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Xia C, Zuo G, Wang M, Wang Y, Guo Y, Han Y, Xiang H, Cheng Y, Xu J, He J, Zhang W. Targeting HINT1 to improve synaptic plasticity: toward loganin as a new antidepressant strategy. Mol Psychiatry 2025:10.1038/s41380-025-02959-5. [PMID: 40133424 DOI: 10.1038/s41380-025-02959-5] [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: 12/12/2024] [Revised: 02/25/2025] [Accepted: 03/14/2025] [Indexed: 03/27/2025]
Abstract
Histidine triad nucleotide-binding protein 1 (HINT1) is related to depression. However, the underlying mechanisms and whether HINT1 is a therapeutic target for depression remain unclear. In this study, we report that loganin, an antidepressant candidate from our previous research, directly targets HINT1 to alleviate depressive-like behaviors. Overexpression of HINT1 in the hippocampus induces depressive-like behaviors. Mechanistically, HINT1 hinders sigma-1 receptor (Sigma-1R) binding to N-methyl-D-aspartate receptor (NMDAR), promotes postsynaptic density protein (PSD95) binding to NMDAR, inhibits brain derived neurotrophic factor (BDNF) signaling, and impairs synaptic plasticity. The interaction between HINT1 and NMDAR is disturbed by loganin. The antidepressant-like effects of loganin are reversed by HINT1 overexpression, Sigma-1R inhibitor and tropomyosin kinase receptor B (TrkB) inhibitor. These results not only indicate that HINT1 induces depression via impairing synaptic plasticity but also provide a candidate targeting HINT1 for depression therapy. Zhang et al. reported that a natural compound, loganin, improves synaptic plasticity and reduces depressive-like behaviors via its direct target HINT1. Mechanistically, overexpressed HINT1 hinders NMDAR/Sigma-1R interactions and increases NMDAR/PSD95 interactions, and HINT1/NMDAR interactions are disrupted by loganin treatment.
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Affiliation(s)
- Congyuan Xia
- Institute of Clinical Medical Sciences & Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, P. R. China
| | - Guoyan Zuo
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, P. R. China
| | - Manni Wang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, P. R. China
| | - Yuming Wang
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, P. R. China
| | - Yuxuan Guo
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, P. R. China
| | - Yan Han
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, P. R. China
| | - Honglin Xiang
- Institute of Clinical Medical Sciences & Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, P. R. China
| | - Yungchi Cheng
- Department of Pharmacology, School of Medicine, Yale University, Connecticut, New Haven, USA
| | - Jiekun Xu
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, 100029, P. R. China.
| | - Jun He
- Institute of Clinical Medical Sciences & Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, P. R. China.
| | - Weiku Zhang
- Institute of Clinical Medical Sciences & Department of Pharmacy, China-Japan Friendship Hospital, Beijing, 100029, P. R. China.
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Yang YQ, Tiliwaerde M, Gao NN, Gu W, Zhang TT, Jin ZL. GW117 induces anxiolytic effects by improving hippocampal functions. Pharmacol Biochem Behav 2025; 247:173927. [PMID: 39613193 DOI: 10.1016/j.pbb.2024.173927] [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: 09/13/2024] [Revised: 11/23/2024] [Accepted: 11/26/2024] [Indexed: 12/01/2024]
Abstract
GW117 functions as both an MT1/MT2 receptor agonist and a 5-HT2C receptor antagonist. This study aimed to investigate the anxiolytic effects of GW117 through behavioral assessments, including the open field test and novelty-suppressed feeding test (NSFT) within a chronic unpredictable mild stress (CUMS) model. GW117 was administered via oral gavage for 21 days to evaluate its sustained anxiolytic effects, with behavioral tests including the NSFT, the Vogel-conflict test, and the O-maze test. To explore the underlying mechanisms, we performed Western blot analyses to assess the expression levels of BCL2-Associated X (Bax), cleaved caspase-3, B-cell lymphoma-2 (Bcl-2), brain-derived neurotrophic factor (BDNF), and glial fibrillary acidic protein (GFAP). Additionally, BrdU labeling and immunofluorescence staining were used to examine changes in neuronal regeneration and astrocytogenesis. Our results demonstrated that GW117 produced significant anxiolytic effects across all behavioral assays, both in the CUMS model and during long-term administration. Mechanistic studies revealed that GW117 notably increased the expression of BDNF, GFAP, and Bcl-2, while reducing Bax and cleaved caspase-3 levels in the hippocampus of CUMS model rats. Furthermore, the populations of BrdU-positive and GFAP-positive cells were elevated. These findings suggest that GW117 exerts anxiolytic effects, potentially through enhancements in hippocampal function.
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Affiliation(s)
- Ya-Qi Yang
- Department of Pharmacy, Beijing Chaoyang Hospital, Capital Medical University, Beijing 100020, China; Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Murezati Tiliwaerde
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
| | - Na-Na Gao
- Department of Gastrointestinal Surgery and Clinical Nutrition, Beijing Shijitan Hospital, Captial Medical University, Beijing 100038, China
| | - Wei Gu
- Beijing GreatWay Pharmaceutical Technology Co., Ltd, Beijing 100070, China
| | - Ting-Ting Zhang
- Department of Neurology, Xuanwu Hospital, Captial Medical University, Beijing 100053, China
| | - Zeng-Liang Jin
- Department of Pharmacology, School of Basic Medical Sciences, Capital Medical University, Beijing 100069, China
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Talaee N, Azad Yekta M, Vaseghi S. New insights into individual differences in response to chronic unpredictable mild stress (CUMS) in rats with respect to hippocampal BDNF and GSK3-β expression levels. Physiol Behav 2024; 287:114718. [PMID: 39426694 DOI: 10.1016/j.physbeh.2024.114718] [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: 09/11/2024] [Revised: 10/15/2024] [Accepted: 10/16/2024] [Indexed: 10/21/2024]
Abstract
Preclinical and clinical studies have shown a wide-range of individual differences in response to stressors or novel environments which can affect the susceptibility to develop abnormal behaviors and neuropsychiatric disorders. Both vulnerability and resiliency have been observed in animals and humans experiencing stressful events. Chronic unpredictable mild stress (CUMS) is a rodent depression model consisting of various stressors. This protocol leads to depressive- and anhedonic-like behaviors in rodents. The present study aimed to evaluate potential individual differences in response to CUMS in rats, with respect to the expression level of brain-derived neurotrophic factor (BDNF) and glycogen synthase kinases 3-beta (GSK3-β) (proteins involved in the modulation of mood, neuroplasticity, and cognition) in the hippocampus. CUMS was performed for four consecutive weeks. Depressive-like behavior, locomotor activity, anxiety-like behavior, and pain threshold were also evaluated using forced swim test (FST), open field test (OFT), and the hot plate (HP), respectively. Real-time PCR was used to evaluate BDNF and GSK3-β expression levels. The results showed that CUMS rats can be classified as two clusters: affected and non-affected (depressed and non-depressed). Affected rats showed depressive- and anxiety-like behaviors, decreased locomotor activity, and increased pain threshold. However, non-affected rats were similar to controls. In addition, there was a downregulation of BDNF and upregulation of GSK3-β in affected rats. Spearman correlation analysis also showed a relationship between BDNF and GSK3-β expression levels with individual differences. In conclusion, the present study showed that BDNF and GSK3-β may be involved in individual differences in CUMS rats.
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Affiliation(s)
- Nastaran Talaee
- Department of Psychology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mehrnaz Azad Yekta
- Department of Psychology, Faculty of Educational Sciences and Psychology, Islamshahr Branch, Islamic Azad University, Islamshahr, Iran.
| | - Salar Vaseghi
- Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran; Cognitive Neuroscience Lab, Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran
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Jafarabady K, Shafiee A, Bahri RA, Rajai Firouzabadi S, Mohammadi I, Amini MJ. Brain-derived neurotrophic factor levels in perinatal depression: A systematic review and meta-analysis. Acta Psychiatr Scand 2024; 150:308-319. [PMID: 37974390 DOI: 10.1111/acps.13632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/04/2023] [Revised: 10/12/2023] [Accepted: 10/28/2023] [Indexed: 11/19/2023]
Abstract
BACKGROUND This systematic review and meta-analysis aim to synthesize the available evidence and determine the overall brain-derived neurotrophic factor (BDNF) levels in individuals diagnosed with perinatal depression (PND). METHODS We performed a thorough search of electronic databases, including PubMed, Embase, PsycINFO, and Web of Science, from their start until April 30, 2023. Our search strategy involved using specific keywords and medical subject headings (MeSH) terms related to BDNF, perinatal, post-partum, and antepartum depression. In the meta-analysis, we employed a random-effects model, and subgroup analyses were conducted to investigate any variations in the results. RESULTS A total of 15 studies met the inclusion criteria, of which 10 were used in the quantitative analysis. The meta-analysis demonstrated a significant decrease in BDNF levels in both individuals with antepartum depression (SMD: -0.31; 95% CI: -0.48 to -0.13; p-value = 0.0008; I2 = 71%), and post-partum depression (SMD: -0.61; 95% CI: -0.99 to -0.22; p-value = 0.0002 I2 = 77%). Furthermore, a significantly higher rate of PND among individuals in the lowest BDNF quartile (OR: 2.64; 95% CI: 1.01 to 6.89; p-value = 0.05; I2 = 90%) was seen. The results of subgroup analyses showed a statistically significant effect of the depression assessment tool on overall heterogeneity between studies. CONCLUSION This systematic review and meta-analysis provide evidence of lower BDNF protein levels in individuals diagnosed with PND. The results indicate that BDNF dysregulation may play a part in the development of PND. More research is needed to understand the mechanisms behind this and explore potential therapeutic applications.
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Affiliation(s)
- Kyana Jafarabady
- Department of Gynecology and Obstetrics, Alborz University of Medical Sciences, Karaj, Iran
- School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Arman Shafiee
- School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
- Department of Psychiatry and Mental Health, Alborz University of Medical Sciences, Karaj, Iran
| | | | | | - Ida Mohammadi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Xing S, Xu S, Wang L, Guo L, Zhou X, Wu H, Wang W, Liu L. Salidroside exerts antidepressant-like action by promoting adult hippocampal neurogenesis through SIRT1/PGC-1α signalling. Acta Neuropsychiatr 2024:1-11. [PMID: 39344773 DOI: 10.1017/neu.2024.28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/01/2024]
Abstract
Depression is one of the major mental disorders, which seriously endangers human health, brings a serious burden to patients’ families. In this study, we intended to further explore the antidepressant-like effect and possible molecular mechanisms of Salidroside (SAL). We built corticosterone (CORT)-induced depressive mice model and used behavioural tests to evaluate depression behaviour. To explore the molecular mechanisms of SAL, we employed a variety of methods such as immunofluorescence, western blot, pharmacological interference, etc. The results demonstrated that SAL both at 25 mg/kg and 50 mg/kg can reduce immobility time in the tail suspension test (TST). At the same time, SAL treatment could restore the reduced sugar water intake preference in the sucrose preference test (SPT) in CORT-induced depressive mice and reduce the immobility time in TST and forced swimming experiments (FST). In addition, SAL treatment reversed the reduction in the number of Ki-67, BrdU, and NeuN in the hippocampus due to CORT treatment. SAL treatment also restored the expression of SIRT1, PGC-1α, brain-derived neurotrophic factor (BDNF) and other proteins in the hippocampus. In addition, after blocking SIRT1 signalling with EX527, we found that the treatment with SAL failed to reduce the immobility time in TST and FST, the level of SIRT1 and PGC-1α activity were correspondingly downregulated, and the expression of DCX and Ki-67 in the hippocampus failed to be activated. These findings suggested that SAL exerts antidepressant-like effects by promoting hippocampal neurogenesis through the SIRT1/PGC-1α signalling pathway.
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Affiliation(s)
- Shan Xing
- School of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Shuyi Xu
- School of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Linjiao Wang
- School of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Liyuan Guo
- Zhejiang Chinese Medical University, Hangzhou, China
| | - Xin Zhou
- School of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Haoxin Wu
- School of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Wei Wang
- School of Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Lanying Liu
- Department of Psychiatry, Shanghai Mental Health Center, Shanghai, China
- Department of Psychiatry, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Institute of Mental Diseases of Traditional Chinese Medicine, Shanghai, China
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Yin Y, Ju T, Zeng D, Duan F, Zhu Y, Liu J, Li Y, Lu W. "Inflamed" depression: A review of the interactions between depression and inflammation and current anti-inflammatory strategies for depression. Pharmacol Res 2024; 207:107322. [PMID: 39038630 DOI: 10.1016/j.phrs.2024.107322] [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: 05/21/2024] [Revised: 07/13/2024] [Accepted: 07/18/2024] [Indexed: 07/24/2024]
Abstract
Depression is a common mental disorder, the effective treatment of which remains a challenging issue worldwide. The clinical pathogenesis of depression has been deeply explored, leading to the formulation of various pathogenic hypotheses. Among these, the monoamine neurotransmitter hypothesis holds a prominent position, yet it has significant limitations as more than one-third of patients do not respond to conventional treatments targeting monoamine transmission disturbances. Over the past few decades, a growing body of research has highlighted the link between inflammation and depression as a potential key factor in the pathophysiology of depression. In this review, we first summarize the relationship between inflammation and depression, with a focus on the pathophysiological changes mediated by inflammation in depression. The mechanisms linking inflammation to depression as well as multiple anti-inflammatory strategies are also discussed, and their efficacy and safety are assessed. This review broadens the perspective on specific aspects of using anti-inflammatory strategies for treating depression, laying the groundwork for advancing precision medicine for individuals suffering from "inflamed" depression.
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Affiliation(s)
- Yishu Yin
- School of Medicine and Health, Harbin Institute of Technology, Harbin 150001, China; School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin 150001, China; National and Local Joint Engineering Laboratory for Synthesis, Transformation and Separation of Extreme Environmental Nutrients, Harbin 150001, China
| | - Ting Ju
- School of Medicine and Health, Harbin Institute of Technology, Harbin 150001, China; School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin 150001, China; National and Local Joint Engineering Laboratory for Synthesis, Transformation and Separation of Extreme Environmental Nutrients, Harbin 150001, China
| | - Deyong Zeng
- School of Medicine and Health, Harbin Institute of Technology, Harbin 150001, China; National and Local Joint Engineering Laboratory for Synthesis, Transformation and Separation of Extreme Environmental Nutrients, Harbin 150001, China
| | - Fangyuan Duan
- School of Medicine and Health, Harbin Institute of Technology, Harbin 150001, China; School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin 150001, China; National and Local Joint Engineering Laboratory for Synthesis, Transformation and Separation of Extreme Environmental Nutrients, Harbin 150001, China
| | - Yuanbing Zhu
- School of Medicine and Health, Harbin Institute of Technology, Harbin 150001, China; School of Chemistry and Chemical Engineering, Harbin Institute of Technology, Harbin 150001, China; National and Local Joint Engineering Laboratory for Synthesis, Transformation and Separation of Extreme Environmental Nutrients, Harbin 150001, China
| | - Junlian Liu
- China Astronaut Research and Training Center, Beijing 100094, China
| | - Yongzhi Li
- China Astronaut Research and Training Center, Beijing 100094, China.
| | - Weihong Lu
- School of Medicine and Health, Harbin Institute of Technology, Harbin 150001, China; National and Local Joint Engineering Laboratory for Synthesis, Transformation and Separation of Extreme Environmental Nutrients, Harbin 150001, China.
