CELL BIOCHEMISTRY AND FUNCTION
·
2024
·Vol. 42
·期 3
·e4003
·
IF 2.8
Mengnan Xing,Xinlei Yang,Sinan Jin,Xiangping Xu
Neuronal pentraxin 2 (Nptx2), a member of the synaptic protein family linked to excitatory synaptic formation, is found to be upregulated in epileptic mice, yet its role in epilepsy has been unclear. In vivo, we constructed a mouse model of epilepsy by using kainic acid induction. In vitro experiments, a Mg 2+ -free medium was used to induce epileptiform discharges in neurons. The results showed that the Nptx2 was upregulated in epileptic mice. Moreover, Nptx2 knockdown reduced the number of seizures and seizure duration. Knocking down Nptx2 not only reduced the number and duration of seizures but also showed a decrease in electroencephalogram amplitude. Behavioral tests indicated improvements in learning and memory abilities after Nptx2 knockdown. The Nissl staining and Timms staining revealed that Nptx2 silencing mitigated epilepsy-induced brain damage. The immunofluorescence staining revealed that Nptx2 absence resulted in a reduction of apoptosis. Nptx2 knockdown reduced Bax, cleaved caspase3, and cleaved caspase9 expression, while increased Bcl-2 expression. Notably, Nptx2 knockdown inhibited GluA1 phosphorylation at the S831 site and reduced the GluA1 membrane expression. The PSD95 expression declined in the epilepsy model, while the Nptx2 knockdown reversed it. Collectively, our study indicated that Nptx2 silencing not only alleviated brain damage and neuron apoptosis but also improved learning and memory ability in epileptic mice, suggesting Nptx2 as a promising target for epilepsy treatment. Significant statement Nptx2 is associated with excitatory synaptic formation, while the role of Nptx2 in epilepsy remains unclear. Our finding indicated an upregulation of Nptx2 in epileptic mice, and knockdown of Nptx2 leading to a reduction in seizure frequency and duration, alongside improvements in learning and memory. Nptx2 knockdown alleviated neuron apoptosis. More importantly, GluA1 phosphorylation in the S831 site was increased in KA mice, while knockdown of Nptx2 reversed it. Nptx2 knockdown decreased the GluA1 membrane expression. Overall, our study suggested that Nptx2 silencing alleviated brain damage and inhibited neuron apoptosis. This study offers novel insights into epilepsy treatment.
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
PHARMACOLOGICAL RESEARCH
·
2020
·
IF 5.893
Yongzhou Yu,Zuxiao Yang,Baohua Jin,Xia Qin,Xiaoque Zhu,Jiahui Sun,Lifang Huo,Ri Wang,Yongyun Shi,Zhanfeng Jia,Yun Stone Shi,Shifeng Chu,Dezhi Kong,Wei Zhang
Cannabidiol (CBD) is a major phytocannabinoid in Cannabis sativa. CBD is being increasingly reported as a clinical treatment for neurological diseases. Febrile seizure is one of the most common diseases in children with limited therapeutic options. We investigated possible therapeutic effects of CBD on febrile seizures and the underlying mechanism. Use of a hyperthermia-induced seizures model revealed that CBD significantly prolonged seizure latency and reduced the severity of thermally-induced seizures. Hippocampal neuronal excitability was significantly decreased by CBD. Further, CBD significantly reduced the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) mediated evoked excitatory postsynaptic currents (eEPSCs) and the amplitude and frequency of miniature EPSCs (mEPSCs). Furthermore, CBD significantly accelerated deactivation in GluA1 and GluA2 subunits. Interestingly, CBD slowed receptor recovery from desensitization of GluA1, but not GluA2. These effects on kinetics were even more prominent when AMPAR was co-expressed with γ-8, the high expression isoform 8 of transmembrane AMPAR regulated protein (TARPγ8) in the hippocampus. The inhibitory effects of CBD on AMPAR depended on its interaction with the distal N-terminal domain of GluA1/GluA2. CBD inhibited AMPAR activity and reduced hippocampal neuronal excitability, thereby improving the symptoms of febrile seizure in mice. The putative binding site of CBD in the N-terminal domain of GluA1/GluA2 may be a drug target for allosteric gating modulation of AMPAR.
研究领域:
神经科学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Communications Biology
·
2026
·
IF 5.8
Gu Xunhu,Liu Xu,Xiong Yong,Chen Xuefen,Zhang Yancai,Zheng Li-Li,Wang Wei
Major depressive disorder is associated with impaired excitatory synaptic transmission, but the molecular mechanisms linking chronic stress to altered AMPA receptor trafficking remain incompletely understood. Here we show that chronic mild stress increases OGT-mediated O-GlcNAcylation of PIN at serine 88, which stabilizes PIN and enhances its interaction with nitric oxide synthase. This suppresses nitric oxide synthase activity, reduces stargazin S-nitrosylation, weakens stargazin-GluA1 binding, and impairs GluA1-containing AMPA receptor trafficking. Genetic or pharmacological inhibition of OGT restores this signaling pathway and alleviates stress-induced depression-like behaviors in mice. These findings identify the OGT-PIN-NOS-stargazin axis as a regulator of stress-induced synaptic dysfunction and suggest that targeting OGT may help restore AMPA receptor trafficking in depression-related conditions.
