Anti-epileptic and Neuroprotective Effects of Ultra-low Dose NADPH Oxidase Inhibitor Dextromethorphan on Kainic Acid-induced Chronic Temporal Lobe Epilepsy in Rats  

作　　者：Jing-Jing Yang Ying-Xin Liu Yan-Fang Wang Bi-Ying Ge Ying Wang Qing-Shan Wang Sheng Li Jian-Jie Zhang Ling-Ling Jin Jau-Shyong Hong Sheng-Ming Yin Jie Zhao 

机构地区：[1]College of Basic Medical Sciences,Dalian Medical University,Dalian,116044,China [2]Department of Neurology,The First Affiliated Hospital of Dalian Medical University,Dalian,116011,China [3]National and Local Joint Engineering Research Center for Drug Research and Development of Neurodegenerative Diseases,Dalian,116044,China [4]School of Public Health,Dalian Medical University,Dalian,116044,China [5]Neurobiology Laboratory,National Institute of Environmental Health Sciences,National Institutes of Health,Research Triangle Park,Durham,NC,27709,USA

出　　处：《Neuroscience Bulletin》2024年第5期577-593,共17页神经科学通报（英文版）

基　　金：supported by the National Major Scientific and Technological Special Project for Significant New Drugs Development(2019zx09301102);the Project of Liaoning Provincial Department of Education(LJKZ0826);the Open Project of National and Local Joint Engineering Research Center for Drug Research and Development of Neurodegenerative Diseases(2022GCYJZX-YB02).

摘　　要：Neuroinflammation mediated by microglia and oxidative stress play pivotal roles in the development of chronic temporal lobe epilepsy(TLE).We postulated that kainic acid(KA)-Induced status epilepticus triggers microglia-dependent inflammation,leading to neuronal damage,a lowered seizure threshold,and the emergence of spontaneous recurrent seizures(SRS).Extensive evidence from our laboratory suggests that dextromethorphan(DM),even in ultra-low doses,has anti-inflammatory and neuroprotective effects in many animal models of neurodegenerative disease.Our results showed that administration of DM(10 ng/kg per day;subcutaneously via osmotic minipump for 4 weeks)significantly mitigated the residual effects of KA,including the frequency of SRS and seizure susceptibility.In addition,DM-treated rats showed improved cognitive function and reduced hippocampal neuronal loss.We found suppressed microglial activation-mediated neuroinflammation and decreased expression of hippocampal gp91^(phox) and p47^(phox) proteins in KA-induced chronic TLE rats.Notably,even after discontinuation of DM treatment,ultra-low doses of DM continued to confer long-term anti-seizure and neuroprotective effects,which were attributed to the inhibition of microglial NADPH oxidase 2 as revealed by mechanistic studies.

关 键 词：Temporal lobe epilepsy DEXTROMETHORPHAN NADPH oxidase Ultra-low dose 

分 类 号：R-332[医药卫生] R742.1