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Conrad CD, Peay DN, Acuña AM, Whittaker K, Donnay ME. Corticosterone disrupts spatial working memory during retention testing when highly taxed, which positively correlates with depressive-like behavior in middle-aged, ovariectomized female rats. Horm Behav 2024; 164:105600. [PMID: 39003890 PMCID: PMC11330725 DOI: 10.1016/j.yhbeh.2024.105600] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 07/03/2024] [Accepted: 07/03/2024] [Indexed: 07/16/2024]
Abstract
Major Depressive Disorder affects 8.4 % of the U.S. population, particularly women during perimenopause. This study implemented a chronic corticosterone manipulation (CORT, a major rodent stress hormone) using middle-aged, ovariectomized female rats to investigate depressive-like behavior, anxiety-like symptoms, and cognitive ability. CORT (400 μg/ml, in drinking water) was administered for four weeks before behavioral testing began and continued throughout all behavioral assessments. Compared to vehicle-treated rats, CORT significantly intensified depressive-like behaviors: CORT decreased sucrose preference, enhanced immobility on the forced swim test, and decreased sociability on a choice task between a novel conspecific female rat and an inanimate object. Moreover, CORT enhanced anxiety-like behavior on a marble bury task by reducing time investigating tabasco-topped marbles. No effects were observed on novelty suppressed feeding or the elevated plus maze. For spatial working memory using an 8-arm radial arm maze, CORT did not alter acquisition but disrupted performance during retention. CORT enhanced the errors committed during the highest working memory load following a delay and during the last trial requiring the most items to remember; this cognitive metric positively correlated with a composite depressive-like score to reveal that as depressive-like symptoms increased, cognitive performance worsened. This protocol allowed for the inclusion of multiple behavioral assessments without stopping the CORT treatment needed to produce a MDD phenotype and to assess a battery of behaviors. Moreover, that when middle-age was targeted, chronic CORT produced a depressive-like phenotype in ovariectomized females, who also comorbidly expressed aspects of anxiety and cognitive dysfunction.
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Affiliation(s)
- Cheryl D Conrad
- Arizona State University, Department of Psychology, Box 1104, Tempe 85287, AZ, United States.
| | - Dylan N Peay
- Arizona State University, Department of Psychology, Box 1104, Tempe 85287, AZ, United States
| | - Amanda M Acuña
- Arizona State University, Department of Psychology, Box 1104, Tempe 85287, AZ, United States
| | - Kennedy Whittaker
- Arizona State University, Department of Psychology, Box 1104, Tempe 85287, AZ, United States
| | - Megan E Donnay
- Arizona State University, Department of Psychology, Box 1104, Tempe 85287, AZ, United States
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Wen Y, Xu J, Shen J, Tang Z, Li S, Zhang Q, Li J, Sun J. Esketamine Prevents Postoperative Emotional and Cognitive Dysfunction by Suppressing Microglial M1 Polarization and Regulating the BDNF-TrkB Pathway in Ageing Rats with Preoperative Sleep Disturbance. Mol Neurobiol 2024; 61:5680-5698. [PMID: 38221533 PMCID: PMC11249437 DOI: 10.1007/s12035-023-03860-4] [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: 07/10/2023] [Accepted: 12/04/2023] [Indexed: 01/16/2024]
Abstract
Postoperative depression (POD) and postoperative cognitive dysfunction (POCD) have placed heavy burden on patients' physical and mental health in recent years. Sleep disturbance before surgery is a common phenomenon that has been increasingly believed to affect patients' recovery, especially in aged patients, while little attention has been paid to sleep disruption before surgery and the potential mechanism remains ambiguous. Ketamine has been reported to attenuate POCD after cardiac surgery and elicit rapid-acting and sustained antidepressant actions. The present study aimed to clarify the effect of esketamine's (the S-enantiomer of ketamine) protective effects and possible mechanisms of action in POCD and POD. Our results showed that sleep disturbance before surgery exacerbated microglial M1 polarization and microglial BDNF-TrkB signalling dysfunction induced by surgery, resulting in postoperative emotional changes and cognitive impairments. Notably, treatment with esketamine reversed the behavioural abnormalities through inhibiting the M1 polarization of microglia and the inflammatory response thus improving BDNF-TrkB signalling in vivo and vitro. In addition, esketamine administration also reversed the impaired hippocampal synaptic plasticity which has been perturbed by sleep disturbance and surgery. These findings warrant further investigations into the interplay of esketamine and may provide novel ideas for the implication of preoperative preparations and the prevention of postoperative brain-related complications.
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Affiliation(s)
- Yuxin Wen
- Zhejiang University School of Medicine, Hangzhou, China
| | - Jiawen Xu
- Department of Anesthesiology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Jiahong Shen
- Department of Anesthesiology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China
| | - Zili Tang
- Department of Anesthesiology, The Fourth Clinical School of Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Shuxin Li
- Department of Anesthesiology, The Fourth Clinical School of Medicine, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qun Zhang
- School of Second Clinical Medical College, Wenzhou Medical University, Wenzhou, China
| | - Jiaqi Li
- Zhejiang University School of Medicine, Hangzhou, China
| | - Jianliang Sun
- Zhejiang University School of Medicine, Hangzhou, China.
- Department of Anesthesiology, Affiliated Hangzhou First People's Hospital, School of Medicine, Westlake University, Hangzhou, China.
- Department of Anesthesiology, The Fourth Clinical School of Medicine, Zhejiang Chinese Medical University, Hangzhou, China.
- School of Second Clinical Medical College, Wenzhou Medical University, Wenzhou, China.
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Bregman-Yemini N, Nitzan K, Franko M, Doron R. Connecting the emotional-cognitive puzzle: The role of tyrosine kinase B (TrkB) receptor isoform imbalance in age-related emotional and cognitive impairments. Ageing Res Rev 2024; 99:102349. [PMID: 38823488 DOI: 10.1016/j.arr.2024.102349] [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: 04/14/2024] [Revised: 05/16/2024] [Accepted: 05/26/2024] [Indexed: 06/03/2024]
Abstract
Age-related cognitive and affective disorders pose significant public health challenges. Notably, emotional and cognitive symptoms co-occur across multiple age-associated conditions like normal aging, Alzheimer's disease (AD), and mood disorders such as depression and anxiety. While the intricate interplay underlying this relationship remains poorly understood, this article highlights the possibility that an imbalance between full-length (TrkB.FL) and truncated (TrkB.T1) isoforms of tyrosine kinase receptor TrkB in the neurotrophic system may significantly affect age-associated emotional and cognitive functions, by altering brain-derived neurotrophic factor (BDNF) signaling, integral to neuronal health, cognitive functions and mood regulation. While the contribution of this imbalance to pathogenesis awaits full elucidation, this review evaluates its potential mediating role, linking emotional and cognitive decline across age-related disorders The interplay between TrkB.T1 and TrkB.FL isoforms may be considered as a pivotal shared regulator underlying this complex relationship. The current review aims to synthesize current knowledge on TrkB isoform imbalance, specifically its contribution to age-related cognitive decline and mood disorders. By examining shared pathogenic pathways between aging, cognitive decline, and mood disorders through the lens of TrkB signaling, this review uncovers potential therapeutic targets not previously considered, offering a fresh perspective on combating age-related mental health issues as well as cognitive deficits.
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Affiliation(s)
- Noa Bregman-Yemini
- Department of Education and Psychology, The Open University, Israel; Department of Psychology, The Hebrew University, Israel
| | - Keren Nitzan
- Department of Education and Psychology, The Open University, Israel
| | - Motty Franko
- Department of Education and Psychology, The Open University, Israel; Department of Psychology, Ben-Gurion University, Israel
| | - Ravid Doron
- Department of Education and Psychology, The Open University, Israel.
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Zou Y, Zhang Y, Tu M, Ye Y, Li M, Ran R, Zou Z. Brain-derived neurotrophic factor levels across psychiatric disorders: A systemic review and network meta-analysis. Prog Neuropsychopharmacol Biol Psychiatry 2024; 131:110954. [PMID: 38286331 DOI: 10.1016/j.pnpbp.2024.110954] [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: 08/23/2023] [Revised: 01/07/2024] [Accepted: 01/24/2024] [Indexed: 01/31/2024]
Abstract
As an important neurotrophic factor in the central nervous system, Brain-derived Neurotrophic Factor (BDNF) has been implicated in the pathophysiology of psychiatric disorders in many studies. However, its value as a biomarker for the diagnosis and differential diagnosis of mental disorders is still controversial, and its change patterns among different mental disorders have not been compared. We conducted a network meta-analysis of BDNF levels in different psychiatric disorders including schizophrenia(SCZ), major depressive disorder(MDD), bipolar disorder(BD), panic disorder(PD), post-traumatic stress disorder(PTSD), obsessive-compulsive disorder(OCD), generalized anxiety disorder(GAD) and insomnia. Studies were identified by searching electronic databases through 31/05/2023. BDNF levels decreased in patients with BD, MDD, OCD, PD, SCZ compared with controls, while significantly increased in patients with PTSD. According to the network meta-analysis, BDNF levels were significantly decreased in MDD and SCZ compared with BD (-2.6, 95% CIs [-5.32 to -0.15] and - 2.68 95% CIs [-5.18 to -0.23] respectively). However, in the traditional meta-analysis, there was a trend towards lower BDNF levels in SCZ compared to BD, with no significant difference (SMD = -0.20, 95% CIs [-0.49 to 0.08]). In conclusion, abnormal BDNF levels have been found in psychiatric disorders, and the changes in peripheral BDNF levels in patients with psychiatric disorders were reconfirmed in this study, which suggests BDNF exhibits promising clinical utility and may hold diagnostic value in distinguishing between MDD and BD.
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Affiliation(s)
- Yazhu Zou
- Sichuan Provincial Center for Mental Health, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
| | - Yuan Zhang
- Department of pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
| | - Mengtian Tu
- Sichuan Provincial Center for Mental Health, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
| | - Yu Ye
- Sichuan Provincial Center for Mental Health, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
| | - Mingmei Li
- Sichuan Provincial Center for Mental Health, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
| | - Rongting Ran
- Southwest Medical University, Luzhou, Sichuan, China
| | - Zhili Zou
- Sichuan Provincial Center for Mental Health, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, Sichuan, China; Key Laboratory of psychosomatic medicine, Chinese Academy of Medical Sciences, Chengdu, Sichuan, China.
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Ma H, Li JF, Qiao X, Zhang Y, Hou XJ, Chang HX, Chen HL, Zhang Y, Li YF. Sigma-1 receptor activation mediates the sustained antidepressant effect of ketamine in mice via increasing BDNF levels. Acta Pharmacol Sin 2024; 45:704-713. [PMID: 38097715 PMCID: PMC10943013 DOI: 10.1038/s41401-023-01201-8] [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: 08/31/2023] [Accepted: 11/15/2023] [Indexed: 03/17/2024]
Abstract
Sigma-1 receptor (S1R) is a unique multi-tasking chaperone protein in the endoplasmic reticulum. Since S1R agonists exhibit potent antidepressant-like activity, S1R has become a novel target for antidepression therapy. With a rapid and sustained antidepressant effect, ketamine may also interact with S1R. In this study, we investigated whether the antidepressant action of ketamine was related to S1R activation. Depression state was evaluated in the tail suspension test (TST) and a chronic corticosterone (CORT) procedure was used to induce despair-like behavior in mice. The neuronal activities and structural changes of pyramidal neurons in medial prefrontal cortex (mPFC) were assessed using fiber-optic recording and immunofluorescence staining, respectively. We showed that pharmacological manipulation of S1R modulated ketamine-induced behavioral effect. Furthermore, pretreatment with an S1R antagonist BD1047 (3 mg·kg-1·d-1, i.p., for 3 consecutive days) significantly weakened the structural and functional restoration of pyramidal neuron in mPFC caused by ketamine (10 mg·kg-1, i.p., once). Ketamine indirectly triggered the activation of S1R and subsequently increased the level of BDNF. Pretreatment with an S1R agonist SA4503 (1 mg·kg-1·d-1, i.p., for 3 consecutive days) enhanced the sustained antidepressant effect of ketamine, which was eliminated by knockdown of BDNF in mPFC. These results reveal a critical role of S1R in the sustained antidepressant effect of ketamine, and suggest that a combination of ketamine and S1R agonists may be more beneficial for depression patients.
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Affiliation(s)
- Hui Ma
- Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Jin-Feng Li
- Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
- School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Xin Qiao
- Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Yue Zhang
- Department of Anesthesiology, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China
| | | | - Hai-Xia Chang
- Beijing Institute of Basic Medical Sciences, Beijing, 100850, China
| | - Hong-Lei Chen
- Graduate Collaborative Training Base of Academy of Military Medical Sciences, Hengyang Medical School, University of South China, Hengyang, 421001, China
| | - Yong Zhang
- Department of Neurobiology, School of Basic Medical Sciences and Neuroscience Research Institute, Peking University, Beijing, 100083, China.
- Key Laboratory for Neuroscience, Ministry of Education/National Health Commission of the People's Republic of China, Beijing, 100083, China.
- IDG/McGovern Institute for Brain Research at Peking University, Beijing, 100083, China.
| | - Yun-Feng Li
- Beijing Institute of Basic Medical Sciences, Beijing, 100850, China.
- Beijing Institute of Pharmacology and Toxicology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Key Laboratory of Neuropsychopharmacology, Beijing, 100850, China.
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12
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Abdelaty AO, Tharwat EK, Abdelrahman AI, Elgohary A, Elsaeed H, El-Feky AS, Ebrahim YM, Habib A, Abd El Latif H, Khadrawy YA, Aboul Ezz HS, Noor NA, Fahmy HM, Mohammed FF, Radwan NM, Ahmed NA. Cerebrolysin potentiates the antidepressant effect of lithium in a rat model of depression. J Psychiatr Res 2024; 172:171-180. [PMID: 38394763 DOI: 10.1016/j.jpsychires.2024.02.029] [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: 04/30/2023] [Revised: 01/09/2024] [Accepted: 02/12/2024] [Indexed: 02/25/2024]
Abstract
RATIONALE Depression is the most prevalent psychiatric disorder worldwide. Although numerous antidepressant treatments are available, there is a serious clinical concern due to their severe side effects and the fact that some depressed patients are resistant to them. Lithium is the drug of choice for bipolar depression and has been used as adjunct therapy with other groups of antidepressants. OBJECTIVES The present study aims to investigate the effect of lithium augmentation with cerebrolysin on the neurochemical, behavioral and histopathological alterations induced in the reserpine model of depression. METHODS The animals were divided into control and reserpine-induced model of depression. The model animals were further divided into rat model of depression, rat model treated with lithium, rat model treated with cerebrolysin and rat model treated with a combination of lithium and cerebrolysin. RESULTS Treatment with lithium, cerebrolysin, or their combination alleviated most of the changes in behavior, oxidative stress parameters, acetylcholinesterase and monoamines in the cortex and hippocampus of the reserpine-induced model of depression. It also improved the alterations in brain-derived neurotrophic factor (BDNF) and histopathology induced by reserpine. CONCLUSIONS The augmentation of lithium with cerebrolysin showed a clear beneficial effect in the present model of depression suggesting the use of cerebrolysin as an adjuvant in antidepressant treatment.
