) had disability. The adjusted Poisson regression model showed that depressive symptoms increased the probability of disability (adjusted PR = 1.67; 95% CI: 1.34-2.08; p < 0.001) in older adults living at high altitude. CONCLUSIONS Depressive symptoms was associated with a greater probability of disability in older adults living at high altitude. Longitudinal studies are needed for better understanding of this association in high altitude populations along with timely interventions to reduce the impact of both geriatric syndromes.
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Affiliation(s)
- Mia F Valenzuela-Iglesias
- Facultad de Ciencias de la Salud, Universidad Científica del Sur, Carrera de Medicina Humana, Lima, Peru
| | - J Lorena Ccama-Leiva
- Facultad de Ciencias de la Salud, Universidad Científica del Sur, Carrera de Medicina Humana, Lima, Peru
| | - Diego Urrunaga-Pastor
- Facultad de Ciencias de la Salud, Universidad Científica del Sur, Carrera de Medicina Humana, Lima, Peru
- Dirección de Investigación en Salud, Instituto de Evaluación de Tecnologías en Salud e Investigación-IETSI, EsSalud, Lima, Peru
| | - Fernando M Runzer-Colmenares
- Facultad de Ciencias de la Salud, Universidad Científica del Sur, Carrera de Medicina Humana, Lima, Peru
- Facultad de Medicina Humana, Centro de Investigación del Envejecimiento (CIEN), Universidad de San Martin de Porres, Lima, Peru
| | - José F Parodi
- Facultad de Medicina Humana, Centro de Investigación del Envejecimiento (CIEN), Universidad de San Martin de Porres, Lima, Peru
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The antidepressant drug vilazodone is an allosteric inhibitor of the serotonin transporter. Nat Commun 2021; 12:5063. [PMID: 34417466 PMCID: PMC8379219 DOI: 10.1038/s41467-021-25363-3] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 08/05/2021] [Indexed: 12/12/2022] Open
Abstract
Depression is a common mental disorder. The standard medical treatment is the selective serotonin reuptake inhibitors (SSRIs). All characterized SSRIs are competitive inhibitors of the serotonin transporter (SERT). A non-competitive inhibitor may produce a more favorable therapeutic profile. Vilazodone is an antidepressant with limited information on its molecular interactions with SERT. Here we use molecular pharmacology and cryo-EM structural elucidation to characterize vilazodone binding to SERT. We find that it exhibits non-competitive inhibition of serotonin uptake and impedes dissociation of [3H]imipramine at low nanomolar concentrations. Our SERT structure with bound imipramine and vilazodone reveals a unique binding pocket for vilazodone, expanding the boundaries of the extracellular vestibule. Characterization of the binding site is substantiated with molecular dynamics simulations and systematic mutagenesis of interacting residues resulting in decreased vilazodone binding to the allosteric site. Our findings underline the versatility of SERT allosteric ligands and describe the unique binding characteristics of vilazodone. Vilazodone (VLZ) is a drug for the treatment of major depressive disorders that targets the serotonin transporter (SERT). Here, the authors combine pharmacology measurements and cryo-EM structural analysis to characterize VLZ binding to SERT and observe that VLZ exhibits non-competitive inhibition of serotonin transport and binds with nanomolar affinity to an allosteric site in SERT.
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Terstege DJ, MacDonald DS, Tasker RA. Standardised ginseng extract G115® potentiates the antidepressant-like properties of fluoxetine in the forced swim test. Acta Neuropsychiatr 2021; 33:141-147. [PMID: 33478610 DOI: 10.1017/neu.2021.2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Ginsenosides, biologically active components of the root of Panax ginseng, have been reported to have therapeutic benefits in a number of disease states including psychiatric conditions such as major depressive disorder. Our objective was to determine if a standardised commercial ginseng extract, G115®, could reduce the signs of behavioural despair commonly observed in animal models of depression either alone or in combination with the selective serotonin reuptake inhibitor (SSRI) fluoxetine. METHODS Male Sprague-Dawley (SD) rats (N = 51) were divided into four groups: vehicle control, G115® ginseng root extract, fluoxetine and fluoxetine plus G115®. Rats were trained to voluntarily consume treatments twice daily for 14 days and were then tested in an open field (OF), elevated plus maze (EPM) and forced swim test (FST). Post-mortem hippocampal and prefrontal cortex tissue was analysed for expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) by western blot. RESULTS One-way Analysis of Variance revealed no significant group differences in the OF or plus-maze performance on any variable examined. In the FST, fluoxetine significantly reduced immobility time and increased latency to immobility. The effects of fluoxetine were further significantly potentiated by co-administration of G115®. Post-mortem tissue analysis revealed significant group differences in BDNF expression in the left hippocampus and left prefrontal cortex without any accompanying changes in TrkB expression. CONCLUSIONS We conclude that oral G115® significantly potentiates the antidepressant-like effect of fluoxetine in the FST in the absence of potentially confounding effects on locomotion and anxiety.
