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Chen BK, Whye A, Matthews LC, Moniz T, Mendez-David I, Gardier AM, David DJ, Johns S, Weisblum E, Denny CA. Chronic, combinatorial targeting of NMDARs and 5-HT 4Rs exerts extended behavioral effects against stress-induced perseverative behavior and hyponeophagia. Neuropsychopharmacology 2025:10.1038/s41386-025-02107-1. [PMID: 40263416 DOI: 10.1038/s41386-025-02107-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2025] [Revised: 03/20/2025] [Accepted: 04/07/2025] [Indexed: 04/24/2025]
Abstract
Serotonin (5-HT) receptors and N-methyl-D-aspartate receptors (NMDARs) have both been implicated in stress-induced psychiatric disorders. However, there is a paucity of studies evaluating the effectiveness of novel combinatorial pharmacological treatments to treat stress-related disorders. Here, we evaluated whether administration of combinatorial (R,S)-ketamine, an NMDAR antagonist and Food and Drug Administration (FDA)-approved anesthetic, and prucalopride, a 5-HT type IV receptor (5-HT4R) agonist and FDA-approved drug for chronic idiopathic constipation (CIC), would have additional effects when administered after stress. A single injection of saline (Sal), (R,S)-ketamine (K), prucalopride (P), or a combined dose of (R,S)-ketamine and prucalopride (K + P) was administered for 1x, 2x, or 7x per week for 2 weeks after either contextual fear conditioning (CFC), learned helplessness (LH), stress enhanced fear learning (SEFL), or chronic corticosterone (CORT) stress in both sexes. Drug efficacy was assayed using assays to measure fear, behavioral despair, perseverative, and/or hyponeophagia. Combinatorial drug administration was also tested using intranasal delivery. We found that combinatorial K + P exerted additional effects, compared to either drug alone, in reducing a variety of stress-induced behaviors in both sexes. Moreover, intranasal dosing was also effective. Our results indicate that chronic administration of K + P has extended benefits for combating stress-induced pathophysiology. Our findings provide strong evidence that future clinical studies using this chronic treatment strategy may prove advantageous in decreasing a broad range of stress-induced psychiatric disorders.
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Affiliation(s)
- Briana K Chen
- Doctoral Program in Neurobiology and Behavior (NB&B), Columbia University, New York, NY, 10027, USA
- Department of Psychiatry, Columbia University Irving Medical Center (CUIMC), New York, NY, 10032, USA
| | - Alicia Whye
- Department of Psychiatry, Columbia University Irving Medical Center (CUIMC), New York, NY, 10032, USA
- Division of Systems Neuroscience, Research Foundation for Mental Hygiene, Inc. (RFMH) / New York State Psychiatric Institute (NYSPI), New York, NY, 10032, USA
| | - Louise C Matthews
- Department of Psychiatry, Columbia University Irving Medical Center (CUIMC), New York, NY, 10032, USA
- Division of Systems Neuroscience, Research Foundation for Mental Hygiene, Inc. (RFMH) / New York State Psychiatric Institute (NYSPI), New York, NY, 10032, USA
| | - Taylor Moniz
- School of General Studies, Columbia University, New York, NY, 10027, USA
- Trinity College Dublin, The University of Dublin, Dublin 2, IRL, Dublin, Ireland
| | - Indira Mendez-David
- Université Paris-Saclay, UVSQ, Centre de recherche en Epidémiologie et Santé des Populations (CESP), UMR 1018, CESP-Inserm, Team Moods, Faculté de Pharmacie, Bâtiment Henri MOISSAN, Orsay, FRA, France
| | - Alain M Gardier
- Université Paris-Saclay, UVSQ, Centre de recherche en Epidémiologie et Santé des Populations (CESP), UMR 1018, CESP-Inserm, Team Moods, Faculté de Pharmacie, Bâtiment Henri MOISSAN, Orsay, FRA, France
| | - Denis J David
- Université Paris-Saclay, UVSQ, Centre de recherche en Epidémiologie et Santé des Populations (CESP), UMR 1018, CESP-Inserm, Team Moods, Faculté de Pharmacie, Bâtiment Henri MOISSAN, Orsay, FRA, France
| | | | | | - Christine A Denny
- Department of Psychiatry, Columbia University Irving Medical Center (CUIMC), New York, NY, 10032, USA.
- Division of Systems Neuroscience, Research Foundation for Mental Hygiene, Inc. (RFMH) / New York State Psychiatric Institute (NYSPI), New York, NY, 10032, USA.
