JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
·
2023
·
IF 4.4
Meixi He,Yi Wang,Xiaozhe Zhang,Lihua Zhang
The N-methyl-d-aspartic acid (NMDA) receptors belongs to the family of ionotropic glutamate receptors, which could mediate most excitatory synaptic transmission in the brain. It is interesting to know if some available drugs have regulatory effects on the NMDARs. Herein, the present study reports the discovery of drugs targeting NMDAR using virtual screening. In this study, talniflumate with the EC50 value at 61.49 nM was successfully screened. The interaction analysis of this compound was further explored through molecular dynamics simulation. It is indicated that talniflumate could form stable interactions with GluN1-GluN2B NMDA receptors. In particular, H-bond interactions with high occupancies between GluN1-GluN2B NMDA receptors and talniflumate were observed. Compared to de novo drug discovery, this approach could be an alternative choice for development of safety and efficiency NMDAR inhibitors from available drugs.Communicated by Ramaswamy H. Sarma
研究领域:
神经科学
·
药理学
·
药物发现
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EBioMedicine
·
2019
·
IF 6.68
Qin Yang,Zifeng Huang,Yangfu Luo,Fangshuo Zheng,Yida Hu,Hui Liu,Shuzhen Zhu,Miaoqing He,Demei Xu,Yun Li,Min Yang,Yi Yang,Xiaobo Wei,Xiaoya Gao,Wei Wang,Junhong Ma,Yuanlin Ma,Xuefeng Wang,Qing Wang
Background NACHT and WD repeat domain-containing protein 1 (Nwd1) is a member of the innate immune protein subfamily. Nwd1 contributes to the androgen receptor signaling pathway and is involved in axonal growth. However, the mechanisms that underlie pathophysiological dysfunction in seizures remain unclear. Methods Biochemical methods were used to assess Nwd1 expression and localization in a mouse model of kainic acid (KA)-induced acute seizures and temporal lobe epilepsy (TLE) patients. Electrophysiological recordings were used to measure the role of Nwd1 in regulating synaptic transmission and neuronal hyperexcitability in a model of magnesium-free-induced seizure in vitro . Behavioral experiments were performed, and seizure-induced pathological changes were evaluated in a KA-induced seizure model in vivo . GluN2B expression was measured and its correlation with Tyr1472-GluN2B phosphorylation was analyzed in primary hippocampal neurons. Findings We demonstrated high protein levels of Nwd1 in brain tissues obtained from mice with acute seizures and TLE patients. Silencing Nwd1 in mice using an adeno-associated virus (AAV) profoundly suppressed neuronal hyperexcitability and the occurrence of acute seizures, which may have been caused by reducing GluN2B-containing NMDA receptor-dependent glutamatergic synaptic transmission. Moreover, the decreased activation of Nwd1 reduced GluN2B expression and the phosphorylation of the GluN2B subunit at Tyr1472. Interpretation Here, we report a previously unrecognized but important role of Nwd1 in seizure models in vitro and in vivo , i.e. , modulating the phosphorylation of the GluN2B subunit at Tyr1472 and regulating neuronal hyperexcitability. Meanwhile, our findings may provide a therapeutic strategy for the treatment of epilepsy or other hyperexcitability-related neurological disorders. Fund The funders have not participated in the study design, data collection, data analysis, interpretation, or writing of the report.
研究领域:
神经科学
·
分子生物学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
Translational Psychiatry
·
2026
·
IF 7.5
Liu Jin-Ming,Zhang Yan-Lin,Guo Fang,Li Bin-Wu,Chen Hu,Mo Yuye,Kong Jiangwei,Tan Xiaohui,Wu Weibin,Cao Xiong
Antidepressants that target the glutamatergic system, such as ketamine, have shown promising results. However, the contribution of other potential medications targeting the glutamate system to depression is unclear. Our research found that perampanel can exert a rapid and long-lasting antidepressant effect to improve the behavior of chronic social defeat stress (CSDS) depression susceptible mice. In mechanism, perampanel reduce the abnormal increase in the expression of the NMDA receptor subunit GluN2B (Grin2b) in the medial prefrontal cortex (mPFC), further increase the expression of the AMPA receptor subunit GluA1 (Gria1), and improve the functional impairment of excitatory synaptic transmission in the mPFC in depression susceptible mice. Meanwhile, Naïve mice (non-stressed controls) administered perampanel would rapidly exhibit depression-like behaviors. This is because perampanel inhibits the function of excitatory synaptic transmission in the mPFC of Naïve mice. Indeed, perampanel shows different effects in depression susceptible mice and Naïve mice. Our research reveals that an FDA-approved perampanel for clinical treatment of epilepsy, has rapid antidepressant potential. This finding may provide more treatment options and precise medication guidance for clinical patients with depression and for those with epilepsy accompanied by depression.
