JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
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2023
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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
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药理学
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药物发现
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PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
·
2023
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IF 6.8
Ting Ma,Xiaoxuan Wang,Ting Yu,Juan Liu,Zheqiong Yang,Jinlei Xi
Oxytetracycline (OTC), a tetracycline antimicrobial, is one of the antimicrobial drugs frequently used in the aquaculture and livestock industries. Due to its extensive usage and emissions, OTC has been identified as a significant new emerging pollutant (EP) in a number of environments. OTC frequently causes toxic effects on the central nervous system, but it can be challenging to monitor, and it is still unclear how these toxicities are caused. We used bioinformatic analysis techniques to screen for OTC targets and discovered that NMDA receptors are potential targets of OTC neurotoxicity. To confirm this finding, we exposed zebrafish embryos to 5 mg/L OTC-containing rearing water from 2-hour post fertilization (hpf) to 8-day post fertilization (dpf), performed spontaneous movement and light-dark stimulation assays at 6 and 8 dfp, and discovered that OTC inhibited locomotor activity and attenuated anxiety-like responses in zebrafish larvae. Meanwhile, the qPCR and immunofluorescence staining results suggested that OTC inhibited the expression of multiple subtypes of NMDA receptors (grin1a, grin1b, grin2bb, grin2ca) and induced apoptosis in the brains of zebrafish embryos. Simultaneous administration of NMDA, an NMDA receptor agonist, completely antagonized the inhibitory neurobehavioral changes in zebrafish larvae, as well as the downregulation of N-methyl- D -aspartate (NMDA) receptor expression and apoptosis in the embryonic brains caused by OTC exposure. In conclusion, OTC exhibited significant inhibitory neurobehavioral toxicity in zebrafish larvae during early development, which may be dependent on its suppression of NMDA receptor activity and expression. Furthermore, OTC-induced neurodevelopmental toxicity may be associated with NMDA receptor-regulated neuronal apoptosis.
研究领域:
环境科学
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毒理学
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神经科学
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水生生物学
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PubMed
高影响因子
BEHAVIOURAL BRAIN RESEARCH
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2025
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IF 2.3
Yue-Heng Yan,Hong-Kun Wang,Zi-Hao Wang,Rui-Ze Wang,Ruo-Xuan Li,Li-Li Huang,Yan-Yan Wang
NMDA receptors (NMDAR) are vital in CNS activities such as anxiety, memory, and cognition, and the neurobiological mechanisms behind anxiety disorders are exceedingly complicated. The "glutamic acid theory" posits that glutamate excitotoxicity is a key pathophysiological mechanism in anxiety disorders. However, the exact mechanism by which conditioned fear contributes to anxiety disorders remains unknown.Based on the conditioned fear-induced anxiety disorder model, this work aims to investigate changes in NMDAR and related proteins throughout the acquisition and expression of fear memory, as well as the impact on synaptic structural and functional plasticity. Injecting the NMDA receptor endogenous agonist D-Serine (50 μg/μL) and the noncompetitive antagonist MK-801 (1 μg/μL) into the lateral ventricle of the conditioned fear model rats, as well as conducting behavioral observations, show that NMDAR are closely involved in the development of conditioned fear-induced anxiety. Model rats showed significant changes in glutamate (Glu) and γ-aminobutyric acid (GABA) levels in the amygdala (BLA), as well as expression of NMDAR and downstream BDNF/TrkB signaling pathway components. At the same time, model rats exhibited synaptic and neuronal injury, aberrant long-term potentiation (LTP), and decreased expression of essential synaptic proteins SYP and PSD-95. In conclusion, our study demonstrates that NMDAR and synaptic plasticity play a critical role in the development of conditioned fear-induced anxiety, serving as an important reference for understanding the neurobiological underpinnings of anxiety disorders and providing insights into their treatment and new possible targets.