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Zhang Y, Pan YD, Zheng WY, Li HY, Zhu MZ, Ou Yang WJ, Qian Y, Turecki G, Mechawar N, Zhu XH. Enhancing HIF-1α-P2X2 signaling in dorsal raphe serotonergic neurons promotes psychological resilience. Redox Biol 2024; 69:103005. [PMID: 38150991 PMCID: PMC10788260 DOI: 10.1016/j.redox.2023.103005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Accepted: 12/17/2023] [Indexed: 12/29/2023] Open
Abstract
Major depressive disorder (MDD) is a devastating condition. Although progress has been made in the past seven decades, patients with MDD continue to receive an inadequate treatment, primarily due to the late onset of first-line antidepressant drugs and to their acute withdrawal symptoms. Resilience is the ability to rebound from adversity in a healthy manner and many people have psychological resilience. Revealing the mechanisms and identifying methods promoting resilience will hopefully lead to more effective prevention strategies and treatments for depression. In this study, we found that intermittent hypobaric hypoxia training (IHHT), a method for training pilots and mountaineers, enhanced psychological resilience in adult mice. IHHT produced a sustained antidepressant-like effect in mouse models of depression by inducing long-term (up to 3 months after this treatment) overexpression of hypoxia-inducible factor (HIF)-1α in the dorsal raphe nucleus (DRN) of adult mice. Moreover, DRN-infusion of cobalt chloride, which mimics hypoxia increasing HIF-1α expression, triggered a rapid and long-lasting antidepressant-like effect. Down-regulation of HIF-1α in the DRN serotonergic (DRN5-HT) neurons attenuated the effects of IHHT. HIF-1α translationally regulated the expression of P2X2, and conditionally knocking out P2rx2 (encodes P2X2 receptors) in DRN5-HT neurons, in turn, attenuated the sustained antidepressant-like effect of IHHT, but not its acute effect. In line with these results, a single sub-anesthetic dose of ketamine enhanced HIF-1α-P2X2 signaling, which is essential for its rapid and long-lasting antidepressant-like effect. Notably, we found that P2X2 protein levels were significantly lower in the DRN of patients with MDD than that of control subjects. Together, these findings elucidate the molecular mechanism underlying IHHT promoting psychological resilience and highlight enhancing HIF-1α-P2X2 signaling in DRN5-HT neurons as a potential avenue for screening novel therapeutic treatments for MDD.
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Affiliation(s)
- Yuan Zhang
- School of Psychology, Shenzhen University, Shenzhen, China; Research Center for Brain Health, Pazhou Lab, Guangzhou, China
| | - Yi-da Pan
- Research Center for Brain Health, Pazhou Lab, Guangzhou, China
| | - Wen-Ying Zheng
- School of Psychology, Shenzhen University, Shenzhen, China; Research Center for Brain Health, Pazhou Lab, Guangzhou, China
| | - Huan-Yu Li
- Research Center for Brain Health, Pazhou Lab, Guangzhou, China
| | - Min-Zhen Zhu
- Research Center for Brain Health, Pazhou Lab, Guangzhou, China
| | - Wen-Jie Ou Yang
- School of Psychology, Shenzhen University, Shenzhen, China; Research Center for Brain Health, Pazhou Lab, Guangzhou, China
| | - Yu Qian
- Research Center for Brain Health, Pazhou Lab, Guangzhou, China; School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China
| | - Gustavo Turecki
- Department of Psychiatry, McGill University, McGill Group for Suicide Studies, Douglas Mental Health University Institute, 6875 LaSalle Blvd, Verdun, (Québec), Canada
| | - Naguib Mechawar
- Department of Psychiatry, McGill University, McGill Group for Suicide Studies, Douglas Mental Health University Institute, 6875 LaSalle Blvd, Verdun, (Québec), Canada
| | - Xin-Hong Zhu
- School of Psychology, Shenzhen University, Shenzhen, China; Research Center for Brain Health, Pazhou Lab, Guangzhou, China; School of Biology and Biological Engineering, South China University of Technology, Guangzhou, China.
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3
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Rădulescu I, Drăgoi AM, Trifu SC, Cristea MB. Neuroplasticity and depression: Rewiring the brain's networks through pharmacological therapy (Review). Exp Ther Med 2021; 22:1131. [PMID: 34504581 PMCID: PMC8383338 DOI: 10.3892/etm.2021.10565] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Accepted: 07/19/2021] [Indexed: 12/14/2022] Open
Abstract
In modern society, depression is one of the most common mental illness; however, its pathophysiology is not yet fully understood. A great body of evidence suggests that depression causes changes in neuroplasticity in specific regions of the brain which are correlated to symptom severity, negative emotional rumination as well as fear learning. Depression is correlated with atrophy of neurons in the cortical and limbic brain regions that control mood and emotion. Antidepressant therapy can exhibit effects on neuroplasticity and reverse the neuroanatomical changes found in depressed patients. The investigation of fast-acting agents that reverse behavioral and neuronal deficiencies of chronic depression, especially the glutamate receptor antagonist NMDA ketamine, and the cellular mechanisms underlying the rapid antidepressant actions of ketamine and related agents are of real interest in current research. Actual medication such as serotonin (5-HT) selective reuptake inhibitor (SSRI) antidepressants, require weeks to months of administration before a clear therapeutic response. The current review aimed to underline the negative effects of depression on neuroplasticity and present the current findings on the effects of antidepressant medication.