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Affiliation(s)
- Dylan J Terstege
- Department of Biomedical Sciences, University of Prince Edward Island, Charlottetown, Canada
| | - Debra S MacDonald
- Department of Biomedical Sciences, University of Prince Edward Island, Charlottetown, Canada
| | - R Andrew Tasker
- Department of Biomedical Sciences, University of Prince Edward Island, Charlottetown, Canada
- Translational Neuropsychiatry Unit, Clinical Medicine, Aarhus Universitet, Aarhus, Denmark
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Zhou D, Zhou X, Lin Q, Wang W, Lv Z, Chen X, Nie G, Kuang L. Nonpharmacological interventions for relapse prevention in unipolar depression: A network meta-analysis. J Affect Disord 2021; 282:1255-1262. [PMID: 33601704 DOI: 10.1016/j.jad.2021.01.025] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 01/08/2021] [Accepted: 01/11/2021] [Indexed: 11/28/2022]
Abstract
BACKGROUND The development of prophylactic interventions for major depressive disorder (MDD) is an important issue in clinical practice. We aimed to compare the relative efficacy of nonpharmacological interventions for relapse prevention in adult patients with MDD. METHODS Randomized controlled trials investigating nonpharmachological interventions for relapse prevention were included. A Bayesian network meta-analysis was performed. Hazard ratios are reported as effect sizes with 95% credible intervals. Global inconsistency, local inconsistency, heterogeneity, and transitivity were evaluated. Confidence for the results comparing the active treatment with control conditions or antidepressant medicine (ADM) was assessed. RESULTS Thirty-six trials were included. Most nonpharmacological interventions were various forms of psychotherapy; others were noninvasive neurostimulation techniques (3 studies with electroconvulsive therapy and 1 study with transcranial magnetic stimulation). Psychotherapy as a monotherapy following ADM or psychotherapy produced significantly better outcomes than control conditions, and there was no significant difference between psychotherapy and ADM. The combination of psychotherapy and ADM was superior to either treatment alone. The results were similar for patients with at least 3 previous episodes. Neurostimulation techniques were also superior to controls, either as a monotherapy or combined with ADM. CONCLUSIONS Our study provided evidence that psychotherapy as a monotherapy following ADM or psychotherapy was effective and performed as well as ADM for relapse prevention. Neurostimulation techniques also showed promising results but more studies are needed to confirm their efficacy. These findings may be informative for clinical practice and inspire future research.
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Affiliation(s)
- Dongdong Zhou
- Mental Health Center, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaoxin Zhou
- Medical Department, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Qingxia Lin
- Department of Psychiatry, The First Affiliated Hospital of Wenzhou Medical University, Zhejiang Province, China
| | - Wo Wang
- Mental Health Center, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Zhen Lv
- Mental Health Center, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaorong Chen
- Mental Health Center, University-Town Hospital of Chongqing Medical University, Chongqing, China
| | - Gang Nie
- Department of Gastroenterology, University-Town Hospital of Chongqing Medical University, Shapingba District, Chongqing, 401331, China.
| | - Li Kuang
- Mental Health Center, University-Town Hospital of Chongqing Medical University, Chongqing, China; Department of Psychiatry, The First Affiliated Hospital of Chongqing Medical University, Yuzhong District, Chongqing, 400016, China.
