METABOLIC BRAIN DISEASE
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2018
·Vol. 33
·期 5
·1721-1731
·
IF 2.441
Chen Zhao-Di,Chen Wen-Qiang,Wang Zhi-Yuan,Cao Dan-Ni,Wu Ning,Li Jin
Previous studies have shown that agmatine, a potential neuromodulator or co-transmitter, exhibited antidepressant-like action in animal models, yet its mechanism, especially the receptor mechanism, remains unclear. In the present study, using efaroxan, a preferential antagonist of I 1 imidazoline receptor (I 1 R) and yohimbine, an antagonist of α 2 adrenergic receptor (α 2 AR), we investigated the roles of I 1 R and α 2 AR in agmatine’s antidepressant-like effect in acute and sub-acute depression models in mice. We found that in the tail-suspension test (TST) and the forced swimming test (FST), acute administration of agmatine (20 and 40 mg/kg, p.o.) significantly shortened the immobility time. Concurrent administration of efaroxan (1 mg/kg, i.p.) completely abolished the antidepressant-like effects of agmatine (40 mg/kg, p.o.) whereas yohimbine (5 mg/kg, i.p.) failed to exert similar effects, suggesting that the acute antidepressant-like effects of agmatine was mainly mediated by I 1 R but not α 2 AR. Additionally, in the learned helplessness (LH) test, repeated administration of agmatine (20 mg/kg, p.o., q.d.) for 5 days significantly decreased the escape latency and the number of escape failure, and these effects were respectively abolished by concurrent administration of efaroxan (0.5 mg/kg,i.p., q.d.) and yohimbine (3 mg/kg, i.p., q.d.) for 5 days, suggesting that the antidepressant-like action of agmatine in the LH test was achieved via the activation of both I 1 R and α 2 AR. In summary, we found that the antidepressant-like effects of agmatine in the TST and the FST were mediated by activating I 1 R and in the sub-acute LH test were mediated by activating both I 1 R and α 2 AR.
研究领域:
神经科学
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药理学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Zhangjie Wu,Ying Yin,Ruiyi Liu,Xianhui Li,Yan Sun,Suk-yu Yau,Lei Wu,Yan Liu,Miroslav Adzic,Hailou Zhang,Gang Chen
Ethnopharmacological relevance Jiawei-Xiaoyao Pill (JWX), a classic formula in traditional Chinese medicine, is derived from Xiaoyao Pill by adding significant amounts of Gardeniae Fructus (GF) and Moutan Cortex (MC). It is frequently used for the treatment of depression. JWX has been demonstrated to uniquely elicit rapid antidepressant-like effects within the prescribed dosage range. To date, GF has been shown to have rapid antidepressant-like effects, but a much higher dose is required than its proportion in JWX. It is assumed that the synergism of GF with a minimum number of other herbs in JWX serves as a refined formula that exerts these rapid antidepressant-like effects. Identification of a refined formula is important for prioritizing the herbs and ingredients to optimize the quality control of JWX. However, such a refined formula for JWX has not been identified yet Aim of the study Here we aimed to identify a refined formula derived from JWX for optimized rapid antidepressant-like effects. Since the neuroinflammation mechanism involving in depression treatment has not been previously investigated for JWX, we tested the mechanism for both JWX and the refined formula Materials and methods Individual herbs (MC ; ASR, Angelica Sinensis Radix; Bupleuri Radix; Paeonia Radix Alba ) that show antidepressant-like responses were mixed with GF at the proportional dosage in JWX to identify the refined formula. Rapid antidepressant-like effects were assessed by using NSF (Novelty Suppressed Feeding Test) and other behavioral tests following a single administration. The identified formula was further tested using a lipopolysaccharide (LPS)-induced depressive model, and the molecular signaling mechanisms were investigated using western blot analysis, immunofluorescence, and pharmacological inhibition of mTOR signaling. Scopolamine (Scop) is used as a positive control for induction of rapid antidepressant effects Results A combination of GF, MC and ASR (GMA) at their dosages proportional to JWX induced behavioral signs of rapid antidepressant-like responses in both normal and LPS-treated mice, with the antidepressant-like effects sustained for 5 d. Similar to JWX or