✓ 已验证
DOI
PubMed
高影响因子
Cell Death & Disease
·
2018
·Vol. 9
·期 8
·1-20
·
IF 5.638
Yang Qin,Zheng Fangshuo,Hu Yida,Yang Yi,Li Yun,Chen Guojun,Wang Wei,He Miaoqing,Zhou Ruijiao,Ma Yuanlin,Xu Demei,Tian Xin,Gao Xiaoya,Wang Qing,Wang Xuefeng
Epilepsy is one of the most prevalent and drug-refractory neurological disorders. Zinc finger DHHC-type containing 8 (ZDHHC8) is a putative palmitoyltransferase that is highly expressed in the brain. However, the impact of ZDHHC8 on seizures remains unclear. We aimed to explore the association of ZDHHC8 with epilepsy and investigate its in epileptogenesis in in vivo and in vitro models through behavioral, electrophysiological, and pathological studies. We used kainic acid- and pilocarpine-induced C57BL/6 mice and magnesium-free-induced pyramidal neurons as experimental epileptic models in this study. We first found increased ZDHHC8 expression in the brains of temporal lobe epilepsy (TLE) patients, similar to that observed in chronic epileptic mice, strongly suggesting that ZDHHC8 is correlated with human epilepsy. In the in vitro seizure models, knocking down ZDHHC8 using recombinant adeno-associated virus (rAAV) delayed seizure precipitation and decreased chronic spontaneous recurrent seizures (SRSs) and epileptiform-like discharges, while ZDHHC8 overexpression had the opposite effect. ZDHHC8 levels were consistent with seizure susceptibility in induced mice with SRSs. In an in vitro magnesium-free model, neuronal hyperexcitability and hypersynchrony were reduced in ZDHHC8-knockdown neurons but were increased in ZDHHC8-overexpressing neurons. To further explore the potential mechanisms, we observed that ZDHHC8 had a significant modulatory effect on 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) receptor-related excitatory, but not inhibitory, glutamatergic synaptic neurotransmission, further affecting the inward rectification of AMPA currents in acute hippocampal slices in whole-cell recordings. ZDHHC8 facilitated GluA1 trafficking to the neuronal surface in the hippocampus, as shown by immunoprecipitation and Western blotting. These results suggest that ZDHHC8 may promote the generation and propagation of seizures in humans and that knocking down ZDHHC8 might produce anti-epileptogenic effects in drug-resistant epilepsy. Our study provides evidence that may facilitate the development of an alternative approach for the treatment of epilepsy by modulating AMPA/GluA1-mediated neurotransmission.
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
TOXICOLOGY
·
2019
·
IF 3.547
Yuan Liao,Yuhao Luo,Nanjisha Ding,Juanmei Gao,Xingbao Wang,Wanhua Shen
Xylene and its derivatives are known to be neurotoxic to the central nervous system of animals. Our previous work has shown that para-xylene (PX) can cause an increase in apoptotic cells and abnormal avoidance behavior in Xenopus laevis . However, the mechanism underlying the impact of PX on neuronal structural and functional plasticity is less clear. Here, we examined the effects of PX on neuronal development and plasticity in the developing optic tectum. We found that HuC/D-positive neurons were more vulnerable than SOX2-positive progenitor cells or BLBP-positive radial glial cells after exposure to PX at 1 mM for 48 h. The further measurement of postsynaptic receptors and synaptic vesicle proteins showed that the expression levels of GluA1 and GluA2, but not Rab3a and SNAP25, were significantly decreased in the tectal brain. In vivo time-lapse images and electrophysiological recordings showed that PX exposure resulted in significant deficits in neuronal structure, particularly in the total dendritic branch length (TDBL), and visual stimulation-induced excitatory compound synaptic currents (eCSCs) without altering neurotransmitter release probability. Strikingly, coexposure to d -glucuronolactone (GA) and PX rescued the structural and functional deficits caused by PX exposure alone. Furthermore, we found that visual experience-induced structural, functional and behavioral plasticity was blocked by PX exposure, which was also rescued by the simultaneous administration of GA and PX . Thus, our findings indicate that PX is neurotoxic to brain development and plasticity and that GA may be considered a promising candidate to treat PX-induced defects in neural circuits.
研究领域:
神经科学
·
发育生物学
·
毒理学
✓ 已验证
DOI
PubMed
高影响因子
Molecular Brain
·
2019
·Vol. 12
·期 1
·1-12
·
IF 4.051
Wang Xin-shang,Guan Shao-yu,Liu An,Yue Jiao,Hu Li-ning,Zhang Kun,Yang Liu-kun,Lu Liang,Tian Zhen,Zhao Ming-gao,Liu Shui-bing
Chronic pain is commonly accompanied with anxiety disorder, which complicates treatment. In this study, we investigated the analgesic and anxiolytic effects of Formononetin (FMNT), an active component of traditional Chinese medicine red clover ( Trifolium pratense L.) that is capable of protecting neurons from N-methyl-D-aspartate (NMDA)-evoked excitotoxic injury, on mice suffering from complete Freund’s adjuvant (CFA)-induced chronic inflammatory pain. The results show that FMNT administration significantly reduces anxiety-like behavior but does not affect the nociceptive threshold in CFA-injected mice. The treatment reverses the upregulation of NMDA, GluA1, and GABA A receptors, as well as PSD95 and CREB in the basolateral amygdala (BLA). The effects of FMNT on NMDA receptors and CREB binding protein (CBP) were further confirmed by the potential structure combination between these compounds, which was analyzed by in silico docking technology. FMNT also inhibits the activation of the NF-κB signaling pathway and microglia in the BLA of mice suffering from chronic inflammatory pain. Therefore, the anxiolytic effects of FMNT are partially due to the attenuation of inflammation and neuronal hyperexcitability through the inhibition of NMDA receptor and CBP in the BLA.
研究领域:
药理学
·
神经科学
·
疼痛研究
·
传统中药
✓ 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
危险品化学品经营许可证（带存储）