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Lages YVM, Rossi AD, Krahe TE, Landeira-Fernandez J. Effect of chronic unpredictable mild stress on the expression profile of serotonin receptors in rats and mice: a meta-analysis. Neurosci Biobehav Rev 2021; 124:78-88. [PMID: 33524415 DOI: 10.1016/j.neubiorev.2021.01.020] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 01/19/2021] [Accepted: 01/22/2021] [Indexed: 12/17/2022]
Abstract
Chronic-stress-induced depression is recognized as a widespread public health concern. Selective serotonin reuptake inhibitors (SSRIs) have been the most common treatment for this illness. However, the role of 5-hydroxytryptamine (5-HT) receptor subtypes in stress-induced depression remains unclear. Evidence from Animal studies has reported a variety of results regarding the effects of chronic unpredictable mild stress (CUMS) on serotonin signaling pathways and 5-HT receptor subtypes. This divergence may rely on differences in protocols, methods, and studied pathways. Thus, the aim of this systematic review was to weigh the currently available findings regarding serotonin receptor changes in animal models of CUMS. Overall, our meta-analysis results showed the association of altered expression of 5-HT1A receptors in the frontal cortex and 5-HT2A receptors both in the whole cortex and the hypothalamus of rats following CUMS. Moreover, by using a qualitative-structured analysis and the application of risk-of-bias tools, we identified possible sources of data variation between the studied literature, which should be taken into account in future animal studies of chronic-stress induced depression.
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Affiliation(s)
- Y V M Lages
- Department of Psychology, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - A D Rossi
- Department of Genetics, Institute of Biology, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - T E Krahe
- Department of Psychology, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro, Brazil
| | - J Landeira-Fernandez
- Department of Psychology, Pontifical Catholic University of Rio de Janeiro, Rio de Janeiro, Brazil.
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Lai WT, Deng WF, Xu SX, Zhao J, Xu D, Liu YH, Guo YY, Wang MB, He FS, Ye SW, Yang QF, Liu TB, Zhang YL, Wang S, Li MZ, Yang YJ, Xie XH, Rong H. Shotgun metagenomics reveals both taxonomic and tryptophan pathway differences of gut microbiota in major depressive disorder patients. Psychol Med 2021; 51:90-101. [PMID: 31685046 DOI: 10.1017/s0033291719003027] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND The microbiota-gut-brain axis, especially the microbial tryptophan (Trp) biosynthesis and metabolism pathway (MiTBamp), may play a critical role in the pathogenesis of major depressive disorder (MDD). However, studies on the MiTBamp in MDD are lacking. The aim of the present study was to analyze the gut microbiota composition and the MiTBamp in MDD patients. METHODS We performed shotgun metagenomic sequencing of stool samples from 26 MDD patients and 29 healthy controls (HCs). In addition to the microbiota community and the MiTBamp analyses, we also built a classification based on the Random Forests (RF) and Boruta algorithm to identify the gut microbiota as biomarkers for MDD. RESULTS The Bacteroidetes abundance was strongly reduced whereas that of Actinobacteria was significantly increased in the MDD patients compared with the abundance in the HCs. Most noteworthy, the MDD patients had increased levels of Bifidobacterium, which is commonly used as a probiotic. Four Kyoto Encyclopedia of Genes and Genomes (KEGG) orthologies (KOs) (K01817, K11358, K01626, K01667) abundances in the MiTBamp were significantly lower in the MDD group. Furthermore, we found a negative correlation between the K01626 abundance and the HAMD scores in the MDD group. Finally, RF classification at the genus level can achieve an area under the receiver operating characteristic curve of 0.890. CONCLUSIONS The present findings enabled a better understanding of the changes in gut microbiota and the related Trp pathway in MDD. Alterations of the gut microbiota may have the potential as biomarkers for distinguishing MDD patients form HCs.