Scop, GMA rapidly reduced the neuroinflammation signaling of Iba-1-NF-кB, enhanced neuroplasticity signaling of CaMKII-mTOR-BDNF, and attenuated the upregulated expressions of the NMDAR sub-units GluN1 and GluN2B in the hippocampus of LPS-treated mice. GMA, JWX and Scop rapidly restored the number of BDNF-positive cells reduced by LPS treatment, in the CA3 region of the hippocampus. Furthermore, rapamycin, a selective inhibitor of mTOR, blunted the rapid antidepressant-like effects and hippocampal BDNF signaling upregulation by GMA Conclusion GMA may serve as a refined formula from JWX, capable of inducing rapid antidepressant-like effects. In LPS-induced depression model, the effects of GMA were mediated via rapidly alleviating neuroinflammation and enhancing neuroplasticity
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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行为科学
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DOI
PubMed
高影响因子
Natural Product Communications
·
2022
·
IF 1.496
Minghui Tang,Yong Ai,Siyang Zhu,Ni Song,Xian Xu,Leyi Liang,Baoshan Rong,Xiaomin Zheng,Lanyue Zhang,Tinggang He
Citrus reticulata Blanco has been widely used to cure some diseases such as cold, cough and indigestion. This study is aimed at determining the antidepressant-like effect of C. reticulata essential oils (CREOs) in reserpine-induced depression mice, as well as its possible mechanisms. The compositions of CREOs are firstly analyzed by gas chromatography-mass spectrometry (GC-MS), in which d-limonene is the main component. Moreover, the results from the forced swimming and tail suspension tests show that the inhalation of CREOs can significantly improve the depressive behavior of reserpine-induced depressed mice by reducing the weight of the mice and shortening the immobile time. After sniffing CREOs, the number of normal neurons in the hippocampus of reserpine-induced depressed mice is greatly increased. In addition, CREOs significantly increase the expression level of 5-hydroxytryptamine-1A receptors (5HT-1A), glucocorticoid receptors (GR) and brain-derived neurotrophic factor (BDNF) in the reserpine-treated mice brain tissue. Thus, these results have indicated that CREOs can be potential materials for drug and food development against depression.
研究领域:
药理学
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神经科学
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传统医学
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DOI
高影响因子
BRAIN BEHAVIOR AND IMMUNITY
·
2021
·
IF 7.217
Yun Wang,Ce Gao,Tianyu Gao,Lu Zhao,Shiguang Zhu,Lin Guo
A growing body of studies indicated that exosomes are one of vital players in pathological process of neuropsychiatric diseases, but their role in major depressive disorder (MDD) remains poorly understood. Here we purified plasma exosomes from depression including lipopolysaccharide (LPS)-challenged depression, chronic restraint stress (CRS)-induced depression, MDD subjects, and from control mice or volunteers. The therapeutic effect of these exogenous exosomes was assessed utilizing behavioral tests and biochemical approaches in the LPS-caused depression or microglial BV2 cells. The expression of exosomal sigma-1 receptor (Sig-1R) was evaluated by western blotting. The role of Sig-1R in the biological function of exosomes was determined using Sig-1R knockout mice and HEK 293 cells. Our results revealed that injection of exosomes from depression models or patients rather than normal controls significantly ameliorated depressive-like behaviors, deficiency of BDNF expression and neuro-inflammation in LPS-challenged mice. In addition, co-culture with exosomes from depression models or patients instead of from controls prevented LPS-induced inflammation responses in microglial BV2 cells. Moreover, Sig-1R was demonstrated for the first time to significantly be enriched in exosomes from depression models or patients compared with that from normal controls. However, Sig-1R null exosomes no longer emerged antidepressant-like action in LPS-challenged mice. Thus, we demonstrated that plasma exosomes from depression exerted antidepressant-like effects in a Sig-1R dependent manner in the LPS-induced depression. This work improves our understanding of the exosomes in depression, suggesting a novel exosomes-based approach for MDD treatment.