研究领域:
神经科学
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行为学
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分子生物学
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PubMed
高影响因子
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
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2024
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IF 7.7
Gong Chen,Panyang Gu,Wenfang Wu,Yuan Yin,Liangyu Pan,Shu Huang,Wei Lin,Meichun Deng
Histone methylations play a crucial role in the development of neuropathic pain, and SET domain containing 2 (SETD2), a histone methyltransferase, serves as the sole tri-methylase known to catalyze H3K36me3 at the gene body. The N -methyl- d -aspartate receptor (NMDAR) is activated and mediates excitatory synaptic transmission in neuropathic pain. Nevertheless, the involvement of SETD2 in neuropathic pain and the specific regulatory mechanisms affecting NMDARs remain poorly understood. The expression levels of SETD2 were significantly decreased in the spinal cord and dorsal root ganglion (DRG) of rodents undergoing neuropathic pain induced by sciatic nerve chronic constrictive injury. Lentiviral shRNA-mediated SETD2 knockdown and conditional knockout in sensory neurons caused sustained NMDAR upregulation in DRG and spinal cord, which resulted in heightened neuronal excitability and increased pain hypersensitivity. SETD2 deficiency also led to reduced H3K36me3 deposition within the Grin1 (glutamate ionotropic receptor NMDA type subunit 1) gene body, thereby promoting aberrant transcription of the NMDARs subunit GluN1. The absence of SETD2 in the DRG potentiated neuronal excitability and increased presynaptic NMDAR activity in the spinal dorsal horn. Chromatin immunoprecipitation sequencing targeting H3K36me3 identified NFAT5 as a co-transcription factor in the transcriptional regulation of Grin1 . These findings highlight SETD2 as a key regulator in pain signal transmission and offered new perspectives on the development of analgesics through the targeted modulation of epigenetic mechanisms.
研究领域:
神经科学
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表观遗传学
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疼痛研究
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DOI
PubMed
高影响因子
NEUROCHEMICAL RESEARCH
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2025
·Vol. 50
·期 2
·1-13
·
IF 3.8
Wang Jun,Zhang Nan,Liu Hong-Zheng,Wang Jin-Liang,Zhang Yong-Bo,Su Dong-Dong,Zhang Li-Min,Li Bao-Dong,Miao Hui-Tao,Miao Jun
Neuropathic pain (NP) imposes a significant burden on individuals, manifesting as nociceptive anaphylaxis, hypersensitivity, and spontaneous pain. Previous studies have shown that traumatic stress in the nervous system can lead to excessive production of hydrogen sulfide (H 2 S) in the gut. As a toxic gas, it can damage the nervous system through the gut-brain axis. However, whether traumatic stress in the nervous system leading to excessive production of H 2 S in the gut can ultimately cause neuropathic pain through the gut-brain axis remains to be investigated. This study established a model of chronic constriction injury (CCI) in mice to determine its effects on gut H 2 S production, the associated damage via the gut-brain axis, the potential neuropathic pain, as well as the probable mechanism. A CCI mouse model was developed using a spinal nerve ligation approach. Subsequently, the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) were used to determine the mice’s pain thresholds. A variety of assays were performed, including immunofluorescence, western blotting, real-time quantitative Polymerase Chain Reaction (PCR), and membrane clamp whole-cell recordings. Mice subjected to CCI showed decreased MWT and TWL, decreased ZO-1 staining, decreased HuD staining, increased Glial fibrillary acidic protein (GFAP) staining, increased expression of tumor necrosis factor-alpha (TNF-α) protein and interleukin-6 (IL-6) protein, increased expression of NMDAR2B (NR2B) protein and NR2B mRNA, increased colocalization of vGlut2- and c-fos-positive cells, and a higher amplitude of evoked excitatory postsynaptic potential (EPSP) compared to Sham group. These changes were significantly reversed by H 2 S inhibitor treatment, and the specific NMDA receptor inhibitor MK-801 effectively restored the neurotoxicity of H 2 S. H 2 S is involved in CCI-induced neuropathic pain in mice, which might be mediated by the activation of the NMDA signaling pathway.