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Affiliation(s)
- Ahmed O Abdelaty
- Zoology Department, Faculty of Science, Cairo University, Cairo, Egypt
| | - Engy K Tharwat
- Bioinformatics Group Center of Informatics Science, Nile University, Giza, Egypt
| | | | - Ayatallah Elgohary
- School of Biotechnology, Badr University in Cairo, Badr City, Cairo, Egypt
| | | | - Amena S El-Feky
- Biophysics Department, Faculty of Science, Cairo University, Cairo, Egypt
| | - Yasmina M Ebrahim
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Abdelaziz Habib
- Biophysics Department, Faculty of Science, Cairo University, Cairo, Egypt
| | | | - Yasser A Khadrawy
- Medical Physiology Department, Medical Division, National Research Center, Egypt
| | - Heba S Aboul Ezz
- Zoology Department, Faculty of Science, Cairo University, Cairo, Egypt
| | - Neveen A Noor
- Zoology Department, Faculty of Science, Cairo University, Cairo, Egypt.
| | - Heba M Fahmy
- Biophysics Department, Faculty of Science, Cairo University, Cairo, Egypt
| | - Faten F Mohammed
- Faculty of Veterinary Medicine, Cairo University, Cairo, Egypt; Department of Pathology, College of Veterinary Medicine, King Faisal University, Al Ahsa, 31982, Saudi Arabia
| | - Nasr M Radwan
- Zoology Department, Faculty of Science, Cairo University, Cairo, Egypt
| | - Nawal A Ahmed
- Zoology Department, Faculty of Science, Cairo University, Cairo, Egypt
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13
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Been LE, Halliday AR, Blossom SM, Bien EM, Bernhard AG, Roth GE, Domenech Rosario KI, Pollock KB, Abramenko PE, Behbehani LM, Pascal GJ, Kelly ME. Long-Term Oral Tamoxifen Administration Decreases Brain-Derived Neurotrophic Factor in the Hippocampus of Female Long-Evans Rats. Cancers (Basel) 2024; 16:1373. [PMID: 38611051 PMCID: PMC11010888 DOI: 10.3390/cancers16071373] [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: 12/22/2023] [Revised: 01/24/2024] [Accepted: 03/29/2024] [Indexed: 04/14/2024] Open
Abstract
Tamoxifen, a selective estrogen receptor modulator (SERM), is commonly used as an adjuvant drug therapy for estrogen-receptor-positive breast cancers. Though effective at reducing the rate of cancer recurrence, patients often report unwanted cognitive and affective side effects. Despite this, the impacts of chronic tamoxifen exposure on the brain are poorly understood, and rodent models of tamoxifen exposure do not replicate the chronic oral administration seen in patients. We, therefore, used long-term ad lib consumption of medicated food pellets to model chronic tamoxifen exposure in a clinically relevant way. Adult female Long-Evans Hooded rats consumed tamoxifen-medicated food pellets for approximately 12 weeks, while control animals received standard chow. At the conclusion of the experiment, blood and brain samples were collected for analyses. Blood tamoxifen levels were measured using a novel ultra-performance liquid chromatography-tandem mass spectrometry assay, which found that this administration paradigm produced serum levels of tamoxifen similar to those in human patients. In the brain, brain-derived neurotrophic factor (BDNF) was visualized in the hippocampus using immunohistochemistry. Chronic oral tamoxifen treatment resulted in a decrease in BDNF expression across several regions of the hippocampus. These findings provide a novel method of modeling and measuring chronic oral tamoxifen exposure and suggest a putative mechanism by which tamoxifen may cause cognitive and behavioral changes reported by patients.
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Affiliation(s)
- Laura E. Been
- Department of Psychology and Neuroscience Program, Haverford College, Haverford, PA 19041, USA; (A.R.H.); (S.M.B.); (E.M.B.); (A.G.B.); (G.E.R.); (K.I.D.R.); (K.B.P.); (P.E.A.); (L.M.B.); (G.J.P.); (M.E.K.)
| | - Amanda R. Halliday
- Department of Psychology and Neuroscience Program, Haverford College, Haverford, PA 19041, USA; (A.R.H.); (S.M.B.); (E.M.B.); (A.G.B.); (G.E.R.); (K.I.D.R.); (K.B.P.); (P.E.A.); (L.M.B.); (G.J.P.); (M.E.K.)
| | - Sarah M. Blossom
- Department of Psychology and Neuroscience Program, Haverford College, Haverford, PA 19041, USA; (A.R.H.); (S.M.B.); (E.M.B.); (A.G.B.); (G.E.R.); (K.I.D.R.); (K.B.P.); (P.E.A.); (L.M.B.); (G.J.P.); (M.E.K.)
| | - Elena M. Bien
- Department of Psychology and Neuroscience Program, Haverford College, Haverford, PA 19041, USA; (A.R.H.); (S.M.B.); (E.M.B.); (A.G.B.); (G.E.R.); (K.I.D.R.); (K.B.P.); (P.E.A.); (L.M.B.); (G.J.P.); (M.E.K.)
| | - Anya G. Bernhard
- Department of Psychology and Neuroscience Program, Haverford College, Haverford, PA 19041, USA; (A.R.H.); (S.M.B.); (E.M.B.); (A.G.B.); (G.E.R.); (K.I.D.R.); (K.B.P.); (P.E.A.); (L.M.B.); (G.J.P.); (M.E.K.)
| | - Grayson E. Roth
- Department of Psychology and Neuroscience Program, Haverford College, Haverford, PA 19041, USA; (A.R.H.); (S.M.B.); (E.M.B.); (A.G.B.); (G.E.R.); (K.I.D.R.); (K.B.P.); (P.E.A.); (L.M.B.); (G.J.P.); (M.E.K.)
| | - Karina I. Domenech Rosario
- Department of Psychology and Neuroscience Program, Haverford College, Haverford, PA 19041, USA; (A.R.H.); (S.M.B.); (E.M.B.); (A.G.B.); (G.E.R.); (K.I.D.R.); (K.B.P.); (P.E.A.); (L.M.B.); (G.J.P.); (M.E.K.)
| | - Karlie B. Pollock
- Department of Psychology and Neuroscience Program, Haverford College, Haverford, PA 19041, USA; (A.R.H.); (S.M.B.); (E.M.B.); (A.G.B.); (G.E.R.); (K.I.D.R.); (K.B.P.); (P.E.A.); (L.M.B.); (G.J.P.); (M.E.K.)
| | - Petra E. Abramenko
- Department of Psychology and Neuroscience Program, Haverford College, Haverford, PA 19041, USA; (A.R.H.); (S.M.B.); (E.M.B.); (A.G.B.); (G.E.R.); (K.I.D.R.); (K.B.P.); (P.E.A.); (L.M.B.); (G.J.P.); (M.E.K.)
| | - Leily M. Behbehani
- Department of Psychology and Neuroscience Program, Haverford College, Haverford, PA 19041, USA; (A.R.H.); (S.M.B.); (E.M.B.); (A.G.B.); (G.E.R.); (K.I.D.R.); (K.B.P.); (P.E.A.); (L.M.B.); (G.J.P.); (M.E.K.)
| | - Gabriel J. Pascal
- Department of Psychology and Neuroscience Program, Haverford College, Haverford, PA 19041, USA; (A.R.H.); (S.M.B.); (E.M.B.); (A.G.B.); (G.E.R.); (K.I.D.R.); (K.B.P.); (P.E.A.); (L.M.B.); (G.J.P.); (M.E.K.)
| | - Mary Ellen Kelly
- Department of Psychology and Neuroscience Program, Haverford College, Haverford, PA 19041, USA; (A.R.H.); (S.M.B.); (E.M.B.); (A.G.B.); (G.E.R.); (K.I.D.R.); (K.B.P.); (P.E.A.); (L.M.B.); (G.J.P.); (M.E.K.)
- Neuroscience Program, University of Pennsylvania, Philadelphia, PA 19104, USA
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14
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Du Q, Gao C, Tsoi B, Wu M, Shen J. Niuhuang Qingxin Wan ameliorates depressive-like behaviors and improves hippocampal neurogenesis through modulating TrkB/ERK/CREB signaling pathway in chronic restraint stress or corticosterone challenge mice. Front Pharmacol 2024; 14:1274343. [PMID: 38273824 PMCID: PMC10808638 DOI: 10.3389/fphar.2023.1274343] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Accepted: 12/18/2023] [Indexed: 01/27/2024] Open
Abstract
Introduction: Chronic stress-associated hormonal imbalance impairs hippocampal neurogenesis, contributing to depressive and anxiety behaviors. Targeting neurogenesis is thus a promising antidepressant therapeutic strategy. Niuhuang Qingxin Wan (NHQXW) is an herbal formula for mental disorders in Traditional Chinese Medicine (TCM) practice, but its anti-depressant efficacies and mechanisms remain unverified. Methods: In the present study, we tested the hypothesis that NHQXW could ameliorate depressive-like behaviors and improve hippocampal neurogenesis by modulating the TrkB/ERK/CREB signaling pathway by utilizing two depression mouse models including a chronic restraint stress (CRS) mouse model and a chronic corticosterone (CORT) stress (CCS) induced mouse model. The depression-like mouse models were orally treated with NHQXW whereas fluoxetine was used as the positive control group. We evaluated the effects of NHQXW on depressive- and anxiety-like behaviors and determined the effects of NHQXW on inducing hippocampal neurogenesis. Results: NHQXW treatment significantly ameliorated depressive-like behaviors in those chronic stress mouse models. NHQXW significantly improved hippocampal neurogenesis in the CRS mice and CCS mice. The potential neurogenic mechanism of NHQXW was identified by regulating the expression levels of BDNF, TrkB, p-ERK (T202/T204), p-MEK1/2 (S217/221), and p-CREB (S133) in the hippocampus area of the CCS mice. NHQXW revealed its antidepressant and neurogenic effects that were similar to fluoxetine. Moreover, NHQXW treatment revealed long-term effects on preventing withdrawal-associated rebound symptoms in the CCS mice. Furthermore, in a bioactivity-guided quality control study, liquiritin was identified as one of the bioactive compounds of NHQXW with the bioactivities of neurogenesis-promoting effects. Discussion: Taken together, NHQXW could be a promising TCM formula to attenuate depressive- and anxiety-like behaviors against chronic stress and depression. The underlying anti-depressant mechanisms could be correlated with its neurogenic activities by stimulating the TrkB/ERK/CREB signaling pathway.
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Affiliation(s)
- Qiaohui Du
- School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Chong Gao
- School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
- The Institute of Brain and Cognitive Sciences, School of Medicine, Zhejiang University City College, Hangzhou, China
| | - Bun Tsoi
- School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
- Department of Food Science and Nutrition, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China
| | - Meiling Wu
- School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
| | - Jiangang Shen
- School of Chinese Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China
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15
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Augusto-Oliveira M, Arrifano GP, Leal-Nazaré CG, Santos-Sacramento L, Lopes-Araújo A, Royes LFF, Crespo-Lopez ME. Exercise Reshapes the Brain: Molecular, Cellular, and Structural Changes Associated with Cognitive Improvements. Mol Neurobiol 2023; 60:6950-6974. [PMID: 37518829 DOI: 10.1007/s12035-023-03492-8] [Citation(s) in RCA: 27] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Accepted: 07/07/2023] [Indexed: 08/01/2023]
Abstract
Physical exercise is well known as a non-pharmacological and holistic therapy believed to prevent and mitigate numerous neurological conditions and alleviate ageing-related cognitive decline. To do so, exercise affects the central nervous system (CNS) at different levels. It changes brain physiology and structure, promoting cognitive improvements, which ultimately improves quality of life. Most of these effects are mediated by neurotrophins release, enhanced adult hippocampal neurogenesis, attenuation of neuroinflammation, modulation of cerebral blood flow, and structural reorganisation, besides to promote social interaction with beneficial cognitive outcomes. In this review, we discuss, based on experimental and human research, how exercise impacts the brain structure and function and how these changes contribute to cognitive improvements. Understanding the mechanisms by which exercise affects the brain is essential to understand the brain plasticity following exercise, guiding therapeutic approaches to improve the quality of life, especially in obesity, ageing, neurodegenerative disorders, and following traumatic brain injury.
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Affiliation(s)
- Marcus Augusto-Oliveira
- Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal Do Pará, Belém, PA, Brazil.
| | - Gabriela P Arrifano
- Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal Do Pará, Belém, PA, Brazil
| | - Caio G Leal-Nazaré
- Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal Do Pará, Belém, PA, Brazil
| | - Letícia Santos-Sacramento
- Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal Do Pará, Belém, PA, Brazil
| | - Amanda Lopes-Araújo
- Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal Do Pará, Belém, PA, Brazil
| | - Luiz Fernando Freire Royes
- Laboratório de Bioquímica Do Exercício, Centro de Educacão Física E Desportos, Universidade Federal de Santa Maria, Santa Maria, RGS, Brazil
| | - Maria Elena Crespo-Lopez
- Laboratório de Farmacologia Molecular, Instituto de Ciências Biológicas, Universidade Federal Do Pará, Belém, PA, Brazil.
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16
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Zhang Y, Li X, Liu Z, Zhao X, Chen L, Hao G, Ye X, Meng S, Xiao G, Mu J, Mu X, Qiu J, Qian Y. The neurobehavioral impacts of typical antibiotics toward zebrafish larvae. CHEMOSPHERE 2023; 340:139829. [PMID: 37598953 DOI: 10.1016/j.chemosphere.2023.139829] [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: 05/22/2023] [Revised: 07/26/2023] [Accepted: 08/13/2023] [Indexed: 08/22/2023]
Abstract
Due to the widely usage in livestock, aquaculture and clinics, antibiotic residues are existed in aqueous environments and their potential toxicity to aquatic organisms is concerning. Here, we used zebrafish as the model to investigate the neurotoxicity and involved mechanism of seven antibiotics that were frequently detected in surface waters. The results revealed that the short-term exposure to clarithromycin (CLA), chlortetracycline (CTC) and roxithromycin (ROX) induced behavioral effects, with effective concentration of 1 μg/L (CTC and ROX) and 100 μg/L (CLA, CTC and ROX) respectively. A significant decrease in the travel distance and velocity as well as an increase in turn angle was measured. TUNEL assay identified increased cell apoptosis in brain sections of larvae exposed to three neurotoxic antibiotics, which raised the possibility that the behavioral symptoms were associated with neural damage. Transcriptome sequencing showed that the three antibiotics could affect the nervous system of zebrafish including the alteration of synaptogenesis and neurotransmission. Additionally, ROX and CTC affected pathways involved in mitochondrial stress response and endocrine system in zebrafish larvae. Besides, BDNF, ASCL1, and CREBBP are potential upstream regulatory factors that mediated these impacts. These findings indicated that exposure of CTC, ROX and CLA may cause abnormal behavior toward zebrafish larvae under environmental relevant concentration and revealed the potential role of neural cell apoptosis and synaptogenesis signaling in mediating this effect.