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Affiliation(s)
- Wen-Tao Lai
- Department of Psychiatry, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, Guangdong, China
| | - Wen-Feng Deng
- Laboratory of Brain Stimulation and Biological Psychiatry, Brain Function and Psychosomatic Medicine Institute, Second People's Hospital of Huizhou, Huizhou, Guangdong, China
| | - Shu-Xian Xu
- Laboratory of Brain Stimulation and Biological Psychiatry, Brain Function and Psychosomatic Medicine Institute, Second People's Hospital of Huizhou, Huizhou, Guangdong, China
| | - Jie Zhao
- Department of Psychiatry, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, Guangdong, China
| | - Dan Xu
- Department of Psychiatry, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, Guangdong, China
| | - Yang-Hui Liu
- Department of Psychiatry, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, Guangdong, China
| | - Yuan-Yuan Guo
- Department of Psychiatry, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, Guangdong, China
| | - Ming-Bang Wang
- Xiamen Branch, Shanghai Key Laboratory of Birth Defects, Division of Neonatology, Children's Hospital of Fudan University, National Center for Children's Health, Shanghai, China
| | | | - Shu-Wei Ye
- Department of Psychiatry, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, Guangdong, China
| | - Qi-Fan Yang
- Laboratory of Brain Stimulation and Biological Psychiatry, Brain Function and Psychosomatic Medicine Institute, Second People's Hospital of Huizhou, Huizhou, Guangdong, China
| | - Tie-Bang Liu
- Department of Psychiatry, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, Guangdong, China
| | - Ying-Li Zhang
- Department of Depression, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, Guangdong, China
| | - Sheng Wang
- Department of Psychiatry, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, Guangdong, China
| | - Min-Zhi Li
- Department of Psychiatry, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, Guangdong, China
| | - Ying-Jia Yang
- Department of Depression, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, Guangdong, China
| | - Xin-Hui Xie
- Department of Psychiatry, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, Guangdong, China
- Laboratory of Brain Stimulation and Biological Psychiatry, Brain Function and Psychosomatic Medicine Institute, Second People's Hospital of Huizhou, Huizhou, Guangdong, China
- Center of Acute Psychiatry Service, Second People's Hospital of Huizhou, Huizhou, Guangdong, China
| | - Han Rong
- Department of Psychiatry, Shenzhen Kangning Hospital, Shenzhen Mental Health Center, Shenzhen, Guangdong, China
- Affiliated Shenzhen Clinical College of Psychiatry, Jining Medical University, Jining, Shandong, China
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Bright S, Williams M. Should Australian Psychology Consider Enhancing Psychotherapeutic Interventions with Psychedelic Drugs? A Call for Research. AUSTRALIAN PSYCHOLOGIST 2020. [DOI: 10.1111/ap.12345] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- Stephen Bright
- School of Medical and Health Sciences, Edith Cowan University,
- National Drug Research Institute, Curtin University,
| | - Martin Williams
- Monash Institute of Pharmaceutical Sciences, Monash University,
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Skonieczna-Żydecka K, Jakubczyk K, Maciejewska-Markiewicz D, Janda K, Kaźmierczak-Siedlecka K, Kaczmarczyk M, Łoniewski I, Marlicz W. Gut Biofactory-Neurocompetent Metabolites within the Gastrointestinal Tract. A Scoping Review. Nutrients 2020; 12:E3369. [PMID: 33139656 PMCID: PMC7693392 DOI: 10.3390/nu12113369] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/27/2020] [Accepted: 10/29/2020] [Indexed: 12/12/2022] Open
Abstract
The gut microbiota have gained much scientific attention recently. Apart from unravelling the taxonomic data, we should understand how the altered microbiota structure corresponds to functions of this complex ecosystem. The metabolites of intestinal microorganisms, especially bacteria, exert pleiotropic effects on the human organism and contribute to the host systemic balance. These molecules play key roles in regulating immune and metabolic processes. A subset of them affect the gut brain axis signaling and balance the mental wellbeing. Neurotransmitters, short chain fatty acids, tryptophan catabolites, bile acids and phosphatidylcholine, choline, serotonin, and L-carnitine metabolites possess high neuroactive potential. A scoping literature search in PubMed/Embase was conducted up until 20 June 2020, using three major search terms "microbiota metabolites" AND "gut brain axis" AND "mental health". This review aimed to enhance our knowledge regarding the gut microbiota functional capacity, and support current and future attempts to create new compounds for future clinical interventions.
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Affiliation(s)
- Karolina Skonieczna-Żydecka
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, 71-460 Szczecin, Poland; (K.S.-Ż.); (K.J.); (D.M.-M.); (K.J.)
| | - Karolina Jakubczyk
- Department of Surgical Oncology, Medical University of Gdansk, Smoluchowskiego 17, 80-214 Gdańsk, Poland;
| | - Dominika Maciejewska-Markiewicz
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, 71-460 Szczecin, Poland; (K.S.-Ż.); (K.J.); (D.M.-M.); (K.J.)
| | - Katarzyna Janda
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, 71-460 Szczecin, Poland; (K.S.-Ż.); (K.J.); (D.M.-M.); (K.J.)