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Affiliation(s)
- Ioana Rădulescu
- Faculty of Psychology and Educational Sciences, University of Bucharest, 050663 Bucharest, Romania
| | - Ana Miruna Drăgoi
- Department of Psychiatry, 'Prof. Dr. Alex. Obregia' Clinical Hospital of Psychiatry, 041914 Bucharest, Romania
| | - Simona Corina Trifu
- Department of Clinical Neurosciences, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Mihai Bogdan Cristea
- Department of Morphological Sciences, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania
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Zhang Y, Zhu MZ, Qin XH, Zeng YN, Zhu XH. The Ghrelin/Growth Hormone Secretagogue Receptor System Is Involved in the Rapid and Sustained Antidepressant-Like Effect of Paeoniflorin. Front Neurosci 2021; 15:631424. [PMID: 33664648 PMCID: PMC7920966 DOI: 10.3389/fnins.2021.631424] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 01/26/2021] [Indexed: 12/28/2022] Open
Abstract
Major depressive disorder (MDD) is a debilitating mental illness affecting people worldwide. Although significant progress has been made in the development of therapeutic agents to treat this condition, fewer than half of all patients respond to currently available antidepressants, highlighting the urgent need for the development of new classes of antidepressant drugs. Here, we found that paeoniflorin (PF) produced rapid and sustained antidepressant-like effects in multiple mouse models of depression, including the forced swimming test and exposure to chronic mild stress (CMS). Moreover, PF decreased the bodyweight of mice without affecting food intake and glucose homeostasis, and also reduced the plasma levels of total ghrelin and the expression of ghrelin O-acyltransferase in the stomach; however, the plasma levels of ghrelin and the ghrelin/total ghrelin ratio were unaffected. Furthermore, PF significantly increased the expression of growth hormone secretagogue receptor 1 alpha (GHSR1α, encoded by the Ghsr gene) in the intestine, whereas the levels of GHSR1α in the brain were only marginally downregulated following subchronic PF treatment. Finally, the genetic deletion of Ghsr attenuated the antidepressant-like effects of PF in mice exposed to CMS. These results suggested that increased GHSR1α expression in the intestine mediates the antidepressant-like effects of PF. Understanding peripheral ghrelin/GHSR signaling may provide new insights for the screening of antidepressant drugs that produce fast-acting and sustained effects.
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Affiliation(s)
- Yuan Zhang
- Institute of Mental Health, School of Basic Medical Science, Southern Medical University, Guangzhou, China.,Key Laboratory of Mental Health of the Ministry of Education & Guangdong Province Key Laboratory of Psychiatric Disorders, Guangzhou, China.,Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, China
| | - Min-Zhen Zhu
- Institute of Mental Health, School of Basic Medical Science, Southern Medical University, Guangzhou, China.,Key Laboratory of Mental Health of the Ministry of Education & Guangdong Province Key Laboratory of Psychiatric Disorders, Guangzhou, China.,Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, China
| | - Xi-He Qin
- Eusyn Medical Technology Company, Guangzhou, China
| | - Yuan-Ning Zeng
- Institute of Mental Health, School of Basic Medical Science, Southern Medical University, Guangzhou, China.,Key Laboratory of Mental Health of the Ministry of Education & Guangdong Province Key Laboratory of Psychiatric Disorders, Guangzhou, China.,Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, China
| | - Xin-Hong Zhu
- Institute of Mental Health, School of Basic Medical Science, Southern Medical University, Guangzhou, China.,Key Laboratory of Mental Health of the Ministry of Education & Guangdong Province Key Laboratory of Psychiatric Disorders, Guangzhou, China.,Guangdong-Hong Kong-Macao Greater Bay Area Center for Brain Science and Brain-Inspired Intelligence, Guangzhou, China.,School of Psychology, Shenzhen University, Shenzhen, China
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Retinoic acid and depressive disorders: Evidence and possible neurobiological mechanisms. Neurosci Biobehav Rev 2020; 112:376-391. [DOI: 10.1016/j.neubiorev.2020.02.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2020] [Revised: 02/09/2020] [Accepted: 02/11/2020] [Indexed: 12/13/2022]
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Lathe R, Singadia S, Jordan C, Riedel G. The interoceptive hippocampus: Mouse brain endocrine receptor expression highlights a dentate gyrus (DG)-cornu ammonis (CA) challenge-sufficiency axis. PLoS One 2020; 15:e0227575. [PMID: 31940330 PMCID: PMC6961916 DOI: 10.1371/journal.pone.0227575] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Accepted: 12/20/2019] [Indexed: 12/19/2022] Open
Abstract
The primeval function of the mammalian hippocampus (HPC) remains uncertain. Implicated in learning and memory, spatial navigation, and neuropsychological disorders, evolutionary theory suggests that the HPC evolved from a primeval chemosensory epithelium. Deficits in sensing of internal body status ('interoception') in patients with HPC lesions argue that internal sensing may be conserved in higher vertebrates. We studied the expression patterns in mouse brain of 250 endocrine receptors that respond to blood-borne ligands. Key findings are (i) the proportions and levels of endocrine receptor expression in the HPC are significantly higher than in all other comparable brain regions. (ii) Surprisingly, the distribution of endocrine receptor expression within mouse HPC was found to be highly structured: receptors signaling 'challenge' are segregated in dentate gyrus (DG), whereas those signaling 'sufficiency' are principally found in cornu ammonis (CA) regions. Selective expression of endocrine receptors in the HPC argues that interoception remains a core feature of hippocampal function. Further, we report that ligands of DG receptors predominantly inhibit both synaptic potentiation and neurogenesis, whereas CA receptor ligands conversely promote both synaptic potentiation and neurogenesis. These findings suggest that the hippocampus acts as an integrator of body status, extending its role in context-dependent memory encoding from 'where' and 'when' to 'how I feel'. Implications for anxiety and depression are discussed.