研究领域:
神经科学
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药理学
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分子生物学
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精神病学
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产品关联
DOI
PubMed
高影响因子
CNS Neuroscience & Therapeutics
·
2024
·
IF 4.8
Mingyan Wang,Xin Wei,Yugai Jia,Chaonan Wang,Xinliu Wang,Xin Zhang,Depei Li,Yuanyuan Wang,Yonggang Gao
Background Depression is a serious mental disorder and the most prevalent cause of disability and suicide worldwide. Chronic unpredictable mild stress (CUMS) can lead to a significant acceleration of depression development. Quercetin (Que) is a flavonoid compound with a wide range of pharmacological effects. Recent studies have shown that quercetin can improve CUMS‐induced depression‐like behavior, but the mechanism of its improvement is still unclear. α2δ‐1 is a regulatory subunit of voltage‐gated calcium channel, which can interact with N‐methyl‐D‐aspartate receptor (NMDAR) to form a complex. Objective In this study, we found that Que could inhibit the increase of α2δ‐1 and NMDAR expression in rat hypothalamus induced by CUMS. In pain, chronic hypertension and other studies have shown that α2δ‐1 interacts with the NMDAR to form a complex, which subsequently affects the expression level of NMDAR. Consequently, the present study aimed to investigate the antidepressant effect of Que in vivo and in vitro and to explore its mechanism of action in terms of the interaction between α2δ‐1 and NMDAR. Methods Rats were randomly exposed to two stressors every day for 4 weeks to establish a CUMS rat model, then sucrose preference test (SPT), forced swimming test (FST), tail suspension test (TST), and open field test (OFT) were performed to detect the behavior of CUMS rats, so as to evaluate whether the CUMS rat model was successfully established and the improvement effect of Que on CUMS‐induced depression‐like behavior in rats. Experimental techniques such as serum enzyme‐linked immunosorbent assay (ELISA), immunofluorescence, Western blot, and co‐immunoprecipitation, as well as in vitro experiments, were used to investigate the mechanisms by which Que exerts its antidepressant effects. Results Behavioral and ELISA test results showed that Que could produce a reduction in the excitability of the hypothalamic–pituitary–adrenal (HPA) axis in CUMS rats and lead to significant improvements in their depressive behavior. Western blot, immunofluorescence, and co‐immunoprecipitation experiments showed that Que produced a decrease in NMDAR1 and α2δ‐1 expression levels and interfered with α2δ‐1 and NMDAR1 binding. In addition, the neural regulation mechanism of Que on antidepressant effect in PC12 cells knocked out α2δ‐1 gene was further verified. Cellular experiments demonstrated that Que led to a reversal of up‐regulation of NMDAR1 and α2δ‐1 expression levels in corticosterone‐injured PC12 cells, while Que had no effects on NMDAR1 expression in PC12 cells with the α2δ‐1 gene knockout. Conclusions Que has a good antidepressant effect and can significantly improve the depression‐like behavior caused by CUMS. It exerts antidepressant effects by inhibiting the expression level of α2δ‐1, interfering with the interaction between α2δ‐1 and NMDAR, and then reducing the excitability of the HPA axis.