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Affiliation(s)
- Yining Zhang
- Institute of Quality Standard and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Xue Li
- Institute of Quality Standard and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing, China; Agro-Environmental Protection Institute, Ministry of Agriculture and Rural Affairs, Tianjin, China
| | - Zaiteng Liu
- Institute of Quality Standard and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Xiaoyu Zhao
- Institute of Quality Standard and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Lu Chen
- Institute of Quality Standard and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Guijie Hao
- Key Laboratory of Healthy Freshwater Aquaculture, Ministry of Agriculture and Rural Affairs; Key Laboratory of Fish Health and Nutrition of Zhejiang Province; Zhejiang Institute of Freshwater Fisheries, Huzhou, China
| | - Xueping Ye
- Key Laboratory of Healthy Freshwater Aquaculture, Ministry of Agriculture and Rural Affairs; Key Laboratory of Fish Health and Nutrition of Zhejiang Province; Zhejiang Institute of Freshwater Fisheries, Huzhou, China
| | - Shunlong Meng
- Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Jiangsu Province, China.
| | - Guohua Xiao
- Hebei Ocean and Fisheries Science Research Institute, Qinhuangdao, China; Hebei Marine Living Resources and Environment Key Laboratory, Qinhuangdao, China
| | - Jiandong Mu
- Hebei Ocean and Fisheries Science Research Institute, Qinhuangdao, China; Hebei Marine Living Resources and Environment Key Laboratory, Qinhuangdao, China
| | - Xiyan Mu
- Institute of Quality Standard and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing, China.
| | - Jing Qiu
- Institute of Quality Standard and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Yongzhong Qian
- Institute of Quality Standard and Testing Technology for Agro-Products, Chinese Academy of Agricultural Sciences, Beijing, China
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17
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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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18
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Wei MD, Huang YY, Zeng Y, Lan YX, Lu K, Wang Y, Chen WY. Homocysteine Modulates Social Isolation-Induced Depressive-Like Behaviors Through BDNF in Aged Mice. Mol Neurobiol 2023; 60:4924-4934. [PMID: 37198386 PMCID: PMC10191402 DOI: 10.1007/s12035-023-03377-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Accepted: 05/01/2023] [Indexed: 05/19/2023]
Abstract
Social isolation is an unpleasant experience associated with an increased risk of mental disorders. Exploring whether these experiences affect behaviors in aged people is particularly important, as the elderly is very likely to suffer from periods of social isolation during their late-life. In this study, we analyzed the depressive-like behaviors, plasma concentrations of homocysteine (Hcy), and brain-derived neurotropic factor (BDNF) levels in aged mice undergoing social isolation. Results showed that depressive-like behavioral performance and decreased BDNF level were correlated with increased Hcy levels that were detected in 2-month isolated mice. Elevated Hcy induced by high methionine diet mimicked the depressive-like behaviors and BDNF downregulation in the same manner as social isolation, while administration of vitamin B complex supplements to reduce Hcy alleviated the depressive-like behaviors and BDNF reduction in socially isolated mice. Altogether, our results indicated that Hcy played a critical role in social isolation-induced depressive-like behaviors and BDNF reduction, suggesting the possibility of Hcy as a potential therapeutic target and vitamin B intake as a potential value in the prevention of stress-induced depression.
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Affiliation(s)
- Mei-Dan Wei
- Department of Pharmacy, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, Guangdong, China.
- School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, China.
| | - Ya-Yan Huang
- Department of Pharmacy, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, Guangdong, China
| | - Ying Zeng
- Department of Pharmacy, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, Guangdong, China
| | - Yan-Xian Lan
- Department of Pharmacy, Minzu Hospital of Guangxi Zhuang Autonomous Region, Nanning, 530001, Guangxi, China
| | - Kun Lu
- Department of Pediatric Orthopaedic, Zhengzhou Orthopaedics Hospital, Zhengzhou, 450052, Henan, China
| | - Yan Wang
- Department of Pharmacy, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, Guangdong, China
| | - Wen-Ying Chen
- Department of Pharmacy, The Third Affiliated Hospital of Southern Medical University, Guangzhou, 510630, Guangdong, China
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19
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Dong X, Zhao D. Ferulic acid as a therapeutic agent in depression: Evidence from preclinical studies. CNS Neurosci Ther 2023; 29:2397-2412. [PMID: 37183361 PMCID: PMC10401106 DOI: 10.1111/cns.14265] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Revised: 04/17/2023] [Accepted: 05/03/2023] [Indexed: 05/16/2023] Open
Abstract
Depression is a common but severe mood disorder with a very high prevalence across the general population. Depression is of global concern and poses a threat to human physical and mental health. Ferulic acid (FA) is a natural active ingredient that has antioxidative, anti-inflammatory, and free radical scavenging properties. Furthermore, studies have shown that FA can exert antidepressant effects through a variety of mechanisms. The aim of the review was to comprehensively elucidate the mechanisms in FA that alleviate depression using animal models. The in vivo (animal) studies on the mechanism of FA treatment of depression were searched in PubMed, Chinese National Knowledge Infrastructure, Baidu academic, and Wan fang databases. Thereafter, the literature conclusions were summarized accordingly. Ferulic acid was found to significantly improve the depressive-like behaviors of animal models, suggesting that FA is a potential natural product in the treatment of depression. The mechanisms are achieved by enhancing monoamine oxidase A (MOA) activity, inhibiting microglia activation and inflammatory factor release, anti-oxidative stress, promoting hippocampal nerve regeneration, increasing brain-derived neurotrophic factor secretion, regulating gut microbiome, and activating protein kinase B/collapsin response mediator protein 2 (AKT/CRMP2) signaling pathway. Ferulic acid produces significant antidepressant effects in animal depression models through various mechanisms, suggesting its potential value as a treatment of depression. However, clinical research trials involving FA are required further to provide a solid foundation for its clinical application.
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Affiliation(s)
- Xiaoyu Dong
- Department of NeurologyShengjing Hospital of China Medical UniversityShenyangLiaoningChina
| | - Dongxue Zhao
- Department of NeurologyShengjing Hospital of China Medical UniversityShenyangLiaoningChina
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20
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Qiu LL, Tan XX, Yang JJ, Ji MH, Zhang H, Zhao C, Xia JY, Sun J. Lactate Improves Long-term Cognitive Impairment Induced By Repeated Neonatal Sevoflurane Exposures Through SIRT1-mediated Regulation of Adult Hippocampal Neurogenesis and Synaptic Plasticity in Male Mice. Mol Neurobiol 2023; 60:5273-5291. [PMID: 37286723 DOI: 10.1007/s12035-023-03413-9] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Accepted: 05/25/2023] [Indexed: 06/09/2023]
Abstract
Repeated neonatal exposures to sevoflurane induce long-term cognitive impairment that has been reported to have sex-dependent differences. Exercise promotes learning and memory by releasing lactate from the muscle. The study tested the hypothesis that lactate may improve long-term cognitive impairment induced by repeated neonatal exposures to sevoflurane through SIRT1-mediated regulation of adult hippocampal neurogenesis and synaptic plasticity. C57BL/6 mice of both genders were exposed to 3% sevoflurane for 2 h daily from postnatal day 6 (P6) to P8. In the intervention experiments, mice received lactate at 1 g/kg intraperitoneally once daily from P21 to P41. Behavioral tests including open field (OF), object location (OL), novel object recognition (NOR), and fear conditioning (FC) tests were performed to assess cognitive function. The number of 5-Bromo-2'- deoxyuridine positive (BrdU+) cells and BrdU+/DCX+ (doublecortin) co-labeled cells, expressions of brain-derived neurotrophic factor (BDNF), activity-regulated cytoskeletal-associated protein (Arc), early growth response 1 (Egr-1), SIRT1, PGC-1α and FNDC5, and long-term potentiation (LTP) were evaluated in the hippocampus. Repeated exposures to sevoflurane induced deficits in OL, NOR and contextual FC tests in male but not female mice. Similarly, adult hippocampal neurogenesis, synaptic plasticity-related proteins and hippocampal LTP were impaired after repeated exposures to sevoflurane in male but not female mice, which could rescue by lactate treatment. Our study suggests that repeated neonatal exposures to sevoflurane inhibit adult hippocampal neurogenesis and induce defects of synaptic plasticity in male but not female mice, which may contribute to long-term cognitive impairment. Lactate treatment rescues these abnormalities through activation of SIRT1.
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Affiliation(s)
- Li-Li Qiu
- Department of Anesthesiology, Surgery and Pain Management, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Dingjiaqiao Road, Nanjing, 210009, China
| | - Xiao-Xiang Tan
- Department of Anesthesiology, Surgery and Pain Management, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Dingjiaqiao Road, Nanjing, 210009, China
| | - Jiao-Jiao Yang
- Department of Anesthesiology, Surgery and Pain Management, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Dingjiaqiao Road, Nanjing, 210009, China
| | - Mu-Huo Ji
- Department of Anesthesiology, the Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Hui Zhang
- Department of Anesthesiology, Surgery and Pain Management, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Dingjiaqiao Road, Nanjing, 210009, China
| | - Chunjie Zhao
- Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, School of Medicine, Southeast University, Nanjing, China
| | - Jiang-Yan Xia
- Department of Anesthesiology, Surgery and Pain Management, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Dingjiaqiao Road, Nanjing, 210009, China.
| | - Jie Sun
- Department of Anesthesiology, Surgery and Pain Management, School of Medicine, Zhongda Hospital, Southeast University, No. 87 Dingjiaqiao Road, Nanjing, 210009, China.
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21
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Wilson JB, Epstein M, Lopez B, Brown AK, Lutfy K, Friedman TC. The role of Neurochemicals, Stress Hormones and Immune System in the Positive Feedback Loops between Diabetes, Obesity and Depression. Front Endocrinol (Lausanne) 2023; 14:1224612. [PMID: 37664841 PMCID: PMC10470111 DOI: 10.3389/fendo.2023.1224612] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 07/25/2023] [Indexed: 09/05/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM) and depression are significant public health and socioeconomic issues. They commonly co-occur, with T2DM occurring in 11.3% of the US population, while depression has a prevalence of about 9%, with higher rates among youths. Approximately 31% of patients with T2DM suffer from depressive symptoms, with 11.4% having major depressive disorders, which is twice as high as the prevalence of depression in patients without T2DM. Additionally, over 80% of people with T2DM are overweight or obese. This review describes how T2DM and depression can enhance one another, using the same molecular pathways, by synergistically altering the brain's structure and function and reducing the reward obtained from eating. In this article, we reviewed the evidence that eating, especially high-caloric foods, stimulates the limbic system, initiating Reward Deficiency Syndrome. Analogous to other addictive behaviors, neurochemical changes in those with depression and/or T2DM are thought to cause individuals to increase their food intake to obtain the same reward leading to binge eating, weight gain and obesity. Treating the symptoms of T2DM, such as lowering HbA1c, without addressing the underlying pathways has little chance of eliminating the disease. Targeting the immune system, stress circuit, melatonin, and other alterations may be more effective.
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Affiliation(s)
- Julian B. Wilson
- Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States
| | - Ma’ayan Epstein
- Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States
- Psychiatric Emergency Room, Olive View – University of California, Los Angeles (UCLA) Medical Center, Sylmar, CA, United States
| | - Briana Lopez
- Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States
- Friends Research Institute, Cerritos, CA, United States
| | - Amira K. Brown
- Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States
| | - Kabirullah Lutfy
- Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States
- College of Pharmacy, Western University of Health Sciences, Pomona, CA, United States
| | - Theodore C. Friedman
- Department of Internal Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, CA, United States
- Friends Research Institute, Cerritos, CA, United States
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22
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Tong T, Chen Y, Hao C, Shen J, Chen W, Cheng W, Yan S, Li J, Li Y, Gulizhaerkezi T, Zeng J, Meng X. The effects of acupuncture on depression by regulating BDNF-related balance via lateral habenular nucleus BDNF/TrkB/CREB signaling pathway in rats. Behav Brain Res 2023; 451:114509. [PMID: 37244435 DOI: 10.1016/j.bbr.2023.114509] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2023] [Revised: 05/08/2023] [Accepted: 05/24/2023] [Indexed: 05/29/2023]
Abstract
Depression is a major mental disease worldwide, causing dysfunction of Lateral Habenular (LHb). As a non-invasive alternative, acupuncture (AP) has been widely used to treat depression in clinic, yet few basic studies have been focused on the effects and mechanism of acupuncture on synaptic plasticity in LHb. Therefore, this study aimed to explore the potential mechanism of the antidepressant effect of acupuncture. Male Sprague-Dawley (SD) rats were randomly divided into control, chronic unpredictable mild stress (CUMS), AP, fluoxetine (FLX), acupoint catgut embedding (ACE), sham-ACE groups (n = 9/group). Rats were given a 28-day treatment at the Shangxing (GV23) and Fengfu (GV16) acupoints with acupuncture, ACE, sham-ACE or fluoxetine (2.1 mg/kg). The results showed that AP, FLX and ACE suppressed the behavioral deficits, increased the level of the 5-hydroxytryptamine and FNDC5/IRISIN in serum, also reduced the expression of pro-BDNF impacted by CUMS. Both AP and FLX ameliorated the %area of IBA-1, GFAP, BrdU and DCX in the LHb and increased the expression of BDNF/TrkB/CREB, with non-significant difference between the two groups These findings suggest that AP therapy relieves depression-related manifestations in depressed rats, suggesting a potential mechanism via the BDNF/TrkB/CREB pathway in LHb.
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Affiliation(s)
- Tao Tong
- Department of Traditional Chinese Medicine, School of Medicine, Xiamen University, Xiamen, Fujian, P. R. China; Second Clinical College, Shanxi University of Traditional Chinese Medicine, Taiyuan, Shanxi, P. R. China
| | - Yiping Chen
- Department of Traditional Chinese Medicine, School of Medicine, Xiamen University, Xiamen, Fujian, P. R. China; Second Clinical College, Shanxi University of Traditional Chinese Medicine, Taiyuan, Shanxi, P. R. China
| | - Chonyao Hao
- Second Clinical College, Shanxi University of Traditional Chinese Medicine, Taiyuan, Shanxi, P. R. China
| | - Junliang Shen
- Department of Traditional Chinese Medicine, School of Medicine, Xiamen University, Xiamen, Fujian, P. R. China
| | - Wenjie Chen
- Department of Traditional Chinese Medicine, School of Medicine, Xiamen University, Xiamen, Fujian, P. R. China
| | - Wenjing Cheng
- Department of Rehabilitation Medicine, Ezhou Central Hospital, Ezhou, Hubei, P. R. China
| | - Simin Yan
- Department of Traditional Chinese Medicine, School of Medicine, Xiamen University, Xiamen, Fujian, P. R. China
| | - Jianguo Li
- Second Clinical College, Shanxi University of Traditional Chinese Medicine, Taiyuan, Shanxi, P. R. China
| | - Yuhan Li
- The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, P. R. China
| | - Tuergong Gulizhaerkezi
- Department of Traditional Chinese Medicine, School of Medicine, Xiamen University, Xiamen, Fujian, P. R. China
| | - Jingyu Zeng
- Department of Traditional Chinese Medicine, School of Medicine, Xiamen University, Xiamen, Fujian, P. R. China
| | - Xianjun Meng
- Department of Traditional Chinese Medicine, School of Medicine, Xiamen University, Xiamen, Fujian, P. R. China.