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Affiliation(s)
- Richard Lathe
- Division of Infection Medicine, University of Edinburgh Medical School, Little France, Edinburgh, Scotland, United Kingdom
- * E-mail: (RL); (GR)
| | - Sheena Singadia
- Division of Behavioral Neuroscience, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, Scotland, United Kingdom
| | - Crispin Jordan
- Division of Biomedical Sciences, University of Edinburgh Medical School, George Square, Edinburgh, Scotland, United Kingdom
| | - Gernot Riedel
- Division of Behavioral Neuroscience, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, Scotland, United Kingdom
- * E-mail: (RL); (GR)
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7
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Qi X, Xu H, Wang L, Zhang Z. Comparison of Therapeutic Effects of TREK1 Blockers and Fluoxetine on Chronic Unpredicted Mild Stress Sensitive Rats. ACS Chem Neurosci 2018; 9:2824-2831. [PMID: 29952548 DOI: 10.1021/acschemneuro.8b00225] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The animal model for depressive behavior due to chronic unpredicted mild stress (CUMS) is commonly used to evaluate antidepressant treatments. The CUMS model has faced some criticism because of the heterogeneity of behavioral effects. Spadin and SID1900 are TREK1 blockers with a quick antidepressant effect. However, to date, their effectiveness and the long-term therapeutic mechanisms are not known. We hypothesize that early intervention with TREK1 blockers can fully reverse depressive-like behaviors, that the chronic administration of TREK1 blockers has a more pronounced effect than the SSRI fluoxetine, and that its long-term therapeutic effects may be mediated by improvement of impaired neurogenesis. Furthermore, we optimized the use of the CUMS model for increased homogeneity by screening the rats after the CUMS induction procedure. Depressive-like behavior was assessed by a forced swimming test, sucrose preference, and open field tests. To evaluate neurogenesis, cell proliferation and newly generated cell apoptosis were measured in the hippocampal dentate gyrus. Of 32 rats that underwent the CUMS procedure, 26 rats that exhibited depressive-like behaviors were grouped as CUMS sensitive rats (CUMSS), while six that did not were grouped as CUMS resistant ones (CUMSR). The CUMSR rats exhibited minor neurogenesis impairments, while the CUMSS rats had a more pronounced effect. Treatment with TREK1 blockers could reverse depressive-like behaviors at least 1 week earlier than that of fluoxetine. Chronic administration of both the TREK1 blockers and fluoxetine could restore neurogenesis impairments. This study underlines the importance of model validation by determination of CUMS sensitivity. The TREK1 blockers were found to have an effect that was more rapid and more pronounced than that of fluoxetine. Therapeutic benefits after chronic administration were associated with a restoration of impaired neurogenesis.
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Affiliation(s)
- Xinyang Qi
- Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Hua Xu
- Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Liping Wang
- Shenzhen Key Lab of Neuropsychiatric Modulation and Collaborative Innovation Center for Brain Science, CAS Center for Excellence in Brain Science and Intelligence Technology, Brain Cognition and Brain Disease Institute (BCBDI) for Collaboration Research of SIAT at CAS, and McGovern Institute at MIT, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Zhijun Zhang
- Department of Neurology, Affiliated ZhongDa Hospital, Neuropsychiatric Institute, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
- Shenzhen Key Lab of Neuropsychiatric Modulation and Collaborative Innovation Center for Brain Science, CAS Center for Excellence in Brain Science and Intelligence Technology, Brain Cognition and Brain Disease Institute (BCBDI) for Collaboration Research of SIAT at CAS, and McGovern Institute at MIT, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
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8
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Salagre E, Solé B, Tomioka Y, Fernandes BS, Hidalgo-Mazzei D, Garriga M, Jimenez E, Sanchez-Moreno J, Vieta E, Grande I. Treatment of neurocognitive symptoms in unipolar depression: A systematic review and future perspectives. J Affect Disord 2017. [PMID: 28651185 DOI: 10.1016/j.jad.2017.06.034] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND Cognitive symptoms in Major Depressive Disorder (MDD) are persistent and commonly entail neurocognitive impairment and a decline in quality of life. This systematic review gathers the current scientific evidence on therapeutic strategies for neuropsychological impairment in MDD. METHOD A systematic search on PubMed, PsycINFO and Clinicaltrials.gov was carried out on December 2016 according to PRISMA using Boolean terms to identify interventions for the treatment of cognitive dysfunction in MDD. Only English-written articles providing original data and focusing in adults with MDD were included with no time restrictions. RESULTS A total of 95 studies reporting data on 40 pharmacological and non-pharmacological interventions were included. Interventions were grouped into the following categories: 1) Pharmacological Therapies (antidepressants, stimulants, compounds acting on NMDA receptors, compounds acting on the cholinergic system, compounds showing anti-inflammatory or antioxidant properties, other mechanisms of action), 2) Physical Therapies and 3) Psychological Therapies, 4) Exercise. There are some promising compounds showing a positive impact on cognitive symptoms including vortioxetine, lisdexamfetamine or erythropoietin. LIMITATIONS The studies included showed significant methodological differences in heterogeneous samples. The lack of a standardized neuropsychological battery makes comparisons between studies difficult. CONCLUSION Current evidence is not sufficient to widely recommend the use of procognitive treatments in MDD although promising results are coming to light.