研究领域:
神经科学
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药理学
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分子生物学
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行为科学
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产品关联
DOI
PubMed
高影响因子
Pharmaceuticals
·
2025
·Vol. 18
·期 7
·1079
·
IF 4.8
Rui Wang,Yuqian Yang,Tong Zhou,Bingjie Zou,Li Ding
Objectives: (R)-ketamine hydrochloride injection is a novel, rapid-acting antidepressant for the treatment of treatment-resistant depression. The aim of this study was to assess the pharmacokinetics, safety, and tolerability of (R)-ketamine hydrochloride injection in healthy Chinese subjects following ascending single intravenous doses ranging from 10.0 mg to 180 mg.Methods: This randomized, double-blind, placebo-controlled study was conducted in 50 healthy male and female Chinese subjects after single ascending doses of (R)-ketamine hydrochloride injection (10.0, 30.0, 60.0, 120, and 180 mg). Ten subjects (including two subjects treated with a placebo) were included in each dose cohort. Pharmacokinetic characteristics, safety, and tolerability profiles of the study drug were evaluated.Results:After the intravenous doses administered from 10.0 mg to 180 mg of (R)-ketamine hydrochloride injection to the subjects, the Cmaxand AUC values for both (R)-ketamine and its metabolite (R)-norketamine in the subjects increased approximately proportionally to the doses. The average peak plasma concentration levels at the five dose cohorts ranged from 56.0 to 1424 ng/mL and 27.7 to 491 ng/mL for (R)-ketamine and (R)-norketamine, respectively. The adverse events of (R)-ketamine hydrochloride injection were temporary and recovered spontaneously without treatment.Conclusions: In summary, (R)-ketamine hydrochloride injection was safe and well tolerated in healthy Chinese subjects. The clinical study results laid a foundation for the further clinical studies of (R)-ketamine hydrochloride injection in patients.
研究领域:
药理学
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临床医学
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神经科学
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精神病学
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药物研究
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DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2024
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IF 4.2
Yuan Liu,Xiaohui Jin,Caiyin Li,Jingjing Bu,Baoying Wang,Ming Bai,Pan Su,Erping Xu,Yucheng Li
Defective mitophagy is closely related to the neuronal dysfunction and major depressive disorder (MDD). Our previous study found that baicalin could enhance nip-like protein (NIX)-mediated mitophagy and exhibit antidepressant effects, and predicted that AMPK may be the pharmacological target of baicalin. However, validated experiments are lacking. In the present study, we first demonstrated the effect of baicalin on hippocampal NIX-mediated mitophagy in CORT-induced depressive mice. Secondly, we transfected siRNA to knockdown AMPK, PGC-1α, and NIX respectively in HT22 cells, and detected the effects of baicalin on mitochondrial function, AMPK/PGC-1α/NIX pathway protein expression and mitophagy levels. Finally, AAV-shAMPKα was injected into hippocampal CA3 to knockdown AMPK in mice to validate the antidepressant effects of baicalin in vivo. The results showed that CORT induced depressive-like behaviors, accompanied with neuronal damage, mitochondrial injury, and inhibited mitophagy in the hippocampus, which were prevented by baicalin (20 mg/kg) treatment. In HT22 cells, baicalin remarkably ameliorated mitochondrial dysfunction and mitophagy disturbance induced by CORT, and these protective effects of baicalin were blocked by knockdown of AMPK, PGC-1α and NIX. Moreover, the beneficial effects of baicalin on depressive-like behaviors and NIX-mediated mitophagy were suppressed by knockdown of AMPKα in mice. Our present results further demonstrated that baicalin promotes NIX-mediated mitophagy and improves depression in an AMPK-dependent manner.