研究领域:
医学
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神经科学
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PubMed
高影响因子
INTERNATIONAL IMMUNOPHARMACOLOGY
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2024
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IF 4.8
Rong-Xin Song,Xiao-Yi Ma,Ting-Ting Zhou,Zhi-Fang Yu,Jun Wang,Bao-Dong Li,Yu-Mo Jing,Han Wang,Yue Fu,Rui-Zhao Lv,Shi-Yan Jia,Xiao-Ming Li,Li-Min Zhang
Objective Hemorrhagic shock and resuscitation (HSR) cause inflammatory responses in the gastrointestinal tract and is associated with substantial morbidity and mortality rates. Hydrogen sulfide (H 2 S), a gasotransmitter with pleiotropic activity, exhibits anti-inflammatory benefits at physiological levels. However, deleterious effects are observed when its concentration increases. In this investigation, we employed a mouse model of HSR to examine the effects of an H 2 S scavenger on the gastrointestinal tract and brain, with emphasis on N-Methyl- d -Aspartate (NMDA) receptor function. Methods Mice were immediately administered dl -propargylglycine (PAG) intragastrically as an H 2 S scavenger after HSR exposure. The O-maze and buried beads tests were used to assess compulsive- and anxiety-like behaviors. Pathological changes in the intestine were evaluated at 24 and 30 days after HSR. Subsequently, at 30 days after HSR, we examined electrophysiological and pathological changes in the amygdala. Results Within 24 h of HSR exposure, animals treated with PAG showed significantly lower colonic injury. Additionally, compared to the HSR-treated mice 30 days after HSR, the PAG-treated mice displayed reduced buried beads, increased open-arm time, lower blood levels of Diamine Oxidase (DAO) and considerably improved ZO-1 intensity, a stronger association between the delta rhythm phase and beta activity amplitude, and lower neuroinflammatory response in the amygdala. MK-801, an NMDA receptor inhibitor, significantly reversed H 2 S-induced intestinal and cerebral injury. Conclusion This experimental data suggests that H 2 S-induced excessive activation of NMDA receptors contributes to anxiety- and compulsive-like behaviors caused by HSR.
研究领域:
神经科学
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药理学
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病理生理学
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行为科学
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DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
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2022
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IF 5.307
Wenda Zhu,Yiping Fan,Yanbing Li,Lizhi Peng,Yifang Li,Fengxia Yan,Jiaqiang Zhao,Lei Zhang,Hiroshi Kurihara,Rongrong He,Heru Chen
Eight hybrids of amantadine ( ATD ) with a natural modulator gardenamide A ( GA ) via an alkylene carbonyl bridge or alkylene bridge have been designed and synthesized. Evaluated by electrophysiological assay, compound 5b was confirmed an enhanced NMDAR antagonist compared to ATD with IC 50 value of 10.2 ± 1.2 μM. 5b has been demonstrated to reverse the damages of behavioral performance, the loss of dopaminergic neurons, the reduction of TH positive, and the increase of α-synuclein in both MPTP-treated mice and zebrafish models. In both ethological and ecological experiments, the activity of 5b was confirmed better than ATD or ATD/GA combination, and was almost equal to the positive selegiline. In vivo and in vitro , 5b is shown to reverse the ascend of NR1 and i- NOS levels. This candidate was also demonstrated the activity to down-regulated MPTP-increased Ca 2+ influx in SH-SY5Y cells in a steep and sharp mode. It is displayed that 5b exerts neuroprotective effect partly by activating the PI3K/Akt signaling pathway. Taken all together, our data support that 5b is a more promising agent against PD than ATD .