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Affiliation(s)
- E Salagre
- Bipolar Disorders Unit, Hospital Clinic, Institute of Neurosciences, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain
| | - B Solé
- Bipolar Disorders Unit, Hospital Clinic, Institute of Neurosciences, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain
| | - Y Tomioka
- Bipolar Disorders Unit, Hospital Clinic, Institute of Neurosciences, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain
| | - B S Fernandes
- Deakin University, IMPACT Strategic Research Centre, School of Medicine, Barwon Health, Geelong, Australia; Laboratory of Calcium Binding Proteins in the Central Nervous System, Department of Biochemistry, Federal University of Rio Grande do Sul, Porto Alegre, Brazil
| | - D Hidalgo-Mazzei
- Bipolar Disorders Unit, Hospital Clinic, Institute of Neurosciences, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain
| | - M Garriga
- Bipolar Disorders Unit, Hospital Clinic, Institute of Neurosciences, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain
| | - E Jimenez
- Bipolar Disorders Unit, Hospital Clinic, Institute of Neurosciences, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain
| | - J Sanchez-Moreno
- Bipolar Disorders Unit, Hospital Clinic, Institute of Neurosciences, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain
| | - E Vieta
- Bipolar Disorders Unit, Hospital Clinic, Institute of Neurosciences, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain.
| | - I Grande
- Bipolar Disorders Unit, Hospital Clinic, Institute of Neurosciences, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, Catalonia, Spain
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Castilla-Ortega E, Ladrón de Guevara-Miranda D, Serrano A, Pavón FJ, Suárez J, Rodríguez de Fonseca F, Santín LJ. The impact of cocaine on adult hippocampal neurogenesis: Potential neurobiological mechanisms and contributions to maladaptive cognition in cocaine addiction disorder. Biochem Pharmacol 2017; 141:100-117. [DOI: 10.1016/j.bcp.2017.05.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Accepted: 05/03/2017] [Indexed: 12/14/2022]
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10
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Wu ZM, Zheng CH, Zhu ZH, Wu FT, Ni GL, Liang Y. SiRNA-mediated serotonin transporter knockdown in the dorsal raphe nucleus rescues single prolonged stress-induced hippocampal autophagy in rats. J Neurol Sci 2015; 360:133-40. [PMID: 26723990 DOI: 10.1016/j.jns.2015.11.056] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 11/26/2015] [Accepted: 11/30/2015] [Indexed: 02/02/2023]
Abstract
The neurobiological mechanisms underlying the development of post-traumatic stress disorder (PTSD) remain elusive. One of the hypotheses is the dysfunction of serotonin (5-HT) neurotransmission, which is critically regulated by serotonin transporter (SERT). Therefore, we hypothesized that attenuation of SERT gene expression in the hippocampus could prevent hippocampal autophagy and the development of PTSD-like behavior. To this end, we infused SLC6A4 siRNAs into the dorsal raphe nucleus (DRN) to knockdown SERT gene expression after a single prolonged stress (SPS) treatment in rats. Then, we evaluated the effects of SERT gene knockdown on anxiety-related behaviors and extinction of contextual fear memory. We also examined the histological changes and the expression of Beclin-1, LC3-I, and LC3-II in the hippocampus. We found that SPS treatment did not alter anxiety-related behaviors but prolonged the extinction of contextual fear memory, and such a behavioral phenomenon was correlated with increased hippocampal autophagy, decreased 5-HT level, and increased expression of Beclin-1 and LC3-II/LC3-I ratio in the hippocampus. Furthermore, intra-DRN infusion of SLC6A4 siRNAs promoted the extinction of contextual fear memory, prevented hippocampal autophagy, increased 5-HT level, and decreased expression of Beclin-1 and LC3-II/LC3-I ratio. These results indicated that SERT may play a critical role in the pathogenesis of hippocampal autophagy, and is likely involved in the development of PTSD.
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Affiliation(s)
- Zhong-Min Wu
- Department of anatomy, Medical College of Taizhou University, Taizhou 318000, China; Department of Neurology, First People's Hospital of Linhai City, Linhai 317000, China
| | - Chun-Hua Zheng
- Outpatient Office, Taizhou Hospital, Taizhou 317000, China
| | - Zhen-Hua Zhu
- Department of Pediatrics, Taizhou Central Hospital, Taizhou 318000, China
| | - Feng-Tian Wu
- City Colloege of Zhejiang University, Hanzhou 310031, China
| | - Gui-Lian Ni
- Department of Neurology, First People's Hospital of Linhai City, Linhai 317000, China
| | - Yong Liang
- Department of anatomy, Medical College of Taizhou University, Taizhou 318000, China.
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11
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Leffa DD, Valvassori SS, Varela RB, Lopes-Borges J, Daumann F, Longaretti LM, Dajori ALF, Quevedo J, Andrade VM. Effects of palatable cafeteria diet on cognitive and noncognitive behaviors and brain neurotrophins' levels in mice. Metab Brain Dis 2015; 30:1073-82. [PMID: 25998605 DOI: 10.1007/s11011-015-9682-0] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Accepted: 05/11/2015] [Indexed: 01/24/2023]
Abstract
The consumption of palatable high-fat and high-sugar foods have increased dramatically over the past years. Overconsumption of calorically dense food contributes to increasing rates of overweight and obesity that are associated with psychiatry disorders, in particular mood and anxiety disorders. This study evaluated the impact of palatable cafeteria diet (CAF) intake on cognitive and noncognitive behaviors, as well as identified factors related to these behaviors through an evaluation of brain neurotrophic factor (BDNF, NGF, and GDNF) levels in hippocampus of mice. Male Swiss mice received two different diets during 13 weeks: standard chow (STA) and highly CAF. Posteriorly, forced swimming test (FST), tail suspension test (TST), plus-maze test (PMT), open-field tests (OFT), and object recognition task (ORT) were utilized as behavioral tests. In addition, brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), and nerve growth factor (NGF) neurotrophins' levels were evaluated in hippocampus of mice. The results demonstrated that mice from the CAF group showed a decrease in the immobility time in the FST and TST. Besides, mice in the CAF group spent more time in the open arms of the PMT. No significant differences were observed in the cognitive behaviors, which were evaluated in the OFT and ORT. In addition, the CAF group showed that BDNF and NGF protein levels increased in the hippocampus of mice. In conclusion, our data suggest that the consumption of palatable high-fat and high-sugar foods induces antidepressant- and anxiolytic-like behaviors, which can be related with BDNF and NGF expression increases in hippocampus of mice in the CAF group.