| | | | - Mariusz Kaczmarczyk
- Department of Clinical and Molecular Biochemistry, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland;
| | - Igor Łoniewski
- Department of Human Nutrition and Metabolomics, Pomeranian Medical University in Szczecin, 71-460 Szczecin, Poland; (K.S.-Ż.); (K.J.); (D.M.-M.); (K.J.)
| | - Wojciech Marlicz
- Department of Gastroenterology, Pomeranian Medical University, 71-252 Szczecin, Poland
- The Centre for Digestive Diseases Endoklinika, 70-535 Szczecin, Poland
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Munir S, Shahid A, Aslam B, Ashfaq UA, Akash MSH, Ali MA, Almatroudi A, Allemailem KS, Rajoka MSR, Khurshid M. The Therapeutic Prospects of Naturally Occurring and Synthetic Indole Alkaloids for Depression and Anxiety Disorders. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2020; 2020:8836983. [PMID: 33123212 PMCID: PMC7585661 DOI: 10.1155/2020/8836983] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 09/10/2020] [Accepted: 09/21/2020] [Indexed: 11/17/2022]
Abstract
Depression and anxiety are the most common disorders among all age groups. Several antidepressant drugs including benzodiazepine, antidepressant tricyclics, azapirone, noradrenaline reuptake inhibitors, serotonin selective reuptake inhibitors, serotonin, noradrenaline reuptake inhibitors, and monoamine oxidase inhibitors have been used to treat these psychiatric disorders. However, these antidepressants are generally synthetic agents and can cause a wide range of side effects. The potential efficacy of plant-derived alkaloids has been reviewed against various neurodegenerative diseases including Alzheimer's disease, Huntington disease, Parkinson's disease, schizophrenia, and epilepsy. However, data correlating the indole alkaloids and antidepressant activity are limited. Natural products, especially plants and the marine environment, are rich sources of potential new drugs. Plants possess a variety of indole alkaloids, and compounds that have an indole moiety are related to serotonin, which is a neurotransmitter that regulates brain function and cognition, which in turn alleviates anxiety, and ensures a good mood and happiness. The present review is a summary of the bioactive compounds from plants and marine sources that contain the indole moiety, which can serve as potent antidepressants. The prospects of naturally occurring as well as synthetic indole alkaloids for the amelioration of anxiety and depression-related disorders, structure-activity relationship, and their therapeutic prospects have been discussed.
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Affiliation(s)
- Samman Munir
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
| | - Aqsa Shahid
- Department of Microbiology, Government College University, Faisalabad, Pakistan
| | - Bilal Aslam
- Department of Microbiology, Government College University, Faisalabad, Pakistan
| | - Usman Ali Ashfaq
- Department of Bioinformatics and Biotechnology, Government College University, Faisalabad, Pakistan
| | | | | | - Ahmad Almatroudi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | - Khaled S. Allemailem
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia
| | | | - Mohsin Khurshid
- Department of Microbiology, Government College University, Faisalabad, Pakistan
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Antidepressant-Like Properties of Fish Oil on Postpartum Depression-Like Rats Model: Involvement of Serotonergic System. Brain Sci 2020; 10:brainsci10100733. [PMID: 33066310 PMCID: PMC7602049 DOI: 10.3390/brainsci10100733] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 08/27/2020] [Accepted: 09/07/2020] [Indexed: 01/23/2023] Open
Abstract
Pathophysiology of postpartum depression (PPD) has been associated with many factors, such as neuroendocrine, neuroinflammation and neurotransmitter changes. Fish oil (FO) improves PPD both in humans and animals. However, little is known with regards to its pharmacology on a PPD-like rat model. Hence, the current study aimed at investigating the effects of FO on a PPD-like rat model. Female rats were induced with PPD-like symptoms and then randomly divided into six groups (n = 6) for two experimental protocols. Protocol 1 consisted of PPD-like rats (2 mL distilled water), PPD-like + FO (9 g/kg/d) and PPD-like + Fluoxetine (FLX) (15 mg/kg/d) groups of rats, whereas Protocol 2 consisted of PPD-like rats (2 mL distilled water) + PCPA (p-chlorophenylalanine) 150 mg/kg, PPD-like + FO (9 g/kg/d) + PCPA 150 mg/kg and PPD-like + FLX (15 mg/d) + PCPA 150 mg/kg groups of rats, respectively. All treatments were administered orally for 10 days postpartum, except PCPA, which was given intraperitoneally. Prior to euthanasia, the antidepressant-like effect of the FO was evaluated using the forced swimming test (FST) and open field test (OFT) on day 10 postpartum. Biochemical analysis of serotonin, serotonin metabolite and serotonin turnover from their prefrontal cortex and hippocampus were also measured. The results showed that FO decreased immobility time and increased swimming time significantly, but not climbing time in FST. Further, it also decreased serotonin metabolite and turnover significantly in the hippocampus of the PPD-like rats. In contrast, administration with PCPA reversed all the outcomes. The antidepressant-like effects of FO were found to be similar with that of FLX. Thus, it can be concluded that FO exerts its antidepressant-like effects in PPD-like rats through modulation of serotonergic system.
