BRAIN BEHAVIOR AND IMMUNITY
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2020
·
IF 6.633
Jinfeng Xie,Bingtian Bi,Yunyun Qin,Wenli Dong,Jiahong Zhong,Mengfan Li,Yufang Cheng,Jiangping Xu,Haitao Wang
Inhibition of phosphodiesterase-4 (PDE4) produces robust anti-inflammatory and antidepressant-like effects in multiple animal models. However, the detailed mechanisms have not been well studied. Receptor for advanced glycation endproducts (RAGE) and inflammasome activation are implicated in the etiology of depression. Here, we aimed to investigate the involvement of RAGE and nucleotide-binding domain (NOD)–like receptor protein 3 (NLRP3) inflammasome in the antidepressant-like effects of PDE4 inhibition in mice. We found that inhibition of PDE4 by roflupram (ROF, 0.5, and 1.0 mg/kg, i.g. ) exerted antidepressant-like effects in mice subjected to chronic unpredictable mild stress (CUMS). Simultaneously, ROF inhibited CUMS-induced microglial activation and restored the morphology of microglial cells in the hippocampus, as evidenced by reduced total process length, area, volume, number of branching points, number of terminal points and total sholl intersections of microglia. ROF also decreased the expression of ionized calcium-binding adapter molecule-1 and the level of interleukin-1β. Western blot analysis showed that PDE4 inhibition suppressed the high-mobility group box 1 protein (HMGB1)/RAGE signaling pathway, as the levels of HMGB1, RAGE, toll-like receptor 4, phosphorylated p38 mitogen-activated protein kinase, and nuclear factor κ-B were decreased in both hippocampus and cortex in mice after treatment with ROF. Moreover, ROF also attenuated the protein levels of NLRP3, the apoptosis-associated speck-like protein containing (ASC), and cysteine-requiring aspartate protease-1 (Caspase-1), which are key proteins in the NLRP3-mediated inflammasome signaling pathway. In summary, these results demonstrate that the down-regulation of HMGB1/RAGE signaling pathway and inflammasome suppression possibly contribute to the antidepressant-like effects of PDE4 inhibitors. And, ROF has potential as a candidate drug in the treatment of depression.
研究领域:
神经科学
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药理学
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免疫学
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精神病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Psychiatry
·
2021
·
IF 4.157
Jiang Ning,Wang Haixia,Huang Hong,Lv Jingwei,Zeng Guirong,Wang Qiong,Bao Yu,Chen Ying,Liu Xinmin
Depression is a common yet severe neuropsychiatric condition that causes imposes considerable personal, economic, and social burdens worldwide. Medicinal plant species (e.g., Panax ginseng and Polygala tenuifolia) demonstrate potent antidepressant-like effects with less toxicity and other side effects. Shen yuan prescription (SY), composed of Panax ginseng (GT) and Polygala tenuifolia (YT). The present study aimed to elucidate the effects of SY treatment on chronic unpredictable mild stress (CUMS) rats and study the underlying mechanism. Our results indicated that SY (67.5, 135, or 270 mg/kg) significantly reverses the depressive-like behaviors in rats with a 5-week CUMS exposure, as demonstrated by increased sucrose consumption in the sucrose preference test, and decreased immobility time in the tail suspension and forced swim test. Moreover, SY altered serum corticosterone levels, pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α), and oxidative markers (SOD, CAT, and MDA), and increased the levels of hippocampal neurotransmitters (5-HT, DA, and NE) in rats exposed to CUMS. Furthermore, rats treated with SY showed a reduction in the protein expression of BDNF, p-TrkB, p-Akt, and p-mTOR proteins induced by CUMS exposure in the hippocampus. In conclusion, SY prevented depressive-like behaviors in CUMS-exposed rats by preventing hypothalamus-pituitary-adrenal axis dysfunction, decreasing the levels of the neurotransmitters, minimizing oxidative stress, suppressing neuroinflammation, and activating the PI3K/Akt/mTOR-mediated BDNF/TrkB pathway, all of which are the key players in the pathological basis of depression.