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23
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Markov DD, Dolotov OV, Grivennikov IA. The Melanocortin System: A Promising Target for the Development of New Antidepressant Drugs. Int J Mol Sci 2023; 24:ijms24076664. [PMID: 37047638 PMCID: PMC10094937 DOI: 10.3390/ijms24076664] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/27/2023] [Accepted: 03/30/2023] [Indexed: 04/05/2023] Open
Abstract
Major depression is one of the most prevalent mental disorders, causing significant human suffering and socioeconomic loss. Since conventional antidepressants are not sufficiently effective, there is an urgent need to develop new antidepressant medications. Despite marked advances in the neurobiology of depression, the etiology and pathophysiology of this disease remain poorly understood. Classical and newer hypotheses of depression suggest that an imbalance of brain monoamines, dysregulation of the hypothalamic-pituitary-adrenal axis (HPAA) and immune system, or impaired hippocampal neurogenesis and neurotrophic factors pathways are cause of depression. It is assumed that conventional antidepressants improve these closely related disturbances. The purpose of this review was to discuss the possibility of affecting these disturbances by targeting the melanocortin system, which includes adrenocorticotropic hormone-activated receptors and their peptide ligands (melanocortins). The melanocortin system is involved in the regulation of various processes in the brain and periphery. Melanocortins, including peripherally administered non-corticotropic agonists, regulate HPAA activity, exhibit anti-inflammatory effects, stimulate the levels of neurotrophic factors, and enhance hippocampal neurogenesis and neurotransmission. Therefore, endogenous melanocortins and their analogs are able to complexly affect the functioning of those body’s systems that are closely related to depression and the effects of antidepressants, thereby demonstrating a promising antidepressant potential.
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Affiliation(s)
- Dmitrii D. Markov
- National Research Center “Kurchatov Institute”, Kurchatov Sq. 2, 123182 Moscow, Russia
| | - Oleg V. Dolotov
- National Research Center “Kurchatov Institute”, Kurchatov Sq. 2, 123182 Moscow, Russia
- Faculty of Biology, Lomonosov Moscow State University, Leninskie Gory, 119234 Moscow, Russia
| | - Igor A. Grivennikov
- National Research Center “Kurchatov Institute”, Kurchatov Sq. 2, 123182 Moscow, Russia
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24
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Cavaleri D, Moretti F, Bartoccetti A, Mauro S, Crocamo C, Carrà G, Bartoli F. The role of BDNF in major depressive disorder, related clinical features, and antidepressant treatment: insight from meta-analyses. Neurosci Biobehav Rev 2023; 149:105159. [PMID: 37019247 DOI: 10.1016/j.neubiorev.2023.105159] [Citation(s) in RCA: 53] [Impact Index Per Article: 26.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2023] [Revised: 03/10/2023] [Accepted: 04/02/2023] [Indexed: 04/05/2023]
Abstract
The brain-derived neurotrophic factor (BDNF) has received considerable attention as a potential biomarker of major depressive disorder (MDD) and antidepressant response. We conducted an overview of meta-analyses investigating the relationship of BDNF with MDD, related clinical features, and antidepressant treatment. Based on a systematic screening on main electronic databases, 11 systematic reviews with meta-analyses were included. Available evidence suggests that people with MDD have peripheral and central BDNF levels lower than non-depressed individuals. A negative correlation between blood BDNF and symptom severity emerged, while no association with suicidality was detected. Moreover, an increase in blood BDNF levels after antidepressant treatment, proportional to symptom improvement, was reported. BDNF levels seem to be increased in both treatment responders and remitters, remaining stable in non-responders. Conversely, no variations of BDNF concentrations after non-pharmacological interventions (electroconvulsive therapy, repetitive transcranial magnetic stimulation, and physical activity) were found. The findings of this overview appear consistent with the neurotrophic hypothesis of depression, suggesting that BDNF may play a role in both MDD pathophysiology and pharmacological treatment response.
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25
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Jiang Y, Zou M, Wang Y, Wang Y. Nucleus accumbens in the pathogenesis of major depressive disorder: A brief review. Brain Res Bull 2023; 196:68-75. [PMID: 36889362 DOI: 10.1016/j.brainresbull.2023.03.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 02/16/2023] [Accepted: 03/05/2023] [Indexed: 03/08/2023]
Abstract
Major depressive disorder (MDD) is the most prevalent mental disorder characterized by anhedonia, loss of motivation, avolition, behavioral despair and cognitive abnormalities. Despite substantial advancements in the pathophysiology of MDD in recent years, the pathogenesis of this disorder is not fully understood. Meanwhile,the treatment of MDD with currently available antidepressants is inadequate, highlighting the urgent need for clarifying the pathophysiology of MDD and developing novel therapeutics. Extensive studies have demonstrated the involvement of nuclei such as the prefrontal cortex (PFC), hippocampus (HIP), nucleus accumbens (NAc), hypothalamus, etc., in MDD. NAc,a region critical for reward and motivation,dysregulation of its activity seems to be a hallmark of this mood disorder. In this paper, we present a review of NAc related circuits, cellular and molecular mechanisms underlying MDD and share an analysis of the gaps in current research and possible future research directions.
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Affiliation(s)
- Yajie Jiang
- Institute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China; Hunan Key Laboratory of Traditional Chinese Medicine Prevention & Treatment of Depressive Diseases, Changsha, China
| | - Manshu Zou
- Hunan Key Laboratory of Traditional Chinese Medicine Prevention & Treatment of Depressive Diseases, Changsha, China
| | - Yeqing Wang
- State Key Laboratory of Developmental Biology of Freshwater Fish, Hunan Provincial Key Laboratory of Animal Intestinal Function and Regulation, Laboratory of Animal Nutrition and Human Health, College of Life Sciences, Hunan Normal University, Changsha 410081, China
| | - Yuhong Wang
- Institute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, China; Hunan Key Laboratory of Traditional Chinese Medicine Prevention & Treatment of Depressive Diseases, Changsha, China.
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26
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Yoon S, Iqbal H, Kim SM, Jin M. Phytochemicals That Act on Synaptic Plasticity as Potential Prophylaxis against Stress-Induced Depressive Disorder. Biomol Ther (Seoul) 2023; 31:148-160. [PMID: 36694423 PMCID: PMC9970837 DOI: 10.4062/biomolther.2022.116] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 12/06/2022] [Accepted: 12/20/2022] [Indexed: 01/26/2023] Open
Abstract
Depression is a neuropsychiatric disorder associated with persistent stress and disruption of neuronal function. Persistent stress causes neuronal atrophy, including loss of synapses and reduced size of the hippocampus and prefrontal cortex. These alterations are associated with neural dysfunction, including mood disturbances, cognitive impairment, and behavioral changes. Synaptic plasticity is the fundamental function of neural networks in response to various stimuli and acts by reorganizing neuronal structure, function, and connections from the molecular to the behavioral level. In this review, we describe the alterations in synaptic plasticity as underlying pathological mechanisms for depression in animal models and humans. We further elaborate on the significance of phytochemicals as bioactive agents that can positively modulate stress-induced, aberrant synaptic activity. Bioactive agents, including flavonoids, terpenes, saponins, and lignans, have been reported to upregulate brain-derived neurotrophic factor expression and release, suppress neuronal loss, and activate the relevant signaling pathways, including TrkB, ERK, Akt, and mTOR pathways, resulting in increased spine maturation and synaptic numbers in the neuronal cells and in the brains of stressed animals. In clinical trials, phytochemical usage is regarded as safe and well-tolerated for suppressing stress-related parameters in patients with depression. Thus, intake of phytochemicals with safe and active effects on synaptic plasticity may be a strategy for preventing neuronal damage and alleviating depression in a stressful life.
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Affiliation(s)
- Soojung Yoon
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Republic of Korea
| | - Hamid Iqbal
- Department of Microbiology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea,Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
| | - Sun Mi Kim
- Department of Psychiatry, Chung-Ang University College of Medicine, Seoul 06974, Republic of Korea,Department of Psychiatry, Chung-Ang University Hospital, Seoul 06973, Republic of Korea
| | - Mirim Jin
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Republic of Korea,Department of Microbiology, College of Medicine, Gachon University, Incheon 21999, Republic of Korea,Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea,Corresponding Author E-mail: , Tel: +82-32-899-6080, Fax: +82-32-899-6029
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27
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Spohr L, de Aguiar MSS, Bona NP, Luduvico KP, Alves AG, Domingues WB, Blödorn EB, Bortolatto CF, Brüning CA, Campos VF, Stefanello FM, Spanevello RM. Blueberry Extract Modulates Brain Enzymes Activities and Reduces Neuroinflammation: Promising Effect on Lipopolysaccharide-Induced Depressive-Like Behavior. Neurochem Res 2023; 48:846-861. [PMID: 36357747 DOI: 10.1007/s11064-022-03813-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 10/10/2022] [Accepted: 10/30/2022] [Indexed: 11/12/2022]
Abstract
Major depressive disorder (MDD) is one of the most common neuropsychiatric disorders with high rates of prevalence and mortality. MDD is pathophysiologically complex, and treatment options are limited. Blueberries are rich in polyphenols and have neuroprotective potential. The aim of this study was to investigate the effects of blueberry extract on neuroinflammatory and neuroplasticity parameters, as well as Na+/K+-ATPase, monoamine oxidase-A (MAO-A), and acetylcholinesterase (AChE) activities in the cerebral cortex and hippocampus of mice subject to lipopolysaccharide (LPS)-induced depressive-like behavior. We also analyzed the interaction between anthocyanins and indoleamine 2 3-dioxygenase (IDO). Male Swiss mice (60-day-old) received vehicle, fluoxetine (20 mg/kg), or blueberry extract (100 or 200 mg/kg) intragastrically for 7 days before intraperitoneal LPS (0.83 mg/kg) injection. Twenty-four hours after LPS administration, the mice were subjected to behavioral tests. Both fluoxetine and blueberry extract (200 mg/kg) decreased the immobility time in the forced swim test, without affecting locomotor activity. Fluoxetine attenuated the decrease of Na+/K+-ATPase in the cerebral cortex, while blueberry extract promoted this same effect in the hippocampus. Additionally, fluoxetine and blueberry extract attenuated the decrease in the activity of MAO-A in the hippocampus. Blueberry extract (200 mg/kg) also prevented LPS-induced increase in AChE activity in the hippocampus as well as LPS upregulation of relative mRNA expression of tumor necrosis factor alpha, interleukin (IL)-1β, and IL-10 in the cerebral cortex. Molecular docking analysis revealed binding sites for malvidin 3-galactoside (- 7.8 kcal/mol) and malvidin 3-glucoside (- 7.9 kcal/mol) residues with IDO. Taken together, these results indicate that blueberry extract improved depression-like behavior and attenuated the neurochemical and molecular changes in the brains of mice challenged with LPS.
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Affiliation(s)
- Luiza Spohr
- Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Programa de Pós-Graduação em Bioquímica e Bioprospecção - Laboratório de Neuroquímica, Inflamação e Câncer, Universidade Federal de Pelotas, Prédio 29, Campus Capão do Leão, s/n, Caixa Postal 354, Pelotas, RS, CEP 9601090, Brazil.
| | - Mayara Sandrielly Soares de Aguiar
- Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Programa de Pós-Graduação em Bioquímica e Bioprospecção - Laboratório de Neuroquímica, Inflamação e Câncer, Universidade Federal de Pelotas, Prédio 29, Campus Capão do Leão, s/n, Caixa Postal 354, Pelotas, RS, CEP 9601090, Brazil
| | - Natália Pontes Bona
- Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Programa de Pós-Graduação em Bioquímica e Bioprospecção - Laboratório de Biomarcadores, Universidade Federal de Pelotas, Pelotas, RS, Brazil
| | - Karina Pereira Luduvico
- Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Programa de Pós-Graduação em Bioquímica e Bioprospecção - Laboratório de Biomarcadores, Universidade Federal de Pelotas, Pelotas, RS, Brazil
| | - Amália Gonçalves Alves
- Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Programa de Pós-Graduação em Bioquímica e Bioprospecção - Laboratório de Bioquímica e Neurofarmacologia Molecular, Universidade Federal de Pelotas, Pelotas, RS, Brazil
| | - William Borges Domingues
- Centro de Desenvolvimento Tecnológico, Programa de Pós-Graduação em Biotecnologia - Laboratório de Genômica Estrutural, Universidade Federal de Pelotas, Pelotas, RS, Brazil
| | - Eduardo Bierhals Blödorn
- Centro de Desenvolvimento Tecnológico, Programa de Pós-Graduação em Biotecnologia - Laboratório de Genômica Estrutural, Universidade Federal de Pelotas, Pelotas, RS, Brazil
| | - Cristiani Folharini Bortolatto
- Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Programa de Pós-Graduação em Bioquímica e Bioprospecção - Laboratório de Bioquímica e Neurofarmacologia Molecular, Universidade Federal de Pelotas, Pelotas, RS, Brazil
| | - César Augusto Brüning
- Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Programa de Pós-Graduação em Bioquímica e Bioprospecção - Laboratório de Bioquímica e Neurofarmacologia Molecular, Universidade Federal de Pelotas, Pelotas, RS, Brazil
| | - Vinicius Farias Campos
- Centro de Desenvolvimento Tecnológico, Programa de Pós-Graduação em Biotecnologia - Laboratório de Genômica Estrutural, Universidade Federal de Pelotas, Pelotas, RS, Brazil
| | - Francieli Moro Stefanello
- Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Programa de Pós-Graduação em Bioquímica e Bioprospecção - Laboratório de Biomarcadores, Universidade Federal de Pelotas, Pelotas, RS, Brazil
| | - Roselia Maria Spanevello
- Centro de Ciências Químicas, Farmacêuticas e de Alimentos, Programa de Pós-Graduação em Bioquímica e Bioprospecção - Laboratório de Neuroquímica, Inflamação e Câncer, Universidade Federal de Pelotas, Prédio 29, Campus Capão do Leão, s/n, Caixa Postal 354, Pelotas, RS, CEP 9601090, Brazil.
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Numakawa T, Kajihara R. Neurotrophins and Other Growth Factors in the Pathogenesis of Alzheimer’s Disease. Life (Basel) 2023; 13:life13030647. [PMID: 36983803 PMCID: PMC10051261 DOI: 10.3390/life13030647] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/12/2023] [Accepted: 02/24/2023] [Indexed: 03/02/2023] Open
Abstract
The involvement of the changed expression/function of neurotrophic factors in the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD), has been suggested. AD is one of the age-related dementias, and is characterized by cognitive impairment with decreased memory function. Developing evidence demonstrates that decreased cell survival, synaptic dysfunction, and reduced neurogenesis are involved in the pathogenesis of AD. On the other hand, it is well known that neurotrophic factors, especially brain-derived neurotrophic factor (BDNF) and its high-affinity receptor TrkB, have multiple roles in the central nervous system (CNS), including neuronal maintenance, synaptic plasticity, and neurogenesis, which are closely linked to learning and memory function. Thus, many investigations regarding therapeutic approaches to AD, and/or the screening of novel drug candidates for its treatment, focus on upregulation of the BDNF/TrkB system. Furthermore, current studies also demonstrate that GDNF, IGF1, and bFGF, which play roles in neuroprotection, are associated with AD. In this review, we introduce data demonstrating close relationships between the pathogenesis of AD, neurotrophic factors, and drug candidates, including natural compounds that upregulate the BDNF-mediated neurotrophic system.