研究领域:
药理学
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神经科学
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药物设计
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神经退行性疾病
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PubMed
高影响因子
JOURNAL OF HAZARDOUS MATERIALS
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2026
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IF 11.3
Manci Chen,Ting Yu,Xiaoxuan Wang,Wei Wu,Qing Wan,Juan Liu,Ke Li,Jiang Yue,Jinlei Xi,Zheqiong Yang
Progestogens, primarily used in assisted reproduction and tocolytic therapy, have emerged as environmental pollutants due to their widespread use in medicine and aquaculture. Their release into various ecosystems has raised concerns about their potential neurodevelopmental effects. Drospirenone (DRS), an extensively used synthetic progestin, was identified in bioinformatic analysis as a potential disruptor of NMDA receptors (NMDARs), crucial for neuronal signaling. To investigate this, zebrafish embryos were exposed to DRS from 2 h post-fertilization (hpf) to 14 days post-fertilization (dpf). Behavioral assays revealed that DRS exposure impaired locomotor activity, reduced anxiety-like responses, and diminished social behaviors. Quantitative PCR and immunofluorescence staining showed that DRS disrupted the expression of several NMDAR subunits, suppressed apoptosis, and promoted neuronal proliferation in the embryonic brain. Co-exposure with NMDA, an NMDAR agonist, reversed the neurobehavioral deficits, normalized NMDARs expression, and restored apoptosis-proliferation balance. Molecular docking, DARTS assays, and downstream marker measurements indicated target engagement between DRS and the Grin1 and Grin2 subunits of NMDAR, suggesting that DRS may alter receptor conformation and function. In conclusion, DRS induces significant neurodevelopmental toxicity in zebrafish larvae, likely by suppressing NMDAR activity and disrupting neuronal apoptosis and proliferation. These findings highlight potential risks of DRS to aquatic life and human health.
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PubMed
高影响因子
AIP Advances
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2024
·Vol. 14
·期 8
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IF 1.4
Zheng Yu,Song Rujuan,Wei Shengjie,Dong Lei,Chen Yazhou
Long-term potentiation (LTP) in the Schaffer-CA1 region of the hippocampus is closely related to learning and memory. Magnetic stimulation, as an effective physical means of regulating synaptic plasticity, has received widespread attention. However, research on the mechanism of the effect of different frequencies of magnetic fields (MFs) on LTP is relatively scarce. This article focuses on Ca 2+ , Na + , K + , NMDA receptors, and AMPA receptors that play important roles in the process of MF regulation of LTP. A combined electrophysiological and pharmacological approach was used to identify Ca 2+ as a key factor in the modulation of LTP by MFs of different frequencies. Subsequently, further experiments revealed that low levels of intracellular Ca 2+ concentration ([Ca 2+ ] i ) intensified the inhibition of low-frequency MFs on LTP, while high levels of [Ca 2+ ] i enhanced the promotion effect of high-frequency MFs on LTP, indicating a positive correlation between [Ca 2+ ] i levels and MF regulation of LTP levels. The research results of this article may help explore the deeper relationship between different frequencies of MFs and synaptic plasticity, and they also have a certain reference value for magnetic stimulation therapy in the treatment of neurological diseases related to LTP injury or learning and memory deficits.
研究领域:
神经科学
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医学
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DOI
高影响因子
NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY
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2025
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IF 3.1
Li Xue,Wang Rui,Ma Xiaonan,Yang Jin,Zhang Shen,Zhang Zimeng,Jiang Han,Liu Jihua,Yu Boyang,Dai Wenling
Effective drugs for neuropathic pain are urgently needed. Natural compound glaucine from Corydalis Rhizoma inhibits spinal sensitization and alleviates neuropathic pain, yet its exact analgesic mechanism remains unclear. A rat model of neuropathic pain was established via chronic constriction injury (CCI) of the sciatic nerve. Behavioral tests (von Frey and Hargreaves tests) were used to assess neuropathic pain symptoms by evaluating mechanical allodynia and thermal hyperalgesia. Primary spinal neurons, glia, and peritoneal macrophages were cultured for in vitro analysis. Molecular pathways were examined using RNA sequencing, Western blot, qRT-PCR, and immunofluorescence. Glaucine significantly suppressed spinal IL-16 expression in CCI rats, and its analgesic effects were reversed by exogenous IL-16 administration. RNA-seq and protein assays confirmed IL-16 upregulation in injured peripheral nerves and spinal cord. Critically, inhibiting IL-16/CD4 signaling at peripheral and spinal levels alleviated neuropathic pain. Dual immunofluorescence in vivo and in vitro revealed IL-16/CD4 localization in neurons, and spinal IL-16 inhibition reduced neuronal activation. Calcium fluorescence imaging further demonstrated that spinal IL-16 blockade reduced spinal neuronal excitability through restraining the NMDA receptor. The IL-16 induced phosphorylation of NMDA receptor was mediated by lymphocyte-specific protein tyrosine kinase (p56 lck ). Additionally, peripheral macrophages were identified as a source of IL-16 after nerve injury. Glaucine alleviates neuropathic pain by inhibiting the IL-16-p56 lck -NMDA axis which promotes pain through enhanced NMDA activity and central sensitization. The targeted inhibition highlights glaucine as a novel therapeutic strategy for alleviating neuropathic pain.