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Affiliation(s)
- Daniela D Leffa
- Laboratory of Molecular and Cellular Biology, Graduate Program in Health Sciences, Health Sciences Unit, University of Southern Santa Catarina, Criciúma, SC, Brazil,
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Protein kinase Mζ is involved in the modulatory effect of fluoxetine on hippocampal neurogenesis in vitro. Int J Neuropsychopharmacol 2014; 17:1429-41. [PMID: 24679950 DOI: 10.1017/s1461145714000364] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The efficacy of chronic selective serotonin reuptake inhibitors (SSRIs) on depression is paralleled by the recovery of deficits in hippocampal neurogenesis related to sustained stress and elevated glucocorticoids. Previous studies have shown that atypical protein kinase C (aPKC) is implicated in the regulation of neurogenesis and the antidepressant response. Whether the specific aPKC isoforms (PKCζ, PKMζ and PKCι) are involved in SSRI-induced hippocampal neurogenesis and the underlying mechanisms is unknown. The present study shows that PKMζ and PKCι but not PKCζ are expressed in rat embryonic hippocampal neural stem cells (NSCs), whereas PKMζ but not PKCι expression is increased by the SSRI fluoxetine both in the absence and presence of the glucocorticoid receptor agonist dexamethasone. PKMζ shRNA significantly decreased neuronal proliferation and neuron-oriented differentiation, increased NSC apoptosis, and blocked the stimulatory effect of fluoxetine on NSC neurogenesis. Fluoxetine significantly increased PKMζ expression in hippocampal NSCs in a 5-hydroxytryptamine-1A (5-HT1A) receptor-dependent manner in both the absence and presence of dexamethasone. The PKMζ peptide blocker ZIP and MEK inhibitor U0126 significantly inhibited the increase in extracellular signal-regulated kinase 1/2 and cyclic adenosine monophosphate response element binding protein phosphorylation in the mitogen-activated protein kinase (MAPK) pathway and hippocampal NSC neurogenesis in response to fluoxetine and the 5-HT1A receptor agonist 8-OH DPAT. Collectively, our results suggest that the SSRI fluoxetine increases hippocampal NSC neurogenesis via a PKMζ-mediated mechanism that links 5-HT1A receptor activation with the phosphorylation of the downstream MAPK signaling pathway.
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Cao X, Li LP, Qin XH, Li SJ, Zhang M, Wang Q, Hu HH, Fang YY, Gao YB, Li XW, Sun LR, Xiong WC, Gao TM, Zhu XH. Astrocytic adenosine 5'-triphosphate release regulates the proliferation of neural stem cells in the adult hippocampus. Stem Cells 2014; 31:1633-43. [PMID: 23630193 DOI: 10.1002/stem.1408] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2012] [Accepted: 03/27/2013] [Indexed: 12/13/2022]
Abstract
Astrocytes are key components of the niche for neural stem cells (NSCs) in the adult hippocampus and play a vital role in regulating NSC proliferation and differentiation. However, the exact molecular mechanisms by which astrocytes modulate NSC proliferation have not been identified. Here, we identified adenosine 5'-triphosphate (ATP) as a proliferative factor required for astrocyte-mediated proliferation of NSCs in the adult hippocampus. Our results indicate that ATP is necessary and sufficient for astrocytes to promote NSC proliferation in vitro. The lack of inositol 1,4,5-trisphosphate receptor type 2 and transgenic blockage of vesicular gliotransmission induced deficient ATP release from astrocytes. This deficiency led to a dysfunction in NSC proliferation that could be rescued via the administration of exogenous ATP. Moreover, P2Y1-mediated purinergic signaling is involved in the astrocyte promotion of NSC proliferation. As adult hippocampal neurogenesis is potentially involved in major mood disorder, our results might offer mechanistic insights into this disease.
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Affiliation(s)
- Xiong Cao
- Department of Neurobiology, School of Basic Medical Sciences; Key Laboratory of Neuroplasticity of Guangdong Higher Education Institutes, and; School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, China
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Minelli A, Maffioletti E, Bortolomasi M, Conca A, Zanardini R, Rillosi L, Abate M, Giacopuzzi M, Maina G, Gennarelli M, Bocchio-Chiavetto L. Association between baseline serum vascular endothelial growth factor levels and response to electroconvulsive therapy. Acta Psychiatr Scand 2014; 129:461-6. [PMID: 23957507 DOI: 10.1111/acps.12187] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/03/2013] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Several studies have shown that vascular endothelial growth factor (VEGF) is implicated in different neuronal processes involved in major depressive disorder (MDD) and in the mechanisms of action of antidepressants. The aim of this study was to investigate whether VEGF serum levels before treatment might be associated with the antidepressant response. METHOD Two groups of patients were enrolled. One was composed of 50 MDD patients receiving an antidepressant drug treatment. Illness severity was measured before the treatment (T0) and after 12 weeks (T1). The second group was composed of 67 treatment-resistant depressed (TRD) patients undergoing electroconvulsive therapy (ECT). Illness severity was assessed before the treatment (T0) and 1 month after the end of ECT (T1). Blood samples for VEGF measurements were collected for both groups at the baseline (T0). RESULTS A significant correlation was observed between baseline VEGF serum levels and the percentage reduction in depressive symptomatology after ECT (P = 0.003). In particular, VEGF levels at baseline were significantly lower in patients showing no response to ECT at follow-up (P = 0.008). No correlation between T0 VEGF concentrations and drug treatment outcome was found. CONCLUSION Our results suggest that VEGF plays a role in the mechanism of response to ECT.