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Affiliation(s)
- Tadahiro Numakawa
- Department of Cell Modulation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan
- Correspondence:
| | - Ryutaro Kajihara
- Department of Biomedical Laboratory Sciences, Faculty of Life Science, Kumamoto University, Kumamoto 862-0976, Japan
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Deyama S, Kaneda K. Role of neurotrophic and growth factors in the rapid and sustained antidepressant actions of ketamine. Neuropharmacology 2023; 224:109335. [PMID: 36403852 DOI: 10.1016/j.neuropharm.2022.109335] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 11/10/2022] [Accepted: 11/12/2022] [Indexed: 11/18/2022]
Abstract
The neurotrophic hypothesis of depression proposes that reduced levels of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) contribute to neuronal atrophy or loss in the prefrontal cortex (PFC) and hippocampus and impaired hippocampal adult neurogenesis, which are associated with depressive symptoms. Chronic, but acute, treatment with typical monoaminergic antidepressants can at least partially reverse these deficits, in part via induction of BDNF and/or VEGF expression, consistent with their delayed onset of action. Ketamine, an N-methyl-d-aspartate receptor antagonist, exerts rapid and sustained antidepressant effects. Rodent studies have revealed that ketamine rapidly increases BDNF and VEGF release and/or expression in the PFC and hippocampus, which in turn increases the number and function of spine synapses in the PFC and hippocampal neurogenesis. Ketamine also induces the persistent release of insulin-like growth factor 1 (IGF-1) in the PFC of male mice. These neurotrophic effects of ketamine are associated with its rapid and sustained antidepressant effects. In this review, we first provide an overview of the neurotrophic hypothesis of depression and then discuss the role of BDNF, VEGF, IGF-1, and other growth factors (IGF-2 and transforming growth factor-β1) in the antidepressant effects of ketamine and its enantiomers. This article is part of the Special Issue on 'Ketamine and its Metabolites'.
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Affiliation(s)
- Satoshi Deyama
- Laboratory of Molecular Pharmacology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan.
| | - Katsuyuki Kaneda
- Laboratory of Molecular Pharmacology, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, 920-1192, Japan
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Zhao T, Piao LH, Li DP, Xu SH, Wang SY, Yuan HB, Zhang CX. BDNF gene hydroxymethylation in hippocampus related to neuroinflammation-induced depression-like behaviors in mice. J Affect Disord 2023; 323:723-730. [PMID: 36529411 DOI: 10.1016/j.jad.2022.12.035] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 10/31/2022] [Accepted: 12/10/2022] [Indexed: 12/23/2022]
Abstract
BACKGROUND Neuroinflammation is a multifactorial condition related to glial cells and neurons activation, and it is implicated in CNS disorders including depression. BDNF is a crucial molecule that related to the pathology of depression, and it is the target of DNA methylation. DNA hydroxymethylation, an active demethylation process can convert 5-mC to 5-hmC by Tets catalyzation to regulate gene transcription. The regulatory function for BDNF gene in response to neuroinflammation remains poorly understood. METHODS Neuroinflammation and depressive-like behaviors were induced by lipopolysaccharide (LPS) administration in mice. The microglial activation and cellular 5-hmC localization in the hippocampus were confirmed by immunostaining. The transcripts of Tets and BDNF were examined by qPCR method. The global 5-hmC levels and enrichment of 5-hmC in BDNF gene in the hippocampus were analyzed using dot bolt and hMeDIP-sequencing analysis. RESULTS LPS administration induced a spectrum of depression-like behaviors (including behavioral despair and anhedonia) and increased expression of Iba-1, a marker for microglia activation, in hippocampus, demonstrating that LPS treatment cloud provide stable model of neuroinflammation with depressive-like behaviors as expected. Our results showed that Tet1, Tet2 and Tet3 mRNA expressions and consequent global 5-hmC levels were significantly decreased in the hippocampus of LPS group compared to saline group. We also demonstrated that 5-hmC fluorescence in the hippocampus located in excitatory neurons identified by CaMK II immunostaining. Furthermore, we demonstrated that the enrichment of 5-hmC in BDNF gene was decreased and corresponding BDNF mRNA was down-regulated in the hippocampus in LPS group compared to saline group. CONCLUSION Neuroinflammation-triggered aberrant BDNF gene hydroxymethylation in the hippocampus is an important epigenetic element that relates with depression-like behaviors.
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Affiliation(s)
- Te Zhao
- Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Lian-Hua Piao
- Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Dan-Ping Li
- Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Shi-Han Xu
- Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China
| | - Shu-Yi Wang
- The Second Bethune Clinical Medical College of Jilin University, Changchun, Jilin 130021, China
| | - Hai-Bo Yuan
- Department of Respiratory Medicine & Sleep Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.
| | - Chun-Xiao Zhang
- Department of Physiology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin 130021, China.
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Sun Y, Hu N, Wang M, Lu L, Luo C, Tang B, Yao C, Sweeney JA, Gong Q, Qiu C, Lui S. Hippocampal subfield alterations in schizophrenia and major depressive disorder: a systematic review and network meta-analysis of anatomic MRI studies. J Psychiatry Neurosci 2023; 48:E34-E49. [PMID: 36750240 PMCID: PMC9911126 DOI: 10.1503/jpn.220086] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 07/28/2022] [Accepted: 10/30/2022] [Indexed: 02/09/2023] Open
Abstract
BACKGROUND Hippocampal disturbances are important in the pathophysiology of both schizophrenia and major depressive disorder (MDD). Imaging studies have shown selective volume deficits across hippocampal subfields in both disorders. We aimed to investigate whether these volumetric alterations in hippocampal subfields are shared or divergent across disorders. METHODS We searched PubMed and Embase from database inception to May 8, 2021. We identified MRI studies in patients with schizophrenia, MDD or both, in which hippocampal subfield volumes were measured. We excluded nonoriginal, animal or postmortem studies, and studies that used other imaging modalities or overlapping data. We conducted a network meta-analysis to estimate and contrast alterations in subfield volumes in the 2 disorders. RESULTS We identified 45 studies that met the initial criteria for systematic review, of which 15 were eligible for network metaanalysis. Compared to healthy controls, patients with schizophrenia had reduced volumes in the bilateral cornu ammonis (CA) 1, granule cell layer of the dentate gyrus, subiculum, parasubiculum, molecular layer, hippocampal tail and hippocampus-amygdala transition area (HATA); in the left CA4 and presubiculum; and in the right fimbria. Patients with MDD had decreased volumes in the left CA3 and CA4 and increased volumes in the right HATA compared to healthy controls. The bilateral parasubiculum and right HATA were smaller in patients with schizophrenia than in patients with MDD. LIMITATIONS We did not investigate medication effects because of limited information. Study heterogeneity was noteworthy in direct comparisons between patients with MDD and healthy controls. CONCLUSION The volumes of multiple hippocampal subfields are selectively altered in patients with schizophrenia and MDD, with overlap and differentiation in subfield alterations across disorders. Rigorous head-to-head studies are needed to validate our findings.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Changjian Qiu
- From the Huaxi MR Research Center, Department of Radiology and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan, China (Sun, Lu, Tang, Yao, Sweeney, Gong, Lui); the Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China (Hu, Luo); the Chinese Evidence-Based Medicine Center and Cochrane China Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China (Wang); the Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio, United States (Sweeney); the Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China (Qiu); the Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, Sichuan, China (Lui); the Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan University, Chengdu, Sichuan, China (Lui)
| | - Su Lui
- From the Huaxi MR Research Center, Department of Radiology and National Clinical Research Center for Geriatrics, West China Hospital of Sichuan University, Chengdu, Sichuan, China (Sun, Lu, Tang, Yao, Sweeney, Gong, Lui); the Department of Radiology, West China Hospital of Sichuan University, Chengdu, Sichuan, China (Hu, Luo); the Chinese Evidence-Based Medicine Center and Cochrane China Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China (Wang); the Department of Psychiatry and Behavioral Neuroscience, University of Cincinnati, Cincinnati, Ohio, United States (Sweeney); the Mental Health Center, West China Hospital of Sichuan University, Chengdu, Sichuan, China (Qiu); the Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu, Sichuan, China (Lui); the Functional and Molecular Imaging Key Laboratory of Sichuan Province, West China Hospital of Sichuan University, Chengdu, Sichuan, China (Lui)
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Cranial electrotherapy stimulation alleviates depression-like behavior of post-stroke depression rats by upregulating GPX4-mediated BDNF expression. Behav Brain Res 2023; 437:114117. [PMID: 36116735 DOI: 10.1016/j.bbr.2022.114117] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 09/11/2022] [Accepted: 09/14/2022] [Indexed: 11/23/2022]
Abstract
To elucidate whether cranial electrotherapy stimulation (CES) improves depression-like behavior of post-stroke depression (PSD) via regulation of glutathione peroxidase 4 (GPX4)-mediated brain-derived neurotrophic factor (BDNF) expression. Middle cerebral artery occlusion (MCAO) and chronic unpredictable mild stress (CUMS) were used to develop a rat PSD model. CES was applied, and RAS-selective lethal 3 (RSL3) was injected into the hippocampus to inhibit GPX4 in PSD rats. The depression behavior was detected by sucrose preference and forced swimming tests. The structure and morphology of the hippocampus were observed and analyzed by histopathological hematoxylin-eosin (HE) staining. The mRNA and protein expressions of GPX4 and BDNF in the hippocampus were detected by qRT-PCR, western blot and immunohistochemical analysis.The degeneration and necrosis of hippocampal neurons, the depression-like behavior were severer and the expression of BDNF in the hippocampus were decreased in PSD rats than those in MCAO and control groups. CES promoted the hippocampal neuron repair, alleviated the depression-like behavior and increased the expression of BDNF in PSD rats. The inhibition of GPX4 by RSL3 exacerbated the depression-like behavior and decreased the expression of BDNF in PSD rats. In addition, we found that RSL3 disrupted the positive effects of CES on the PSD rats. Conclusion: CES improves depression-like behavior of PSD rats through upregulation of GPX4-mediated BDNF expression in the hippocampus.
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Cheung T, Li TMH, Ho YS, Kranz G, Fong KNK, Leung SF, Lam SC, Yeung WF, Lam JYT, Fong KH, Beisteiner R, Xiang YT, Cheng CPW. Effects of Transcranial Pulse Stimulation (TPS) on Adults with Symptoms of Depression-A Pilot Randomized Controlled Trial. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2023; 20:ijerph20032333. [PMID: 36767702 PMCID: PMC9915638 DOI: 10.3390/ijerph20032333] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 01/23/2023] [Accepted: 01/25/2023] [Indexed: 05/29/2023]
Abstract
Transcranial pulse stimulation (TPS) is a recent development in non-invasive brain stimulations (NIBS) that has been proven to be effective in terms of significantly improving Alzheimer patients' cognition, memory, and execution functions. Nonetheless, there is, currently, no trial evaluating the efficacy of TPS on adults with major depression disorder (MDD) nationwide. In this single-blinded, randomized controlled trial, a 2-week TPS treatment comprising six 30 min TPS sessions were administered to participants. Participants were randomized into either the TPS group or the Waitlist Control (WC) group, stratified by gender and age according to a 1:1 ratio. Our primary outcome was evaluated by the Hamilton depression rating scale-17 (HDRS-17). We recruited 30 participants that were aged between 18 and 54 years, predominantly female (73%), and ethnic Chinese from 1 August to 31 October 2021. Moreover, there was a significant group x time interaction (F(1, 28) = 18.8, p < 0.001). Further, when compared with the WC group, there was a significant reduction in the depressive symptom severity in the TPS group (mean difference = -6.60, p = 0.02, and Cohen's d = -0.93). The results showed a significant intervention effect; in addition, the effect was large and sustainable at the 3-month follow-up. In this trial, it was found that TPS is effective in reducing depressive symptoms among adults with MDD.
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Affiliation(s)
- Teris Cheung
- School of Nursing, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Tim Man Ho Li
- Department of Psychiatry, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yuen Shan Ho
- School of Nursing, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Georg Kranz
- Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Kenneth N. K. Fong
- Department of Rehabilitation Sciences, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Sau Fong Leung
- School of Nursing, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | | | - Wing Fai Yeung
- School of Nursing, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Joyce Yuen Ting Lam
- School of Nursing, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Kwan Hin Fong
- School of Nursing, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Roland Beisteiner
- Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria
| | - Yu-Tao Xiang
- Unit of Psychiatry, Department of Public Health and Medicinal Administration, Institute of Translational Medicine, University of Macau, Macao SAR, China
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Xu J, Zhang W, Zhong S, Xie X, Che H, Si W, Tuo X, Xu D, Zhao S. Microcystin-leucine-arginine affects brain gene expression programs and behaviors of offspring through paternal epigenetic information. THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 857:159032. [PMID: 36167133 DOI: 10.1016/j.scitotenv.2022.159032] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 09/01/2022] [Accepted: 09/21/2022] [Indexed: 06/16/2023]
Abstract
Microcystin-leucine-arginine (MC-LR) adversely affects male reproduction and interferes with the development of the offspring. Here, we establish a zebrafish (Danio rerio) model to understand the cross-generational effects of MC-LR in a male-lineage transmission pattern. F0 embryos were reared in water containing MC-LR (0, 5, and 25 μg/L) for 90 days and the developmental indices of F1 and F2 embryos were then measured with no MC-LR treatment. The results show that paternal MC-LR exposure reduced the hatching rate, heart rate and body weight in F1 and F2 generations. Global DNA methylation significantly increased in sperm and testes with the elevation expressions of DNA methyltransferases. Meanwhile, DNA methylation of brain-derived neurotrophic factor (bdnf) promoter was increased in sperm after paternal MC-LR exposure. Subsequently, increased DNA methylation of bdnf promoter and decreased gene expression of bdnf in the brain of F1 male zebrafish were detected. F1 offspring born to F0 males exhibit the depression of BDNF/AKT/CREB pathway and recapitulate these paternal neurodevelopment phenotypes in F2 offspring. In addition, the DNA methylations of dio3b and gad1b promoters were decreased and gene expressions of gad1b and dio3b were increased, accompanied with neurotransmitter disturbances in the brain of F1 male zebrafish after paternal MC-LR exposure. These data revealed that MC-LR displays a potential epigenetic impact on the germ line, reprogramming the epigenetic and transcriptional regulation of brain development, and contributing to aberrant expression of neurodevelopment-related genes and behavior disorders.
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Affiliation(s)
- Jiayi Xu
- School of Public Health, Anhui Medical University, Hefei 230032, China
| | - Weiyun Zhang
- School of Public Health, Anhui Medical University, Hefei 230032, China
| | - Shengzheng Zhong
- School of Public Health, Anhui Medical University, Hefei 230032, China
| | - Xinxin Xie
- School of Public Health, Anhui Medical University, Hefei 230032, China
| | - Huimin Che
- School of Public Health, Anhui Medical University, Hefei 230032, China
| | - Weirong Si
- School of Public Health, Anhui Medical University, Hefei 230032, China
| | - Xun Tuo
- College of Chemistry, Nanchang University, Nanchang 330031, China
| | - Dexiang Xu
- School of Public Health, Anhui Medical University, Hefei 230032, China
| | - Sujuan Zhao
- School of Public Health, Anhui Medical University, Hefei 230032, China.
