Neuronal nitric oxide synthase/reactive oxygen species pathway is involved in apoptosis and pyroptosis in epilepsy

作     者：Xiao-Xue Xu Rui-Xue Shi Yu Fu Jia-Lu Wang Xin Tong Shi-Qi Zhang Na Wang Mei-Xuan Li Yu Tong Wei Wang Miao He Bing-Yang Liu Gui-Lan Chen Feng Guo Xiao-Xue Xu;Rui-Xue Shi;Yu Fu;Jia-Lu Wang;Xin Tong;Shi-Qi Zhang;Na Wang;Mei-Xuan Li;Yu Tong;Wei Wang;Miao He;Bing-Yang Liu;Gui-Lan Chen;Feng Guo

作者机构：Department of Pharmaceutical ToxicologySchool of Pharmaceutical ScienceChina Medical UniversityShenyangLiaoning ProvinceChina Department of Neurologythe First Affiliated Hospital of China Medical UniversityShenyangLiaoning ProvinceChina Key Laboratory of Medical ElectrophysiologyMinistry of Education&Medical Electrophysiological Key Laboratory of Sichuan ProvinceInstitute of Cardiovascular ResearchSouthwest Medical UniversityLuzhouSichuan ProvinceChina Department of Endocrinology and Metabolismthe Fourth Affiliated Hospital of China Medical UniversityShenyangLiaoning ProvinceChina Department of EndocrinologyShengjing Hospital of China Medical UniversityShenyangLiaoning ProvinceChina 

出 版 物：《Neural Regeneration Research》 (中国神经再生研究（英文版）)

年 卷 期：2023年第18卷第6期

页      面：1277-1285页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100204[医学-神经病学] 10[医学] 

基　　金：supported by the Natural Science Foundation of China Nos.81971212 (to FG) 81601129 (to XXX) the Open Fund of the Key Laboratory of Medical Electrophysiology Ministry of Education&Medical Electrophysiological Key Laboratory of Sichuan Province Institute of Cardiovascular Research Southwest Medical University No.KeyME-2018-07 (to FG) Liaoning Province Xingliao Talent Program Project No.XLYC1907164 (to FG) 

主　　题：apoptosis bioinformatics analysis cell death epilepsy nitric oxide synthase oxidative stress pyroptosis RNA sequencing Tremor rat weighted gene co-expression network analysis 

摘      要：Dysfunction of neuronal nitric oxide synthase contributes to neurotoxicity,which triggers cell death in various neuropathological diseases,including epilepsy.Studies have shown that inhibition of neuronal nitric oxide synthase activity increases the epilepsy threshold,that is,has an anticonvulsant effect.However,the exact role and potential mechanism of neuronal nitric oxide synthase in seizures are still unclear.In this study,we performed RNA sequencing,functional enrichment analysis,and weighted gene coexpression network analysis of the hippocampus of tremor rats,a rat model of genetic epilepsy.We found damaged hippocampal mitochondria and abnormal succinate dehydrogenase level and Na+-K+-ATPase activity.In addition,we used a pilocarpine-induced N2a cell model to mimic epileptic injury.After application of neuronal nitric oxide synthase inhibitor 7-nitroindazole,changes in malondialdehyde,lactate dehydrogenase and superoxide dismutase,which are associated with oxidative stress,were reversed,and the increase in reactive oxygen species level was reversed by 7-nitroindazole or reactive oxygen species inhibitor N-acetylcysteine.Application of 7-nitroindazole or N-acetylcysteine downregulated the expression of caspase-3 and cytochrome c and reversed the apoptosis of epileptic cells.Furthermore,7-nitroindazole or N-acetylcysteine downregulated the abnormally high expression of NLRP3,gasdermin-D,interleukin-1βand interleukin-18.This indicated that 7-nitroindazole and N-acetylcysteine each reversed epileptic cell death.Taken together,our findings suggest that the neuronal nitric oxide synthase/reactive oxygen species pathway is involved in pyroptosis of epileptic cells,and inhibiting neuronal nitric oxide synthase activity or its induced oxidative stress may play a neuroprotective role in epilepsy.