研究领域:
神经精神病学
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药理学
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行为神经科学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2023
·
IF 5.4
Yiyang Du,Tingxu Yan,Bo Wu,Bosai He,Ying Jia
Ethnopharmacological relevance Increased inflammatory response and disruption of neuroplasticity are important mechanisms in the hypothesis of the pathogenesis of depression. Thus, these two aspects are conducive to the development of treatments for depression. Suanzaoren Decoction (SZRD) is a classic traditional Chinese medicine compound for the treatment of insomnia, which can clinically relieve depression symptoms, but its antidepressant pharmacological mechanism remains to be elucidated. Aim of this study Based on the hypothesis of inflammation and neuroplasticity in depression, this study aimed to investigate the antidepressant effect of SZRD and its specific molecular mechanism through chronic unpredictable mild stress (CUMS) induced SD rat model and lipopolysaccharide (LPS) induced BV2 cell neuroinflammation model. Materials and methods The body weight and behavioral indexes of CUMS model rats treated with orally or without oral SZRD for 4 weeks were detected. Hematoxylin and eosin staining was used to observe brain pathological damage. Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) staining was used to observe neuronal apoptosis. Immunofluorescence, ELISA kit and Western blotting were used to detect the inflammatory index Iba-1 and inflammatory factors, as well as the important inflammatory pathway TLR4/MyD88/NF-κB. Enzyme linked immunosorbent assay (ELISA) and western blotting were used to detect neuroplasticity indexes proteins-brain-derived neurotrophic factor (BDNF), presynaptic membrane protein-synaptophysin (SYP), and postsynaptic protein- 95(PSD95), and the key pathway Wnt/β-catenin. The possible mechanism of SZRD antidepressant was further explored in LPS-induced BV2 cells. Results In vivo and in vitro experiments showed that SZRD treatment significantly reversed the depression-like behaviors in rats, decreased the levels of inflammatory factors and increased the expression levels of BDNF, SYP, PSD95 in depression model rats. Furthermore, SZRD treatment inhibited the activation of TLR4/MyD88/NF-κB and Wnt/β-catenin pathways and reduced the massive nuclear translocation of NF-κB and β-catenin. The addition of NF-κB pathway agonists could partially offset the inhibitory effect of SZRD on the Wnt pathway, and the addition of Wnt pathway agonists could also partially offset the inhibitory effect of SZRD on the TLR4 pathway. Conclusion This study suggestted that SZRD may exert its antidepressant effect by regulating TLR4/MyD88/NF-κB pathway and Wnt/β-catenin pathway in combination.
研究领域:
药理学
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神经科学
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中医
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BRAIN RESEARCH BULLETIN
·
2024
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IF 3.5
Wenshan Yang,Yuanbo Wang,Xia Li,Rui Jing,Lihua Mu,Yuan Hu
Depressive-cardiac disease is a comorbid state in which both cardiovascular diseases and mental disorders are present. Patients with depression are more likely to develop cardiovascular disease, which increases the risk of cardiovascular events, such as acute coronary syndrome. Cardiovascular diseases also exacerbate the poor mood of patients with psychiatric disorders. Kai-xin-san (KXS), a classic antidepressant formula, has potential antidepressive and cardioprotective effects. In the present study, we first evaluated the antidepressive and cardioprotective effects of KXS in two post-myocardial ischemic depressed rat models: a) isoproterenol (ISO) via intraperitoneal injection combined with chronic unpredictable mild stress (CUMS)-induced myocardial ischemia and depression and b) left anterior descending coronary artery ligation (LAD) combined with chronic restraint stress (CRS)-induced myocardial ischemia and depression. We then induced exogenous corticosterone in a rat model of depressive-cardiac disease. Our study revealed that chronic administration of corticosterone could induce depression-like syndromes accompanied by cardiac insufficiency. The potential mechanism involves parallel onset of HPA axis dysfunction and an imbalance in lipid metabolism. KXS treatment successfully reversed corticosterone-induced depression-like behaviors and cardiac insufficiency. The present study highlights the pivotal role of the HPA axis and lipid metabolism in the development of comorbid depression and cardiovascular disease. Thus, KXS could be a promising therapeutic option for depressive-cardiac disease.