研究领域:
神经科学
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药理学
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分子生物学
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抑郁症
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DOI
PubMed
高影响因子
MICROCHEMICAL JOURNAL
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2025
·
IF 5.1
Moying Yang,Yan Yao,Haotian Shen,Fei Teng,Yunuo Liu,Yuyang Ma,Bin Di,Mengxiang Su
Depression has gradually become a serious public health problem. Traditionally, data on depression are mainly derived from questionnaires or antidepressant prescriptions, and these methods may suffer from update delays and survey bias, resulting in a low actual prevalence of depression. To monitor the prevalence of depression in near real-time, this study developed an analytical method of UPLC-MS/MS by wastewater-based epidemiology to detect 10 typical antidepressants and metabolites in four provinces of China. The method has high sensitivity in that the lower limit of quantification was 2 ng/L. And the method provides recoveries and matrix effects ranging from 85.12 % to 102.98 % and 84.95 % to 112.75 %, respectively. The results showed that among the four provinces, the highest average detected concentration of antidepressants was in Jiangsu (91.82 ± 150.46 ng/L), followed by Guangxi (76.06 ± 130.44 ng/L), Anhui (61.53 ± 94.09 ng/L), and Hainan (27.87 ± 28.33 ng/L). Most wastewater treatment facilities had antidepressants such as venlafaxine, fluvoxamine, and agomelatine. The average back-calculated consumption of venlafaxine and fluvoxamine was 815.88 ± 2015.96 mg/day/1000 inh and 497.02 ± 405.21 mg/day/1000 inh, respectively. Based on this study, the estimated prevalence in the population over 15 in Jiangsu, Anhui, and Hainan was finally determined to be 4.90 %, 5.36 %, and 2.93 %, indicating regional diversity. This study offered a workable way to track the prevalence of depression using wastewater-based epidemiology, which aided public health agencies in comprehending the state of depression prevalence.
研究领域:
环境科学
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分析化学
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流行病学
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公共卫生
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药物监测
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DOI
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
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2024
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IF 4.2
Fengjiao Liu,Yaxin Jia,Liwei Zhao,Li-na Xiao,Xizhen Cheng,Yingying Xiao,Ying Zhang,Yuling Zhang,Huimin Yu,Qiao-en Deng,Yuanyuan Zhang,Yimeng Feng,junfang Wang,Yonggang Gao,Xuan Zhang,Yunyun Geng
Major depressive disorder (MDD) is a prevalent psychiatric disorder associated with brain inflammation and neuronal damage. Derived from the Aesculus chinensis Bunge fruit, escin has shown anti-inflammatory and neuroprotective effects. However, its potential as a treatment for MDD is unclear. This study investigates the antidepressant properties of escin using in vivo experimentation. The chronic unpredictable mild stress (CUMS) model was used to analyze the potential antidepressant effects and underlying mechanisms of escin. Wistar rats were exposed to CUMS for 35 consecutive days to induce MDD. The rats were then given either escin (1, 3, and 10 mg/kg) or fluoxetine (2 mg/kg) on a daily basis. Notably, escin significantly alleviated the depressive behaviors induced by CUMS, as evaluated through a series of behavioral assessments. Moreover, escin administration reduced TNF-α, IL-1β, and IL-6 levels in the hippocampus. It also decreased serum adrenal cortical hormone (ACTH) and corticosterone (CORT) levels while increasing 5-HT and Brain-derived neurotrophic factor (BDNF) levels in the CUMS rats, as measured by the enzyme-linked immunosorbent assay (ELISA). Pathological changes in the hippocampal regions were identified through Nissl staining, and Western blotting was used to quantify the protein levels of BDNF, TrkB, CREB, TLR4, MyD88, and NF-κB. Escin mitigated neuronal injury, elevated TrkB, BDNF, and CREB, and reduced TLR4, MyD88, and NF-κB protein levels in CUMS rats. The data from this study suggest that escin holds the potential for alleviating depression-like symptoms induced by CUMS. This effect may be mediated through the modulation of two signaling pathways, BDNF/TrkB/CREB and TLR4/MyD88/NF-κB.