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Affiliation(s)
- A Minelli
- Biology and Genetic Division, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
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15
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Swimming improves the emotional memory deficit by scopolamine via mu opioid receptors. Physiol Behav 2014; 128:237-46. [DOI: 10.1016/j.physbeh.2014.02.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2013] [Revised: 09/29/2013] [Accepted: 02/04/2014] [Indexed: 11/23/2022]
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Hayley S, Litteljohn D. Neuroplasticity and the next wave of antidepressant strategies. Front Cell Neurosci 2013; 7:218. [PMID: 24312008 PMCID: PMC3834236 DOI: 10.3389/fncel.2013.00218] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2013] [Accepted: 10/29/2013] [Indexed: 12/13/2022] Open
Abstract
Depression is a common chronic psychiatric disorder that is also often co-morbid with numerous neurological and immune diseases. Accumulating evidence indicates that disturbances of neuroplasticity occur with depression, including reductions of hippocampal neurogenesis and cortical synaptogenesis. Improper trophic support stemming from stressor-induced reductions of growth factors, most notably brain derived neurotrophic factor (BDNF), likely drives such aberrant neuroplasticity. We posit that psychological and immune stressors can interact upon a vulnerable genetic background to promote depression by disturbing BDNF and neuroplastic processes. Furthermore, the chronic and commonly relapsing nature of depression is suggested to stem from "faulty wiring" of emotional circuits driven by neuroplastic aberrations. The present review considers depression in such terms and attempts to integrate the available evidence indicating that the efficacy of current and "next wave" antidepressant treatments, whether used alone or in combination, is at least partially tied to their ability to modulate neuroplasticity. We particularly focus on the N-methyl-D-aspartate (NMDA) antagonist, ketamine, which already has well documented rapid antidepressant effects, and the trophic cytokine, erythropoietin (EPO), which we propose as a potential adjunctive antidepressant agent.
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Affiliation(s)
- Shawn Hayley
- Department of Neuroscience, Carleton University Ottawa, ON, Canada
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Osborn M, Rustom N, Clarke M, Litteljohn D, Rudyk C, Anisman H, Hayley S. Antidepressant-like effects of erythropoietin: a focus on behavioural and hippocampal processes. PLoS One 2013; 8:e72813. [PMID: 24019878 PMCID: PMC3760922 DOI: 10.1371/journal.pone.0072813] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Accepted: 07/19/2013] [Indexed: 12/11/2022] Open
Abstract
Depression is a chronic and debilitating condition with a significant degree of relapse and treatment resistance that could stem, at least in part, from disturbances of neuroplasticity. This has led to an increased focus on treatment strategies that target brain derived neurotrophic factor (BDNF), synaptic plasticity and adult neurogenesis. In the current study we aimed to assess whether erythropoietin (EPO) would have antidepressant-like effects given its already established pro-trophic actions. In particular, we assessed whether EPO would diminish the deleterious effects of a social stressor in mice. Indeed, EPO induced anxiolytic and antidepressant-like responses in a forced swim test, open field, elevated-plus maze, and a novelty test, and appeared to blunt some of the negative behavioural effects of a social stressor. Furthermore, EPO promoted adult hippocampal neurogenesis, an important feature of effective antidepressants. Finally, a separate study using the mTOR inhibitor rapamycin revealed that antagonizing this pathway prevented the impact of EPO upon forced swim performance. These data are consistent with previous findings showing that the mTOR pathway and its neurogenic and synaptogenic effects might mediate the behavioral consequences of antidepressant agents. Our findings further highlight EPO as a possible adjunct treatment for affective disorders, as well as other stressor associated disorders of impaired neuroplasticity.
