NEUROREPORT
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2018
·Vol. 29
·期 5
·432
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IF 1.266
Zhang Jinghui,Qiao Nana,Ding Xiufang,Wang Jiwen
Excitotoxicity and neuronal death following epilepsy involve α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). It forms a protein complex with glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and co-internalizes upon activation of AMPA receptors after epilepsy. Disruption of the GluA2 /GAPDH complex with an interfering peptide , TAT- GluA2 NT1-3-2 , protects cells against AMPAR-mediated excitotoxicity, which have been identified in in-vitro and in-vivo models of brain ischemia. We postulated that disruption of the GluA2 /GAPDH interaction with the TAT- GluA2 NT1-3-2 peptide would also protect against AMPAR-induced neuronal injury in an in-vivo model of status epilepticus (SE). In the present study, we divided pilocarpine -induced SE Wistar rats into three main groups: the TAT- GluA2 NT1-3-2 peptide group, the TAT- GluA2 NT-scram peptide group, and the normal saline group, and injected different doses of peptides stereotaxically into the hippocampus of SE rats to investigate whether the GluA2 /GAPDH interaction could be disrupted by our TAT- GluA2 NT1-3-2 peptide and determine its most appropriate dose. Then, the dose was administered stereotaxically at different time points after SE to determine the best administration time of neuronal protection. We found that the TAT- GluA2 NT1-3-2 peptide can disrupt the GluA2 /GAPDH interaction and protects against epilepsy-induced neuronal damage. The GluA2 /GAPDH interaction may be a novel therapeutic target for epilepsy.
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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DOI
PubMed
高影响因子
Oncotarget
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2017
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IF 5.168
Qin Yang,Yi-Da Hu,Xue-Feng Wang,Fang-Shuo Zheng
Epilepsy is the most prevalent chronic neurological disorder, and its pathological mechanism indicates that an imbalance between excitatory and inhibitory neurotransmission leads to neuronal hyperexcitability. Previous studies have suggested that dl-3n-butylphthalide (NBP) regulates the excitatory neurotransmitter glutamate in the brains of epileptic mice, however, the mechanisms are unknown. We investigated behavioral and electrophysiological factors in rats using NBP. In an in vivo pentylenetetrazole (PTZ)-induced epileptic seizure animal model, NBP decreased the generalized tonic-clonic seizure (GTCS) severity. In an acute hippocampal slice 4-aminopyridine (4-AP) epilepsy model in vitro , NBP decreased the epileptiform activity and miniature excitatory postsynaptic current (mEPSC) amplitude; there was no change in the miniature inhibitory postsynaptic current (mIPSC) amplitude or frequency. This effect suggested changes in excitatory synaptic transmission, which was altered through postsynaptic GluA2-lacking calcium-permeable AMPA receptors (CP-AMPARs). These findings showed that NBP suppressed epileptiform activity in these epilepsy models and provided the first detailed electrophysiological analysis of the impact of NBP in epilepsy models, which may be employed in future experimental or clinical therapies for patients with epilepsy.
研究领域:
神经科学
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药理学
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电生理学
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DOI
PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
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2020
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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
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
EPILEPSY RESEARCH
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2022
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IF 2.991
Jinghui Zhang,Nana Qiao,Jiwen Wang,Baomin Li
Recent studies have identified that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) exerts multiple functions besides its role in energy metabolism. It can form a protein complex with GluA2 subunit of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs), translocate into nucleus and confer neurotoxicity in a cerebral ischemia model. We postulate that GAPDH may also induce neurotoxicity by forming a coupling with GluA2 in pilocarpine-induced epileptic model, and disruption of the GluA2/GAPDH coupling can protect against neuronal injury. In this study, induced status epilepticus (SE) in rats by the systemic administration of pilocarpine, collected hippocampal tissues at different time points after SE, and assessed the relationship between GluA2/GAPDH coupling and neuronal apoptosis in SE rats. Then, we interrupted the GluA2/GAPDH coupling by a special interfering peptide and determined whether neuronal injury can be rescued and hippocampus-depended memory function can be improved. We also evaluated the concentrations of GAPDH in nuclear and cytoplasmatic proteins in SE group, non-SE group and after interruption of GluA2/GAPDH coupling, to verify the nuclear translocation of GAPDH in SE model. We found that the apoptosis of hippocampal neurons was most significant at 72 h after SE, which was also the peak time of GluA2/GAPDH coupling expression and GluA2 consumption. After interruption of GluA2/GAPDH coupling, the apoptosis and memorial function of hippocampal neurons were improved and nuclear translocation of GluA2/GAPDH coupling was reduced. In conclusion, GAPDH can be translocated into nucleus in the form of GluA2/GAPDH, which plays an important role in regulating pilocarpine-induced epilepsy via neurotoxicity pathway.
研究领域:
神经科学
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分子生物学
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药理学
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神经病学
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DOI
PubMed
高影响因子
TOXICOLOGY
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2019
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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
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发育生物学
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毒理学
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DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
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2021
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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
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神经科学
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中医
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分子生物学
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DOI
PubMed
高影响因子
Neural Regeneration Research
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2023
·Vol. 18
·期 10
·2315
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IF 6.1
Duan Tian-Qi,Gao Zhao-Lin,Luo Ai-Xiang,Chen Dan,Tong Jian-Bin,Huang Ju-Fang
Adipose mesenchymal stem cells (ADSCs) have protective effects against glutamate -induced excitotoxicity , but ADSCs are limited in use for treatment of optic nerve injury. Studies have shown that the extracellular vesicles (EVs) secreted by ADSCs (ADSC-EVs) not only have the function of ADSCs, but also have unique advantages including non-immunogenicity, low probability of abnormal growth, and easy access to target cells. In the present study, we showed that intravitreal injection of ADSC-EVs substantially reduced glutamate -induced damage to retinal morphology and electroretinography . In addition, R28 cell pretreatment with ADSC-EVs before injury inhibited glutamate -induced overload of intracellular calcium, downregulation of α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid receptor (AMPAR) subunit GluA2 , and phosphorylation of GluA2 and protein kinase C alpha in vitro . A protein kinase C alpha agonist, 12-O-tetradecanoylphorbol 13-acetate, inhibited the neuroprotective effects of ADSC-EVs on glutamate -induced R28 cells . These findings suggest that ADSC-EVs ameliorate glutamate -induced excitotoxicity in the retina through inhibiting protein kinase C alpha activation.
研究领域:
神经科学
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细胞生物学
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眼科学
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干细胞研究
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产品关联
DOI
PubMed
高影响因子
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