研究领域:
药理学
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神经科学
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精神病学
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免疫学
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产品关联
DOI
PubMed
高影响因子
BRAIN BEHAVIOR AND IMMUNITY
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2025
·
IF 7.6
Xiaoyu Yu,Tingting Yang,Di Wu,Chenxue Xu,Zhuoran Li,Ao Sun,Shulei Gao,Heng Li,Zhenyu Fan,Rongrong Huang
Microglial inflammation has been implicated in the pathophysiology of major depressive disorder; however, the underlying biological mechanisms remain inadequately understood. Consequently, we conducted a screening of the Poly ADP-ribose (PAR) polymerase (PARP) family expression in the hippocampus of chronic unpredictable stress (CUS) mouse models and investigated the specific role of PARP14 in microglial inflammation and its association with depression. Here, this study demonstrated the elevated PARP14 expression in the hippocampus of CUS mice. The knockdown of PARP14 in the hippocampus did not mitigate depressive-like behaviors in mice, whereas overexpression of PARP14 significantly mitigated these behaviors. Furthermore, PARP14 was abundant in microglia, and microglial-targeted PARP14 overexpression significantly alleviated depressive-behaviors in CUS, reduced microglial activation, and inhibited the central inflammatory responses. Mechanistically, PARP14 positively regulated nicotinamide nucleotide transhydrogenase (NNT) expression in microglia, and the inflammatory response of microglia induced by PARP14 knockdown was suppressed through NNT overexpression. Additionally, deficiency in NNT led to an accumulation of reactive oxygen species (ROS) and subsequent microglial inflammation, which was effectively inhibited by the ROS inhibitor N-Acetylcysteine. These findings suggest that PARP14 alleviates depressive-like behaviors in mice by inhibiting microglial activation via NTT-mediated clearance of ROS.
研究领域:
神经科学
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免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
Neuropsychiatric Disease and Treatment
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2025
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IF 2.9
Yueyi Zhang,Qianqian Cai,Lingshan Wang,Bei Zhang
Background & Aims Esketamine, a promising treatment for treatment-resistant depression, has shown potential advantages over traditional antidepressants. However, its mechanisms remain unclear. This study explores how esketamine alleviates depressive behaviors through activation of the BDNF/TrkB/PI3K/AKT signaling pathway.Methods Using a Chronic Unpredictable Mild Stress (CUMS) rat model, behavioral assays (Sucrose Preference Test, Morris Water Maze Test) and histological analyses (HE and Nissl’s staining) were performed. Esketamine (5 mg/kg) treatment was administered to evaluate its antidepressant effects, and the PI3K inhibitor, PI3K-IN-6, was used to investigate the role of the PI3K/AKT pathway in the underlying mechanism.Results Esketamine treatment improved depressive behaviors, enhanced neuronal structure, and reduced apoptosis and oxidative stress. These effects were linked to the activation of the BDNF/TrkB/PI3K/AKT pathway. PI3K-IN-6 reversed the effects, confirming the pathway’s involvement.Conclusion Esketamine alleviates depressive behaviors by activating the BDNF/TrkB/PI3K/AKT signaling pathway, reducing oxidative stress and inhibiting neuronal apoptosis. These findings highlight the therapeutic potential of esketamine in treating depression, particularly in cases where traditional treatments fail.
研究领域:
神经药理学
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精神病学
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分子生物学
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神经科学
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DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
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2024
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IF 6.9
Yuan Liang,Yu Yang,Ruiyan Huang,Jiangyue Ning,Xingyan Bao,Zelong Yan,Haotian Chen,Li Ding,Chang Shu
Depression ranks as the fourth most prevalent global disease, with suicide incidents occurring at a younger age. Sulpiride (SUL), an atypical antidepressant drug acting as a dopamine D2 receptor antagonist and possessing anti-inflammatory properties, exhibits limited ability to penetrate the blood brain barrier (BBB). This weak penetration hampers its inhibitory effect on prolactin release in the pituitary gland, consequently leading to hyperprolactinemia. In order to enhance the central nervous system efficacy of sulpiride and reduce serum prolactin levels, we covalently linked sulpiride to VPALR derived from the nuclear DNA repair protein ku70. In vivo study on depressive mice using intraperitoneal injection of VPALR-SUL demonstrated a significant increase in struggle time and total distance compared to those treated with only sulpiride while also reducing serum prolactin concentration. The pharmacokinetic study results showed that VPALR-SUL prolonged half-life and increased bioavailability. In conclusion, VPALR-SUL exhibited potential for enhancing sulpiride transport across the BBB, augmenting its antidepressant effects, and reducing serum prolactin levels. This study laid a foundation for improving sulpiride delivery and developing novel antidepressants.
研究领域:
药理学
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神经科学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
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