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Markers for the central serotonin system correlate to verbal ability and paralinguistic social voice processing in autism spectrum disorder. Sci Rep 2020; 10:14558. [PMID: 32883965 PMCID: PMC7471326 DOI: 10.1038/s41598-020-71254-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 08/12/2020] [Indexed: 01/06/2023] Open
Abstract
Impairment in verbal communication abilities has been reported in autism spectrum disorder (ASD). Dysfunction of the serotonergic system has also been reported in ASD. However, it is still unknown how the brain serotonergic system relates to impairment in verbal communication abilities in individuals with ASD. In the present study, we investigated the correlation between brain serotonergic condition and brain sensitivity to paralinguistic stimuli (i.e., amplitude in the human voice prosodic change-evoked mismatch field) measured by magnetoencephalography (MEG) or verbal ability in 10 adults with ASD. To estimate the brain serotonergic condition, we measured the serotonin transporter nondisplaceable binding potential cerebrum-wide using positron emission tomography with [11C]N,N-dimethyl-2-(2-amino-4-cyanophenylthio)benzylamine ([11C] DASB). The results demonstrated a significant positive correlation between brain activity to paralinguistic stimuli and brain serotonin transporter binding potential in the left lingual gyrus, left fusiform gyrus and left calcarine cortex. In addition, there were significant positive correlations between verbal ability and serotonergic condition in the right anterior insula, right putamen and right central operculum. These results suggested that the occipital cortex is implicated in recognition of the prosodic change in ASD, whereas the right insula-involved serotonergic system is important in nurturing verbal function in ASD.Trial registration: UMIN000011077.
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Johnston JN, Thacker JS, Desjardins C, Kulyk BD, Romay-Tallon R, Kalynchuk LE, Caruncho HJ. Ketamine Rescues Hippocampal Reelin Expression and Synaptic Markers in the Repeated-Corticosterone Chronic Stress Paradigm. Front Pharmacol 2020; 11:559627. [PMID: 32982757 PMCID: PMC7493014 DOI: 10.3389/fphar.2020.559627] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Accepted: 08/18/2020] [Indexed: 11/13/2022] Open
Abstract
Depression is the leading cause of disability worldwide, which necessitates novel therapeutics and biomarkers to approach treatment of this neuropsychiatric disorder. To assess potential mechanisms underlying the fast-acting antidepressant actions of ketamine we used a repeated corticosterone paradigm in adult male rats to assess the effects of ketamine on reelin-positive cells, a protein largely implicated in the pathophysiology of depression. We also assessed the effects of reelin and ketamine on hippocampal and cerebellar synpatosomes, and on serotonin transporter clustering in peripheral lymphocytes to determine reelin and ketamine's impact at the synaptic and peripheral levels. Reelin and ketamine similarly rescue synaptic expression of mTOR and p-mTOR that were decreased by corticosterone. Reelin, but not ketamine, was able to rescue patterns of serotonin transporter clustering in the periphery. These findings display ketamine as a powerful modulator of reelin expression and lend strength to further evaluation of the putative fast antidepressant-like actions of reelin.