研究领域:
神经药理学
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疼痛研究
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分子信号传导
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免疫神经学
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产品关联
DOI
PubMed
高影响因子
Theranostics
·
2025
·Vol. 15
·期 14
·6901
·
IF 13.3
Yifan Ren,Qing Cui,Wuming Liu,Hangcheng Liu,Tao Wang,Hongwei Lu,Yi Lv,Rongqian Wu
Background: Mitochondrial dysfunction caused by Ca 2+ overload in pancreatic acinar cells is an important mechanism in the pathogenesis of acute pancreatitis (AP). Transient receptor potential cation channel melastatin 4 (TRPM4), a non-selective cation channel, can be activated by intracellular Ca 2+ , and is involved in mediating damage to neuronal mitochondrial function. However, the role of TRPM4 activation in mitochondrial dysfunction during AP remains unknown. Methods: We employed three mouse models of AP (intraperitoneal administration of L-arginine, cerulein plus lipopolysaccharides (LPS), or cerulein alone) for in vivo studies. For in vitro studies, cerulein+ LPS was used to induce mitochondrial dysfunction and cell death in AR42J cell. Trpm4 gene-defective mice and plasmids were utilized to downregulate the expression of TRPM4 in mice or overexpress TRPM4 in AR42J. 9-Phenanthrol, a specific inhibitor of TRPM4, was used to antagonize TRPM4 activity both in vitro and in vivo . Results: Pancreatic TRPM4 levels were increased in all three AP models. Blocking TRPM4 activity with 9-phenanthrol or knocking down TRPM4 expression alleviated pancreatic damage and reduced mortality in AP mice. The protective effect of TRPM4 defects on AP was associated with improved mitochondrial function in pancreatic acinar cells. Mechanistically, TRPM4 activation induced mitochondrial dysfunction and cell death in AP were dependent on the presence of N-methyl-D-aspartate receptors (NMDARs). Blocking NMDARs mitigates the aggravated mitochondrial damage, ER stress and cell death caused by TRPM4 activation in AP. Conclusions: TRPM4 activation contributes to pancreatic acinar cells damage via an NMDAs-dependent pathway in AP. The TRPM4/NMDARs complex provides a new target for the future treatment of AP.
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高影响因子
MOLECULES
·
2018
·Vol. 23
·期 5
·996
·
IF 3.098
Wenchao Li,Jingjian Liu,Minghua Fan,Zhongtang Li,Yin Chen,Guisen Zhang,Zhuo Huang,Liangren Zhang
GLYX-13, a NMDAR glycine-site partial agonist, was discovered as a promising antidepressant with rapidly acting effects but no ketamine-like side effects. However, the reported synthetic process route had deficiencies of low yield and the use of unfriendly reagents. Here, we report a scaled-up synthesis of GLYX-13 with an overall yield of 30% on the hectogram scale with a column chromatography-free strategy, where the coupling and deprotection reaction conditions were systematically optimized. Meanwhile, the absolute configuration of precursor compound of GLYX-13 was identified by X-ray single crystal diffraction. Finally, the activity of GLYX-13 was verified in the cortical neurons of mice through whole-cell voltage-clamp technique.Keywords:GLYX-13;NMDA receptor;chromatography-free synthesis;crystal structure;whole-cell voltage-clamp
研究领域:
药理学
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合成化学
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神经科学
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DOI
PubMed
高影响因子
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