研究领域:
药理学
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神经科学
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心脏病学
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精神病学
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代谢学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
NEUROCHEMICAL RESEARCH
·
2022
·Vol. 47
·期 10
·3126-3136
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IF 4.414
Wang Yan,Zhou Sixu,Song Xujiao,Ding Shanshan,Wang Baogui,Wen Jiangfeng,Chen Chunlin
Crocin is a monomer of Chinese traditional herbs extracted from saffron, relieving depression-like behavior. However, its underlying mechanism of action remains unclear. Herein, we explored whether crocin's antidepressant effect depended on the mammalian target of the rapamycin (mTOR) signaling pathway. The model of PC12 cells injury was established by corticosterone, the changes in cell survival rate were tested by the CCK-8 method, and the changes in cellular morphology were observed under a fluorescence microscope. The depression model was established by chronic unpredictable mild stress (CUMS), and its antidepressant effect was estimated by open field test (OFT), forced swimming test (FST), and tail suspension test (TST). Western blot was used to monitor the protein expression. The results showed that crocin could effectively improve cell survival rate and cellular synaptic growth, alleviate the depressive behavior of CUMS mice, and promote the expression of BDNF, P-mTOR, P-ERK, and PSD95. However, when rapamycin was pretreated, the antidepressant effects of crocin were inhibited. In summary, crocin plays a significant antidepressant effect. After pretreatment with rapamycin, the anti-depression effect of crocin was significantly inhibited. It is suggested that the mechanism of the anti-depression effect of crocin may be related to the mTOR signaling pathway. Graphical Abstract
研究领域:
药理学
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神经科学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS
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2023
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IF 3.4
Zhongyuan Qu,Shuang Wu,Yan Zheng,Yifan Bing,Xueqin Liu,Sunan Li,Wenlan Li,Xiang Zou
Background Yueju Wan (YJW), defined in Danxi's Mastery of Medicine , has Qi-regulating and Qi-promoting effects. YJW has frequently been applied in the clinic for the treatment of depression. Substantial evidence has shown that depression is related to metabolic abnormalities of the gut microbiota , and traditional Chinese medicine (TCM) can treat depression by adjusting gut microbiota metabolism. The antidepressant effect of YJW is well established, but thus far, whether its mechanism of action is achieved by regulating the intestinal flora has not been elucidated. Methods In this study, chronic unpredictable mild stress (CUMS) along with isolated feeding created a rat depression model, and YJW was administered for intervention. Rats were put through behavioral tests to determine their level of depression, and ELISA was utilized for measuring the level of monoamine neurotransmitters (MNTs) in the hippocampus. Metagenomic gene sequencing analysis was used to study the effect of depression on the intestinal flora in rats and the regulatory mechanism of YJW on the intestinal flora. Furthermore, ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q/TOF-MS) was utilized for fecal metabolomics studies to further reveal the antidepressant mechanism of YJW. The antidepressant mechanism of YJW was explored and further verified by Western blot analysis . Results Different doses of YJW improved the depressive state of rats and raised the levels of MNTs in the hippocampus. The results of metagenomic sequencing indicated that the YJW recovered the structure and diversity of the intestinal flora in depressed rats. Metabolomics revealed sustained changes in 21 metabolites after the treatment of YJW, suggesting that YJW can play an antidepressant role by improving abnormal metabolic pathways. The results of correlation analysis suggested that YJW might mediate Eubacterium , Oscillibacter , Roseburia , Romboutsia and Bacterium to regulate purine metabolism, tryptophan metabolism, primary bile acid biosynthesis, and glutamate metabolism and exert antidepressant effects. Western blot analysis showed that YJW reduced the content of IL-1β in the hippocampus, inhibited the activation of the NLRP3 inflammasome in the hippocampus of rats, and increased the content of ZO-1 in the colon of rats. Conclusion YJW can alleviate depressive symptoms in depressed rats, and its mechanism is connected to improving intestinal flora and regulating body metabolism.
研究领域:
药理学
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神经科学
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微生物学
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中医
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代谢组学
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行为科学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
ACS Chemical Neuroscience
·
2021
·
IF 4.418
Peng Wang,Xiaoxia Gao,Fang Zhao,Yao Gao,Kexin Wang,Jun-Sheng Tian,Zhenyu Li,Xue-Mei Qin
Depression has drawn increasing attention from the public around the world in recent years. Studies have shown that liver injury caused by chronic stress is relevant to depression and neurotransmitter changes. It is essential to clarify the relationship between neurotransmitter changes and hepatic gene expression in depression. In this study, we used the chronic unpredictable mild stress (CUMS) model combined with UHPLC–MS to explore the changes of neurotransmitters in serum and hippocampus and to decipher the differential gene expression in the liver by using the RNA-Seq combined with multivariate statistical analysis. Compared with the control group, the levels of neurotransmitters including 5-hydroxytryptamine (5-HT), acetylcholine, glutamate (Glu), and dopamine (DA) in the hippocampus and 5-HT, norepinephrine, γ-aminobutyric acid (GABA), and 5-hydroxyindoleacetic acid in serum were significantly changed in the CUMS rats. The results of liver transcriptomic analysis and correlation analysis showed that the Glu, DA, 5-HT, and GABA were impacted by 68 liver genes which were mainly enriched in three pathways including circadian rhythm, serotonergic synapse, and p53 signaling pathway. The expressive levels of clock genes and serotonergic synapse genes were validated by using q-PCR, and the diurnal rhythms of neurotransmitters were validated by in vivo hippocampus microdialysis. The CUMS stressors might cause phase advance of Glu and GABA by adjusting clock genes. The transcriptomic technique combined with correlation analysis and in vivo microdialysis could be used to discover comprehensive pathways of depression. It provides a new strategy for the rational assessment of the mechanism of disease.
研究领域:
神经科学
·
药理学
·
分子生物学
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转录组学
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行为科学
✓ 已验证
DOI
PubMed
高影响因子
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