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Affiliation(s)
| | | | | | - Brian D. Kulyk
- Department of Psychology, University of Saskatchewan, Saskatoon, SK, Canada
| | | | - Lisa E. Kalynchuk
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
| | - Hector J. Caruncho
- Division of Medical Sciences, University of Victoria, Victoria, BC, Canada
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Sowa J, Hess G. Prenatal stress-related alterations in synaptic transmission and 5-HT 7 receptor-mediated effects in the rat dorsal raphe nucleus are ameliorated by the 5-HT 7 receptor antagonist SB 269970. Eur J Neurosci 2020; 52:3295-3305. [PMID: 32402149 DOI: 10.1111/ejn.14778] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 04/10/2020] [Accepted: 05/06/2020] [Indexed: 11/30/2022]
Abstract
Early life adversity exerts a detrimental influence on developing brain neuronal networks and its consequences may include mental health disorders. In rats, prenatal stress may lead to anxiety and depressive-like behavior in the offspring. Several lines of evidence implicated an involvement of prenatal stress in alterations of the brain serotonergic system functions, but the effects of prenatal stress on its core, the dorsal raphe nucleus (DRN), still remain incompletely understood. The present study was aimed at finding whether prenatal stress induces modifications in the glutamatergic and GABAergic inputs to DRN projection cells and whether it affects DRN 5-HT7 receptors, which modulate activity of these synapses. Prenatal stress resulted in an increase in basal frequency of spontaneous excitatory postsynaptic currents (sEPSCs) and in a decrease in basal frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded from putative projection neurons in DRN slices ex vivo. While there were no changes in the excitability of DRN projection neurons, the 5-HT7 receptor-mediated reduction in the sEPSC frequency and rise in the sIPSC frequency, seen in control rats, were largely absent in slices obtained from prenatally stressed rats. Repeated administration of SB 269970, a 5-HT7 receptor antagonist, resulted in a reversal of prenatal stress-induced alterations in 5-HT7 receptor-mediated effects on the sEPSC/sIPSC frequency. Moreover, the treatment reversed prenatal stress-induced alterations in basal excitatory transmission and partially reversed the effect of stress on basal inhibitory transmission in the DRN.
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Affiliation(s)
- Joanna Sowa
- Department of Physiology, Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
| | - Grzegorz Hess
- Department of Physiology, Maj Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland
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Antidepressant-like effect of hydroalcoholic extract from barks of Rapanea ferruginea: Role of monoaminergic system and effect of its isolated compounds myrsinoic acid A and B. Behav Brain Res 2020; 389:112601. [DOI: 10.1016/j.bbr.2020.112601] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 03/02/2020] [Accepted: 03/06/2020] [Indexed: 01/22/2023]
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Mulugeta A, Zhou A, King C, Hyppönen E. Association between major depressive disorder and multiple disease outcomes: a phenome-wide Mendelian randomisation study in the UK Biobank. Mol Psychiatry 2020; 25:1469-1476. [PMID: 31427754 DOI: 10.1038/s41380-019-0486-1] [Citation(s) in RCA: 63] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 05/26/2019] [Accepted: 06/10/2019] [Indexed: 11/09/2022]
Abstract
Depression affects all aspects of an individual's life but evidence relating to the causal effects on health is limited. We used information from 337,536 UK Biobank participants and performed hypothesis-free phenome-wide association analyses between major depressive disorder (MDD) genetic risk score (GRS) and 925 disease outcomes. GRS-disease outcome associations passing the multiple-testing corrected significance threshold (P < 1.9 × 10-3) were followed by Mendelian randomisation (MR) analyses to test for causality. MDD GRS was associated with 22 distinct diseases in the phenome-wide discovery stage, with the strongest signal observed for MDD diagnosis and related co-morbidities including anxiety and sleep disorders. In inverse-variance weighted MR analyses, MDD was associated with several inflammatory and haemorrhagic gastrointestinal diseases, including oesophagitis (OR 1.32, 95% CI 1.18-1.48), non-infectious gastroenteritis (OR 1.25, 95% CI 1.06-1.48), gastrointestinal haemorrhage (OR 1.26, 95% CI 1.11-1.43) and intestinal E.coli infections (OR 3.24, 95% CI 1.74-6.02). Signals were also observed for symptoms/disorders of the urinary system (OR 1.36, 95% CI 1.19-1.56), asthma (OR 1.23, 95% CI 1.06-1.44), and painful respiration (OR 1.28, 95% CI 1.14-1.44). MDD was associated with disorders of lipid metabolism (OR 1.22, 95% CI 1.12-1.34) and ischaemic heart disease (OR 1.30, 95% CI 1.15-1.47). Sensitivity analyses excluding pleiotropic variants provided consistent associations. Our study indicates a causal link between MDD and a broad range of diseases, suggesting a notable burden of co-morbidity. Early detection and management of MDD is important, and treatment strategies should be selected to also minimise the risk of related co-morbidities.