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Affiliation(s)
- Meagan Osborn
- Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada
| | - Nazneen Rustom
- Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada
| | - Melanie Clarke
- Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada
| | - Darcy Litteljohn
- Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada
| | - Chris Rudyk
- Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada
| | - Hymie Anisman
- Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada
| | - Shawn Hayley
- Department of Neuroscience, Carleton University, Ottawa, Ontario, Canada
- * E-mail:
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Affiliation(s)
- Shawn Hayley
- Department of Neuroscience, Carleton University, Ottawa, Ont., Canada
| | - Hymie Anisman
- Department of Neuroscience, Carleton University, Ottawa, Ont., Canada
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Immadisetty K, Geffert LM, Surratt CK, Madura JD. New design strategies for antidepressant drugs. Expert Opin Drug Discov 2013; 8:1399-414. [PMID: 23991860 DOI: 10.1517/17460441.2013.830102] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
INTRODUCTION In spite of research efforts spanning six decades, the most prominent antidepressant drugs to date still carry several adverse effects, often serious enough to warrant discontinuation of the drug. Molecular mechanisms of depression are now better understood such that some of the specific receptors responsible can be targeted for activation or inhibition. This advance, coupled with the recent availability of crystal structures of relevant drug targets or their homologs, has opened the door for new antidepressant therapeutic compounds. AREAS COVERED The authors review the evolution of monoamine-based antidepressant drugs, up to the selective serotonin reuptake inhibitors (SSRIs). The authors discuss classic and contemporary antidepressant drug design strategies, with a focus on virtual screening and fragment-based drug design methods. Furthermore, they discuss the recent advancements in the understanding of the serotonin transporter (SERT) structure/function relationship in the context of recognition of SSRIs and outline a strategy for the use of computational approaches in producing new SSRI lead compounds. EXPERT OPINION The authors suggest that given the long-awaited availability of credible three-dimensional structures for the SERT and related monoamine transporter proteins, cutting-edge computational methods should be the linchpin of future drug discovery efforts regarding monoamine-based antidepressant lead compounds. Because these transporter inhibitors cause a ubiquitous increase in extraneuronal neurotransmitter levels leading to side and adverse therapeutic effects, the drug discovery should extend to appropriate manipulation of the 'downstream' receptors affected by the neurotransmitter boost. Efficient use of new computational strategies will accelerate the drug discovery process and reduce its economic burden.
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Affiliation(s)
- Kalyan Immadisetty
- Duquesne University, Center for Computational Sciences, Department of Chemistry and Biochemistry , 600 Forbes Ave, 308 Mellon Hall, Pittsburgh, PA 15282 , USA +1 412 396 4129 ; +1 412 396 5683 ;
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He BL, Ba YC, Wang XY, Liu SJ, Liu GD, Ou S, Gu YL, Pan XH, Wang TH. BDNF expression with functional improvement in transected spinal cord treated with neural stem cells in adult rats. Neuropeptides 2013; 47:1-7. [PMID: 22959240 DOI: 10.1016/j.npep.2012.06.001] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2009] [Revised: 05/19/2012] [Accepted: 06/19/2012] [Indexed: 02/07/2023]
Abstract
Neural stem cells (NSC) could promote the repair after spinal cord transection (SCT), the underlying mechanism, however, still keeps to be defined. This study reported that NSC grafts significantly improved sensory and locomotor functions in adult rats with SCT in acute stage after injury. NSC could survive; differentiate towards neurons or glia lineage in vitro and vivo. Biotin dextran amine (BDA) tracing showed that little CST regeneration in the injury site, while SEP was recorded in NSC engrafted rats. Immunohistochemistry and Real time PCR confirmed that engrafted NSC expressed BDNF and increased the level of BDNF mRNA in injured site following transplantation. The present data therefore suggested that the functional recovery following SCT with NSC transplantation was correlated with the expression of BDNF, indicating the usage of BDNF with NSC transplantation in the treatment of SCI following injury.
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Affiliation(s)
- Bao-Li He
- Institute of Neuroscience, Kunming Medical College, Kunming 650031, China
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Serafini G. Neuroplasticity and major depression, the role of modern antidepressant drugs. World J Psychiatry 2012; 2:49-57. [PMID: 24175168 PMCID: PMC3782176 DOI: 10.5498/wjp.v2.i3.49] [Citation(s) in RCA: 72] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2011] [Revised: 06/19/2012] [Accepted: 06/20/2012] [Indexed: 02/05/2023] Open
Abstract
The pathophysiology of depression has been traditionally attributed to a chemical imbalance and critical interactions between genetic and environmental risk factors, and antidepressant drugs suggested to act predominantly amplifying monoaminergic neurotransmission. This conceptualization may be currently considered reductive. The current literature about the pathophysiological mechanisms underlying depression, stress-related disorders and antidepressant treatment was examined. In order to provide a critical overview about neuroplasticity, depression and antidepressant drugs, a detailed Pubmed/Medline, Scopus, PsycLit, and PsycInfo search to identify all papers and book chapters during the period between 1980 and 2011 was performed. Pathological stress and depression determine relevant brain changes such as loss of dendritic spines and synapses, dendritic atrophy as well as reduction of glial cells (both in number and size) in specific areas such as the hippocampus and prefrontal cortex. An increased dendritic arborisation and synaptogenesis may instead be observed in the amygdala as a consequence of depression and stress-related disorders. While hippocampal and prefrontal functioning was impaired, amygdala functioning was abnormally amplified. Most of molecular abnormalities and biological changes of aberrant neuroplasticity may be explained by the action of glutamate. Antidepressant treatment is associated with neurogenesis, gliogenesis, dendritic arborisation, new synapse formation and cell survival both in the hippocampus and prefrontal cortex. Antidepressants (ADs) induce neuroplasticity mechanisms reversing the pathological effects of depression and stress-related disorders. The neuroplasticity hypothesis may explain the therapeutic and prophylactic action of ADs representing a new innovative approach to the pathophysiology of depression and stress-related disorders.
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Affiliation(s)
- Gianluca Serafini
- Gianluca Serafini, Department of Neurosciences, Mental Health and Sensory Organs, Suicide Prevention Center, Sant'Andrea Hospital, Sapienza University of Rome, Rome 00189, Italy
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