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Larosa A, Wong TP. The hippocampus in stress susceptibility and resilience: Reviewing molecular and functional markers. Prog Neuropsychopharmacol Biol Psychiatry 2022; 119:110601. [PMID: 35842073 DOI: 10.1016/j.pnpbp.2022.110601] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 06/22/2022] [Accepted: 07/10/2022] [Indexed: 10/17/2022]
Abstract
Understanding the individual variability that comes with the likelihood of developing stress-related psychopathologies is of paramount importance when addressing mechanisms of their neurobiology. This article focuses on the hippocampus as a region that is highly influenced by chronic stress exposure and that has strong ties to the development of related disorders, such as depression and post-traumatic stress disorder. We first outline three commonly used animal models that have been used to separate animals into susceptible and resilient cohorts. Next, we review molecular and functional hippocampal markers of susceptibility and resilience. We propose that the hippocampus plays a crucial role in the differences in the processing and storage of stress-related information in animals with different stress susceptibilities. These hippocampal markers not only help us attain a more comprehensive understanding of the various facets of stress-related pathophysiology, but also could be targeted for the development of new treatments.
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Affiliation(s)
- Amanda Larosa
- Neuroscience Division, Douglas Research Centre, Montreal, QC, Canada; Integrated Program in Neuroscience, McGill University, Montreal, QC, Canada
| | - Tak Pan Wong
- Neuroscience Division, Douglas Research Centre, Montreal, QC, Canada; Dept. of Psychiatry, McGill University, Montreal, QC, Canada.
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Spinal Canal and Spinal Cord in Rat Continue to Grow Even after Sexual Maturation: Anatomical Study and Molecular Proposition. Int J Mol Sci 2022; 23:ijms232416076. [PMID: 36555713 PMCID: PMC9781254 DOI: 10.3390/ijms232416076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 12/13/2022] [Indexed: 12/23/2022] Open
Abstract
Although rodents have been widely used for experimental models of spinal cord diseases, the details of the growth curves of their spinal canal and spinal cord, as well as the molecular mechanism of the growth of adult rat spinal cords remain unavailable. They are particularly important when conducting the experiments of cervical spondylotic myelopathy (CSM), since the disease condition depends on the size of the spinal canal and the spinal cord. Thus, the purposes of the present study were to obtain accurate growth curves for the spinal canal and spinal cord in rats; to define the appropriate age in weeks for their use as a CSM model; and to propose a molecular mechanism of the growth of the adult spinal cord in rats. CT myelography was performed on Lewis rats from 4 weeks to 40 weeks of age. The vertical growth of the spinal canal at C5 reached a plateau after 20 and 12 weeks, and at T8 after 20 and 16 weeks, in males and females, respectively. The vertical growth of the C5 and T8 spinal cord reached a plateau after 24 weeks in both sexes. The vertical space available for the cord (SAC) of C5 and T8 did not significantly change after 8 weeks in either sex. Western blot analyses showed that VEGFA, FGF2, and BDNF were highly expressed in the cervical spinal cords of 4-week-old rats, and that the expression of these growth factors declined as rats grew. These findings indicate that the spinal canal and the spinal cord in rats continue to grow even after sexual maturation and that rats need to be at least 8 weeks of age for use in experimental models of CSM. The present study, in conjunction with recent evidence, proposes the hypothetical model that the growth of rat spinal cord after the postnatal period is mediated at least in part by differentiation of neural progenitor cells and that their differentiation potency is maintained by VEGFA, FGF2, and BDNF.
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Continuous Exposure to Alpha-Glycosyl Isoquercitrin from Gestation Ameliorates Disrupted Hippocampal Neurogenesis in Rats Induced by Gestational Injection of Valproic Acid. Neurotox Res 2022; 40:2278-2296. [PMID: 36094739 DOI: 10.1007/s12640-022-00574-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 08/02/2022] [Accepted: 08/29/2022] [Indexed: 01/04/2023]
Abstract
This study examined the ameliorating effect of alpha-glycosyl isoquercitrin (AGIQ), an antioxidant, on disrupted hippocampal neurogenesis in the dentate gyrus (DG) in a rat model of autism spectrum disorder induced by prenatal valproic acid (VPA) exposure. Dams were intraperitoneally injected with 500 mg/kg VPA on gestational day 12. AGIQ was administered in the diet at 0.25 or 0.5% to dams from gestational day 13 until weaning at postnatal day (PND) 21 and then to pups until PND 63. At PND 21, VPA-exposed offspring showed decreased numbers of type-2a and type-3 neural progenitor cells (NPCs) among granule cell lineage subpopulations. AGIQ treatment at both doses rescued the reduction in type-3 NPCs. AGIQ upregulated Reln and Vldlr transcript levels in the DG at 0.5% and ≥ 0.25%, respectively, and increased the number of reelin+ interneurons in the DG hilus at 0.5%. AGIQ at 0.25% and/or 0.5% also upregulated Ntrk2, Cntf, Igf1, and Chrnb2. At PND 63, there were no changes in the granule cell lineage subpopulations in response to VPA or AGIQ. AGIQ at 0.25% increased the number of FOS+ granule cells, accompanied by Gria2 and Gria3 upregulation and increasing trend in the number of FOS+ granule cells at 0.5%. There was no definitive evidence of VPA-induced oxidative stress in the hippocampus throughout postnatal life. These results indicate that AGIQ ameliorates the VPA-induced disruption of hippocampal neurogenesis at weaning involving reelin, BDNF-TrkB, CNTF, and IGF1 signaling, and enhances FOS-mediated synaptic plasticity in adulthood, potentially through AMPA-receptor upregulation. The ameliorating effects of AGIQ may involve direct interactions with neural signaling cascades rather than antioxidant capacity.
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Seib DR, Princz-Lebel O, Chahley ER, Floresco SB, Snyder JS. Hippocampal neurogenesis promotes effortful responding but does not regulate effort-based choice. Hippocampus 2022; 32:818-827. [PMID: 36177887 DOI: 10.1002/hipo.23472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2022] [Revised: 08/31/2022] [Accepted: 09/13/2022] [Indexed: 01/07/2023]
Abstract
A fundamental trait of depression is low motivation. Hippocampal neurogenesis has been associated with motivational deficits but detailed evidence on how it regulates human-relevant behavioral traits is still missing. We used the hGFAP-TK rat model to deplete actively dividing neural stem cells in the rat hippocampus. Use of the effort-discounting operant task allowed us to identify specific and detailed deficits in motivation behavior. In this task, rats are given a choice between small and large food rewards, where 2-20 lever presses are required to obtain the large reward (four sugar pellets) versus one press to receive the smaller reward (two sugar pellets). We found that depleting adult neurogenesis did not affect effort-based choice or general motivation to complete the task. However, lack of adult neurogenesis reduced the pressing rate and thus increased time to complete the required presses to obtain a reward. In summary, the present study finds that adult hippocampal neurogenesis specifically reduces response vigor to obtain rewards and thus deepens our understanding in how neurogenesis shapes depression.
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Affiliation(s)
- Désirée R Seib
- Department of Psychology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada
| | - Oren Princz-Lebel
- Department of Psychology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada
| | - Erin R Chahley
- Department of Psychology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada
| | - Stan B Floresco
- Department of Psychology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada
| | - Jason S Snyder
- Department of Psychology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada
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Alfonsetti M, d’Angelo M, Castelli V. Neurotrophic factor-based pharmacological approaches in neurological disorders. Neural Regen Res 2022; 18:1220-1228. [PMID: 36453397 PMCID: PMC9838155 DOI: 10.4103/1673-5374.358619] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Aging is a physiological event dependent on multiple pathways that are linked to lifespan and processes leading to cognitive decline. This process represents the major risk factor for aging-related diseases such as Alzheimer's disease, Parkinson's disease, and ischemic stroke. The incidence of all these pathologies increases exponentially with age. Research on aging biology has currently focused on elucidating molecular mechanisms leading to the development of those pathologies. Cognitive deficit and neurodegeneration, common features of aging-related pathologies, are related to the alteration of the activity and levels of neurotrophic factors, such as brain-derived neurotrophic factor, nerve growth factor, and glial cell-derived neurotrophic factor. For this reason, treatments that modulate neurotrophin levels have acquired a great deal of interest in preventing neurodegeneration and promoting neural regeneration in several neurological diseases. Those treatments include both the direct administration of neurotrophic factors and the induced expression with viral vectors, neurotrophins' binding with biomaterials or other molecules to increase their bioavailability but also cell-based therapies. Considering neurotrophins' crucial role in aging pathologies, here we discuss the involvement of several neurotrophic factors in the most common brain aging-related diseases and the most recent therapeutic approaches that provide direct and sustained neurotrophic support.
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Affiliation(s)
- Margherita Alfonsetti
- Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy
| | - Michele d’Angelo
- Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy
| | - Vanessa Castelli
- Department of Life, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy,Correspondence to: Vanessa Castelli, .
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New Atypical Antipsychotics in the Treatment of Schizophrenia and Depression. Int J Mol Sci 2022; 23:ijms231810624. [PMID: 36142523 PMCID: PMC9500595 DOI: 10.3390/ijms231810624] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Revised: 09/09/2022] [Accepted: 09/09/2022] [Indexed: 11/25/2022] Open
Abstract
Schizophrenia and depression are heterogeneous disorders. The complex pathomechanism of the diseases imply that medication responses vary across patients. Many psychotropic drugs are available but achieving optimal therapeutic effect can be challenging. The evidence correlates well with clinical observations, suggesting that new atypical antipsychotic drugs are effective against negative and cognitive symptoms of schizophrenia, as well as against affective symptoms observed in depression. The purpose of this review presents the background and evidence for the use of the new second/third-generation antipsychotics (aripiprazole, cariprazine, lurasidone, asenapine, brexpiprazole, lumateperone, pimavanserin) in treatment of schizophrenia and depression. We have first provided a brief overview of the major neurobiological underpinnings of schizophrenia and depression. We then shortly discuss efficacy, safety and limitations of ongoing pharmacotherapy used in depression and schizophrenia. Mainly, we have focused this review on the therapeutic potential of new atypical antipsychotic drugs—currently existing—to be effective in psychotic, as well as in affective disorders.
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41
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Razavi Y, Najafi M, Haghparast A, Keyhanfar F, Shabani R, Mehdizadeh M. Cannabidiol Modulating the Expression of Neurotrophin Signaling Pathways in Chronic Exposure to Methamphetamine in Rats During Abstinence Period. Basic Clin Neurosci 2022; 13:719-730. [PMID: 37313028 PMCID: PMC10258595 DOI: 10.32598/bcn.2021.3059.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 05/29/2021] [Accepted: 06/09/2021] [Indexed: 11/02/2023] Open
Abstract
Introduction Several neuropsychiatric disorders, such as addiction, have indicated variations in the levels of neurotrophic factors. As an extremely addictive stimulant, methamphetamine (METH) is associated with rising levels of abuse worldwide. We have recently demonstrated that repeated intracerebroventricular (ICV) of cannabidiol (CBD), the most important non-psychotomimetic compound, can lead to diminished impairing memory and hippocampal damage caused by chronic exposure to METH (CEM) in rats over the abstinence period. Furthermore, the results indicated a possible contribution of the neurotrophin signaling pathway (NSP) in regulating neurogenesis and survival. This study intends to evaluate whether these effects remained as measured in molecular pathways after the abstinence period. Methods The animals were given 2mg/kg METH twice a day for 10 days. Then, we adopted real-time polymerase chain reaction (PCR) throughout the 10-day abstinence period to assess the CBD's effect (10 and 50μg/5μL) on the levels of the mRNA expression of the NSP. Results The findings suggested that CEM, when compared to the control group in the hippocampus, downregulated mRNA expression of NSP. Moreover, a dosage of 50 μg/5μL CBD may possibly enhance the mRNA expression level of BDNF/TrkB and NGF/TrkA in the hippocampus. Besides, the expression of RAF-1 mRNA level could be reversed significantly by both doses of CBD. Conclusion According to our results, CBD may partly bring about neuroprotective effects by modulating the NSP. These findings set forth solid evidence demonstrating that CBD is a protective factor attributed to neuropsychiatric disorders, such as METH addiction.
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Affiliation(s)
- Yasaman Razavi
- Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Najafi
- Department of Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Abbas Haghparast
- Neuroscience Research Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Fariborz Keyhanfar
- Department of Pharmacology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ronak Shabani
- Reproductive Sciences and Technology Research Center, Department of Anatomy, Iran University of Medical Sciences, Tehran, Iran
| | - Mehdi Mehdizadeh
- Reproductive Sciences and Technology Research Center, Department of Anatomy, Iran University of Medical Sciences, Tehran, Iran
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Wang J, Liu B, Sun F, Xu Y, Luan H, Yang M, Wang C, Zhang T, Zhou Z, Yan H. Histamine H3R antagonist counteracts the impaired hippocampal neurogenesis in Lipopolysaccharide-induced neuroinflammation. Int Immunopharmacol 2022; 110:109045. [DOI: 10.1016/j.intimp.2022.109045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 06/24/2022] [Accepted: 07/07/2022] [Indexed: 11/05/2022]
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Upadhya D, Attaluri S, Liu Y, Hattiangady B, Castro OW, Shuai B, Dong Y, Zhang SC, Shetty AK. Grafted hPSC-derived GABA-ergic interneurons regulate seizures and specific cognitive function in temporal lobe epilepsy. NPJ Regen Med 2022; 7:38. [PMID: 35915118 PMCID: PMC9343458 DOI: 10.1038/s41536-022-00234-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Accepted: 06/24/2022] [Indexed: 11/25/2022] Open
Abstract
Interneuron loss/dysfunction contributes to spontaneous recurrent seizures (SRS) in chronic temporal lobe epilepsy (TLE), and interneuron grafting into the epileptic hippocampus reduces SRS and improves cognitive function. This study investigated whether graft-derived gamma-aminobutyric acid positive (GABA-ergic) interneurons directly regulate SRS and cognitive function in a rat model of chronic TLE. Human pluripotent stem cell-derived medial ganglionic eminence-like GABA-ergic progenitors, engineered to express hM4D(Gi), a designer receptor exclusively activated by designer drugs (DREADDs) through CRISPR/Cas9 technology, were grafted into hippocampi of chronically epileptic rats to facilitate the subsequent silencing of graft-derived interneurons. Such grafting substantially reduced SRS and improved hippocampus-dependent cognitive function. Remarkably, silencing of graft-derived interneurons with a designer drug increased SRS and induced location memory impairment but did not affect pattern separation function. Deactivation of DREADDs restored both SRS control and object location memory function. Thus, transplanted GABA-ergic interneurons could directly regulate SRS and specific cognitive functions in TLE.