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Affiliation(s)
- Anwar Mulugeta
- Australian Centre for Precision Health, University of South Australia Cancer Research Institute, Adelaide, Australia.,Department of Pharmacology, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia
| | - Ang Zhou
- Australian Centre for Precision Health, University of South Australia Cancer Research Institute, Adelaide, Australia
| | - Catherine King
- Australian Centre for Precision Health, University of South Australia Cancer Research Institute, Adelaide, Australia.,School of Pharmacy and Medical Sciences, University of South Australia, North Terrace, Adelaide, SA, Australia
| | - Elina Hyppönen
- Australian Centre for Precision Health, University of South Australia Cancer Research Institute, Adelaide, Australia. .,Population, Policy and Practice, UCL Great Ormond Street Institute of Child Health, London, UK. .,South Australian Health and Medical Research Institute, Adelaide, Australia.
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49
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Abstract
Pregnancy, a sensitive time when two bodies are changing and developing simultaneously, demands careful consideration in assessing and treating mental health conditions. Add to that the restrictions on researching such a vulnerable population, psychiatric nurses face a challenge in providing evidence-based care. The current article focuses on the epidemiology of postpartum depression and long-term consequences, neurobiology of postpartum depression that guides medication selection, and treatment options for supporting postpartum women and their families. [Journal of Psychosocial Nursing and Mental Health Services, 57(11), 9-14.].
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50
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Hu H, Kang C, Hou X, Zhang Q, Meng Q, Jiang J, Hao W. Blue Light Deprivation Produces Depression-Like Responses in Mongolian Gerbils. Front Psychiatry 2020; 11:233. [PMID: 32322220 PMCID: PMC7156555 DOI: 10.3389/fpsyt.2020.00233] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2019] [Accepted: 03/10/2020] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Depression is a leading cause of disability worldwide and is a major contributor to the overall global burden of disease, but its etiology is poorly understood. It has been reported that a disrupted biological rhythm, in terms of a shortened light duration and total darkness, can cause depression-like behaviors in animals. Blue light was reported to have an inhibitory effect on melatonin, which is considered an important clock rhythm biomarker. In the present study, we investigated the effects of blue light deprivation on depressive-like behaviors in gerbils and explored the underlying mechanisms. METHODS Gerbils were housed under white light with a filter to block the blue light or without a filter. The behaviors of the gerbils were observed. The biological rhythm, 5-HT, hypothalamic-pituitary-adrenal (HPA) axis and melanopsin pathway were analyzed. RESULTS We found that blue light deprivation (BLD) induced depression-like behavior in gerbils. Melatonin lost its rhythm, and corticosterone (CORT) levels decreased in the morning in the BLD group. Lower corticotropin-releasing hormone (CRH) in the hypothalamus and lower adrenocorticotropin hormone (ACTH)/CORT in serum were observed after BLD. Furthermore, 5-HT in the serum and brain were decreased after BLD. Additionally, BLD affected the blue light sensitivity protein melanopsin and its pathway, with downregulation of the proteins melanopsin, PKCα, and c-Fos and the mRNA levels of c-fos and trpc3 and upregulation of the protein p-PKCα. CONCLUSIONS Our findings indicated that BLD might produce depression-like behaviors in gerbils. Melatonin arrhythmicity, HPA axis abnormalities, 5-HT decreases and melanopsin pathway changes might be associated with the depression behavioral phenotype in gerbils.
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Affiliation(s)
- Hong Hu
- Department of Toxicology, School of Public Health, Peking University, Beijing, China
- Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing, China
| | - Chenping Kang
- Department of Toxicology, School of Public Health, Peking University, Beijing, China
- Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing, China
| | - Xiaohong Hou
- Department of Toxicology, School of Public Health, Peking University, Beijing, China
- Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing, China
| | - Qi Zhang
- Department of Toxicology, School of Public Health, Peking University, Beijing, China
- Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing, China
| | - Qinghe Meng
- Department of Toxicology, School of Public Health, Peking University, Beijing, China
- Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing, China
| | - Jianjun Jiang
- Department of Toxicology, School of Public Health, Peking University, Beijing, China
- Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing, China
| | - Weidong Hao
- Department of Toxicology, School of Public Health, Peking University, Beijing, China
- Beijing Key Laboratory of Toxicological Research and Risk Assessment for Food Safety, Beijing, China
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