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2021
·
IF 4.36
Fengming Shen,Zhujin Song,Pan Xie,Lei Li,Bin Wang,Daiyin Peng,Guoqi Zhu
Ethnopharmacological relevance According to traditional Chinese medicine (TCM) theory ( Yi Xue Zheng Zhuan ), the main factors associated with the pathogenesis of depression are deficiencies relating to five zang organs, Qi, and blood. Polygonatum sibiricum F. Delaroche (PS), which may avert these pathological changes, has been used in a variety of formulas to treat depression. However, the effects and mechanism of action of PS, alone, and especially those of its main active component PS polysaccharide (PSP), on depression remain unexplored. Aim of the study To determine the effects of PSP on depression-like behaviors and to elucidate its mechanism of action. Methods PSP was isolated from dried PS rhizomes and qualified using transmission electron microscopy and Fourier transform infrared spectroscopy . Lipopolysaccharide (LPS) and chronic unpredictable mild stress (CUMS)-induced depression models were used to evaluate the antidepressive effects of PSP. Veinal blood and brain tissue were collected to determine the levels of hippocampal 5-HT, serum cortisol (CORT), brain and serum cytokines, and hippocampal oxidation-related indicators. The protein expression levels of phosphorylated extracellular signal-regulated kinase (p-ERK1/2), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), glial fibrillary acidic protein (GFAP), phosphorylated protein kinase B (p-Akt), phosphorylation of the mammalian target of rapamycin (mTOR), caspase-3, GluA1 and GluA2, and GluN2A and GluN2B were determined using western blotting and immunofluorescence. Nissl staining was performed to detect histopathological changes in brain tissues. Results Injection of LPS ( i.p. ) induced depression-like behaviors, reduced the level of hippocampal 5-HT, increased the serum CORT level and hippocampal oxidative stress (ROS), and prompted the activation of ERK1/2, NF-κB, and GFAP and an inflammatory response. Conversely, PSP administration reduced these changes and prevented depression-like behaviors. PSP administration also promoted hippocampal expression of p-Akt, p-mTOR, GluA1, and GluA2; reduced the expression of caspase-3, GluN2A, and GluN2B; and prohibited the loss of granular cells in the DG region. Conclusion These results indicate that PSP prevents depression-like behaviors, and synaptic and neuronal damage probably by reducing ROS/HPA axis hyperfunction and the inflammatory response.
研究领域:
药理学
·
神经科学
·
中医
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2023
·
IF 5.4
Gao-shang Chai,Juan Gong,Jia-jun Wu,Rui-kun Ma,Jun Zhu,Dong-dong Jia,Yu-qi Zhang,Xiao-run Zhai,Hong-xu Sun,Yun juan Nie,Peng Zhao,Yi-liang Xu,Hai tao Yu
Ethnopharmacological relevance Danggui Buxue decoction (DBD) is a classic herbal decoction consisting of Astragali Radix (AR) and Angelica Sinensis Radix (ASR) with a 5:1 wt ratio, which can supplement ‘blood’ and ‘qi’ (vital energy) for the treatment of clinical diseases. According to Traditional Chinese Medicine (TCM) theory, dementia is induced by Blood deficiency and Qi weakness, which causes a decline in cognition. However, the underlying mechanisms of DBD improving cognition deficits in neurodegenerative disease are no clear. Aim of the study This study aims at revealing the underlying mechanisms of DBD plays a protective role in the cognitive deficits and pathology process of Alzheimer's disease (AD). Materials and methods The APP/PS1 (Mo/HuAPP695swe/PS1-dE9) double transgenic mice were adopted as an experimental model of AD. Qualitative and quantitative analysis of 3 compounds in DBT was analyzed by HPLC. Morris water maze test, Golgi staining and electrophysiology assays were used to evaluate the effects of DBD on cognitive function and synaptic plasticity in APP/PS1 mice. Western blot , immunofluorescence and Thioflavin S staining were used for the pathological evaluation of AD. Monitoring the level of ATP, mitochondrial membrane potential, SOD and MDA to evaluate the mitochondrial function, and with the usage of qPCR and CHIP for the changes of histone post-translational modification. Results In the current study, we found that DBD could effectively attenuate memory impairments and enhance long-term potentiation (LTP) with concurrent increased expression of memory-associated proteins. DBD markedly decreased Aβ accumulation in APP/PS1 mice by decreasing the phosphorylation of APP at the Thr668 level but not APP, PS1 or BACE1 . Further studies demonstrated that DBD restored mitochondrial biogenesis deficits and mitochondrial dysfunction. Finally, the restored mitochondrial biogenesis and cognitive deficits are under HADC2-mediated histone H4 lysine 12 (H4K12) acetylation at the peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α) and N-methyl-D-aspartate receptor type 2B (GluN2B) promoters. Conclusions These findings reveal that DBD could ameliorate mitochondrial biogenesis and cognitive deficits by improving H4K12 acetylation. DBD might be a promising complementary drug candidate for AD treatment.
研究领域:
药理学
·
神经科学
·
中医
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）