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Affiliation(s)
- Dinesh Upadhya
- Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX, USA.,Department of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX, USA.,Research Service, Olin E. Teague Veterans' Medical Center, Central Texas Veterans Health Care System, Temple, TX, USA.,Centre for Molecular Neurosciences, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Sahithi Attaluri
- Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX, USA.,Department of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX, USA.,Research Service, Olin E. Teague Veterans' Medical Center, Central Texas Veterans Health Care System, Temple, TX, USA
| | - Yan Liu
- Waisman Center, Departments of Neuroscience and Neurology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Bharathi Hattiangady
- Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX, USA.,Department of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX, USA.,Research Service, Olin E. Teague Veterans' Medical Center, Central Texas Veterans Health Care System, Temple, TX, USA
| | - Olagide W Castro
- Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX, USA.,Department of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX, USA.,Research Service, Olin E. Teague Veterans' Medical Center, Central Texas Veterans Health Care System, Temple, TX, USA.,Institute of Biological Sciences and Health, Federal Univ of Alagoas (UFAL), Maceio, AL, Brazil
| | - Bing Shuai
- Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX, USA.,Department of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX, USA.,Research Service, Olin E. Teague Veterans' Medical Center, Central Texas Veterans Health Care System, Temple, TX, USA
| | - Yi Dong
- Waisman Center, Departments of Neuroscience and Neurology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Su-Chun Zhang
- Waisman Center, Departments of Neuroscience and Neurology, School of Medicine and Public Health, University of Wisconsin, Madison, WI, USA
| | - Ashok K Shetty
- Institute for Regenerative Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX, USA. .,Department of Molecular and Cellular Medicine, Texas A&M Health Science Center College of Medicine, College Station, TX, USA. .,Research Service, Olin E. Teague Veterans' Medical Center, Central Texas Veterans Health Care System, Temple, TX, USA.
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Hesperidin Improves Memory Function by Enhancing Neurogenesis in a Mouse Model of Alzheimer’s Disease. Nutrients 2022; 14:nu14153125. [PMID: 35956303 PMCID: PMC9370591 DOI: 10.3390/nu14153125] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 07/25/2022] [Accepted: 07/28/2022] [Indexed: 02/04/2023] Open
Abstract
Alzheimer’s disease (AD) is an irreversible neurodegenerative disease characterized by memory and cognitive impairments. Neurogenesis, which is related to memory and cognitive function, is reduced in the brains of patients with AD. Therefore, enhancing neurogenesis is a potential therapeutic strategy for neurodegenerative diseases, including AD. Hesperidin (HSP), a bioflavonoid found primarily in citrus plants, has anti-inflammatory, antioxidant, and neuroprotective effects. The objective of this study was to determine the effects of HSP on neurogenesis in neural stem cells (NSCs) isolated from the brain of mouse embryos and five familial AD (5xFAD) mice. In NSCs, HSP significantly increased the proliferation of NSCs by activating adenosine monophosphate (AMP)-activated protein kinase (AMPK)/cAMP-response element-binding protein (CREB) signaling, but did not affect NSC differentiation into neurons and astrocytes. HSP administration restored neurogenesis in the hippocampus of 5xFAD mice via AMPK/brain-derived neurotrophic factor/tropomyosin receptor kinase B/CREB signaling, thereby decreasing amyloid-beta accumulation and ameliorating memory dysfunction. Collectively, these preclinical findings suggest that HSP is a promising candidate for the prevention and treatment of AD.
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The Role of Neurotrophin Signaling in Age-Related Cognitive Decline and Cognitive Diseases. Int J Mol Sci 2022; 23:ijms23147726. [PMID: 35887075 PMCID: PMC9320180 DOI: 10.3390/ijms23147726] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/08/2022] [Accepted: 07/11/2022] [Indexed: 02/07/2023] Open
Abstract
Neurotrophins are a family of secreted proteins expressed in the peripheral nervous system and the central nervous system that support neuronal survival, synaptic plasticity, and neurogenesis. Brain-derived neurotrophic factor (BDNF) and its high affinity receptor TrkB are highly expressed in the cortical and hippocampal areas and play an essential role in learning and memory. The decline of cognitive function with aging is a major risk factor for cognitive diseases such as Alzheimer’s disease. Therefore, an alteration of BDNF/TrkB signaling with aging and/or pathological conditions has been indicated as a potential mechanism of cognitive decline. In this review, we summarize the cellular function of neurotrophin signaling and review the current evidence indicating a pathological role of neurotrophin signaling, especially of BDNF/TrkB signaling, in the cognitive decline in aging and age-related cognitive diseases. We also review the therapeutic approach for cognitive decline by the upregulation of the endogenous BDNF/TrkB-system.
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46
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Promise of irisin to attenuate cognitive dysfunction in aging and Alzheimer's disease. Ageing Res Rev 2022; 78:101637. [PMID: 35504553 PMCID: PMC9844023 DOI: 10.1016/j.arr.2022.101637] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2021] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 01/19/2023]
Abstract
Strategies proficient for relieving cognitive impairments in aging and Alzheimer's disease (AD) have an enormous impact. Regular physical exercise (PE) can prevent age-related dementia and slow down AD progression. However, such a lifestyle change is likely not achievable for individuals displaying age-related frailty. Hence, drugs or biologics that could simulate the benefits of PE have received much attention. Previous studies suggested that the fibronectin-domain III containing 5 (FNDC5) underlies the PE-mediated improved cognitive function. A recent study reports that PE-related cognitive benefits in aging and AD are mediated by irisin, the cleaved form of FNDC5 released into the blood after PE. Such a conclusion was apparent from the deletion of irisin through a global knockout of FNDC5, leading to the loss of PE-induced cognitive benefits or inducing memory impairments in adult or aged models. Furthermore, in AD models, peripherally administered irisin mimicked the cognitive benefits of PE by modulating neuroinflammation. This short review discusses the promise of irisin to simulate the cognitive benefits of PE in age- and AD-related dementia. In addition, critical issues such as how blood-borne irisin acts on neural cells, the role of the brain-derived neurotrophic factor in irisin-mediated cognitive benefits, and irisin's ability to inhibit neuroinflammatory cascades in aging and AD are discussed.
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47
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Targeting NRF2 in Type 2 diabetes mellitus and depression: Efficacy of natural and synthetic compounds. Eur J Pharmacol 2022; 925:174993. [PMID: 35513015 DOI: 10.1016/j.ejphar.2022.174993] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 03/31/2022] [Accepted: 04/28/2022] [Indexed: 12/18/2022]
Abstract
Evidence supports a strong bidirectional association between depression and Type 2 diabetes mellitus (T2DM). The harmful impact of oxidative stress and chronic inflammation on the development of both disorders is widely accepted. Nuclear factor erythroid 2-related factor 2 (NRF2) is a pertinent target in disease management owing to its reputation as the master regulator of antioxidant responses. NRF2 influences the expression of various cytoprotective phase 2 antioxidant genes, which is hampered in both depression and T2DM. Through interaction and crosstalk with several signaling pathways, NRF2 endeavors to contain the widespread oxidative damage and persistent inflammation involved in the pathophysiology of depression and T2DM. NRF2 promotes the neuroprotective and insulin-sensitizing properties of its upstream and downstream targets, thereby interrupting and preventing disease advancement. Standard antidepressant and antidiabetic drugs may be powerful against these disorders, but unfortunately, they come bearing distressing side effects. Therefore, exploiting the therapeutic potential of NRF2 activators presents an exciting opportunity to manage such bidirectional and comorbid conditions.
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48
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Ma W, Xu D, Zhao L, Yuan M, Cui YL, Li Y. Therapeutic role of curcumin in adult neurogenesis for management of psychiatric and neurological disorders: a scientometric study to an in-depth review. Crit Rev Food Sci Nutr 2022; 63:9379-9391. [PMID: 35482938 DOI: 10.1080/10408398.2022.2067827] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Aberrant neurogenesis is a major factor in psychiatric and neurological disorders that have significantly attracted the attention of neuroscientists. Curcumin is a primary constituent of curcuminoid that exerts several positive pharmacological effects on aberrant neurogenesis. First, it is important to understand the different processes of neurogenesis, and whether their dysfunction promotes etiology as well as the development of many psychiatric and neurological disorders; then investigate mechanisms by which curcumin affects neurogenesis as an active participant in pathophysiological events. Based on scientometric studies and additional extensive research, we explore the mechanisms by which curcumin regulates adult neurogenesis and in turn affects psychiatric diseases, i.e., depression and neurological disorders among them traumatic brain injury (TBI), stroke, Alzheimer's disease (AD), Gulf War Illness (GWI) and Fragile X syndrome (FXS). This review aims to elucidate the therapeutic effects and mechanisms of curcumin on adult neurogenesis in various psychiatric and neurological disorders. Specifically, we discuss the regulatory role of curcumin in different activities of neural stem cells (NSCs), including proliferation, differentiation, and migration of NSCs. This is geared toward providing novel application prospects of curcumin in treating psychiatric and neurological disorders by regulating adult neurogenesis.
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Affiliation(s)
- Wenxin Ma
- State Key Laboratory of Component-Based Chinese Medicine, Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Dong Xu
- State Key Laboratory of Component-Based Chinese Medicine, Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Lucy Zhao
- Wolfson Centre for Age-Related Diseases, King's College London, London, UK
| | - Mengmeng Yuan
- State Key Laboratory of Component-Based Chinese Medicine, Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yuan-Lu Cui
- State Key Laboratory of Component-Based Chinese Medicine, Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yue Li
- State Key Laboratory of Component-Based Chinese Medicine, Ministry of Education Key Laboratory of Pharmacology of Traditional Chinese Medicine Formulae, Institute of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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Wang SD, Wang X, Zhao Y, Xue BH, Wang XT, Chen YX, Zhang ZQ, Tian YR, Xie F, Qian LJ. Homocysteine-Induced Disturbances in DNA Methylation Contribute to Development of Stress-Associated Cognitive Decline in Rats. Neurosci Bull 2022; 38:887-900. [PMID: 35435568 PMCID: PMC9352847 DOI: 10.1007/s12264-022-00852-7] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 01/11/2022] [Indexed: 11/28/2022] Open
Abstract
Chronic stress is generally accepted as the main risk factor in the development of cognitive decline; however, the underlying mechanisms remain unclear. Previous data have demonstrated that the levels of homocysteine (Hcy) are significantly elevated in the plasma of stressed animals, which suggests that Hcy is associated with stress and cognitive decline. To test this hypothesis, we analyzed the cognitive function, plasma concentrations of Hcy, and brain-derived neurotropic factor (BDNF) levels in rats undergoing chronic unpredicted mild stress (CUMS). The results showed that decreased cognitive behavioral performance and decreased BDNF transcription and protein expression were correlated with hyperhomocysteinemia (HHcy) levels in stressed rats. Diet-induced HHcy mimicked the cognitive decline and BDNF downregulation in the same manner as CUMS, while Hcy reduction (by means of vitamin B complex supplements) alleviated the cognitive deficits and BDNF reduction in CUMS rats. Furthermore, we also found that both stress and HHcy disturbed the DNA methylation process in the brain and induced DNA hypermethylation in the BDNF promoter. In contrast, control of Hcy blocked BDNF promoter methylation and upregulated BDNF levels in the brain. These results imply the possibility of a causal role of Hcy in stress-induced cognitive decline. We also used ten-eleven translocation (TET1), an enzyme that induces DNA demethylation, to verify the involvement of Hcy and DNA methylation in the regulation of BDNF expression and the development of stress-related cognitive decline. The data showed that TET1-expressing viral injection into the hippocampus inhibited BDNF promoter methylation and significantly mitigated the cognitive decline in HHcy rats. Taken together, novel evidence from the present study suggests that Hcy is likely involved in chronic stress-induced BDNF reduction and related cognitive deficits. In addition, the negative side-effects of HHcy may be associated with Hcy-induced DNA hypermethylation in the BDNF promoter. The results also suggest the possibility of Hcy as a target for therapy and the potential value of vitamin B intake in preventing stress-induced cognitive decline.
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50
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Chai Y, Cai Y, Fu Y, Wang Y, Zhang Y, Zhang X, Zhu L, Miao M, Yan T. Salidroside Ameliorates Depression by Suppressing NLRP3-Mediated Pyroptosis via P2X7/NF-κB/NLRP3 Signaling Pathway. Front Pharmacol 2022; 13:812362. [PMID: 35496273 PMCID: PMC9039222 DOI: 10.3389/fphar.2022.812362] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 03/28/2022] [Indexed: 12/27/2022] Open
Abstract
Depression is a common and serious mental disorder. Data on its pathogenesis remain unclear and the options of drug treatments are limited. Here, we explored the role of pyroptosis, a novel pro-inflammatory programmed cell death process, in depression as well as the anti-depression effects and mechanisms of salidroside (Sal), a bioactive extract from Rhodiola rosea L. We established a corticosterone (CORT)-induced or lipopolysaccharide (LPS)-induced mice in vivo, and CORT, or nigericin (NLRP3 agonist)-induced PC12 cells in vitro. Our findings demonstrated that Sal profoundly mediated CORT or LPS-induced depressive behavior and improved synaptic plasticity by upregulating the expression of brain-derived neurotrophic factor (BDNF) gene. The data showed upregulation of proteins associated with NLRP3-mediated pyroptosis, including NLRP3, cleaved Caspase-1, IL-1β, IL-18, and cleaved GSDMD. The molecular docking simulation predicted that Sal would interact with P2X7 of the P2X7/NF-κB/NLRP3 signaling pathway. In addition, our findings showed that the NLRP3-mediated pyroptosis was regulated by P2X7/NF-κB/NLRP3 signaling pathway. Interestingly, Sal was shown to ameliorate depression via suppression of the P2X7/NF-κB/NLRP3 mediated pyroptosis, and rescued nigericin-induced pyroptosis in the PC12 cells. Besides, knock down of the NLRP3 gene by siRNA markedly increased the inhibitory effects of Sal on pyroptosis and proinflammatory responses. Taken together, our findings demonstrated that pyroptosis plays a crucial role in depression, and Sal ameliorates depression by suppressing the P2X7/NF-κB/NLRP3-mediated pyroptosis. Thus, our study provides new insights into the potential treatment options for depression.
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Affiliation(s)
- Yuhui Chai
- Department of Physiology and Pharmacology, China Pharmaceutic University, Nanjing, China
| | - Yawen Cai
- Department of Physiology and Pharmacology, China Pharmaceutic University, Nanjing, China
| | - Yu Fu
- Department of Physiology and Pharmacology, China Pharmaceutic University, Nanjing, China
| | - Yingdi Wang
- Department of Physiology and Pharmacology, China Pharmaceutic University, Nanjing, China
| | - Yiming Zhang
- Department of Physiology and Pharmacology, China Pharmaceutic University, Nanjing, China
| | - Xue Zhang
- Department of Physiology and Pharmacology, China Pharmaceutic University, Nanjing, China
| | - Lingpeng Zhu
- Center of Clinical Research, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi, China
- *Correspondence: Lingpeng Zhu, ; Mingxing Miao, ; Tianhua Yan,
| | - Mingxing Miao
- Center of National Pharmaceutical Experimental Teaching Demonstration, China Pharmaceutic University, Nanjing, China
- *Correspondence: Lingpeng Zhu, ; Mingxing Miao, ; Tianhua Yan,
| | - Tianhua Yan
- Department of Physiology and Pharmacology, China Pharmaceutic University, Nanjing, China
- *Correspondence: Lingpeng Zhu, ; Mingxing Miao, ; Tianhua Yan,
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