Update on the pathological roles of prostaglandin E_(2) in neurodegeneration in amyotrophic lateral sclerosis  

作　　者：Hiroshi Nango Komugi Tsuruta Hiroko Miyagishi Yuri Aono Tadashi Saigusa Yasuhiro Kosuge 

机构地区：[1]Laboratory of Pharmacology,School of Pharmacy,Nihon University,7-7-1 Narashinodai,Funabashi-Shi,Chiba 274-8555,Japan [2]Department of Pharmacology,School of Dentistry at Matsudo,Nihon University,2-870-1 Sakaechonishi,Matsudo-Shi,Chiba 271-8587,Japan

出　　处：《Translational Neurodegeneration》2023年第1期464-478,共15页转化神经变性病（英文）

基　　金：funded in part by a Nihon University Research Grant for 2022-2023(to YK,HM,YA,and TS);JSPS KAKENHI(22K06654 to YK and TS,and 21K06620 to HM and YK).

摘　　要：Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease characterized by selective degeneration of upper and lower motor neurons.The pathogenesis of ALS remains largely unknown;however,inflammation of the spinal cord is a focus of ALS research and an important pathogenic process in ALS.Prostaglandin E_(2)(PGE_(2))is a major lipid mediator generated by the arachidonic-acid cascade and is abundant at inflammatory sites.PGE_(2)levels are increased in the postmortem spinal cords of ALS patients and in ALS model mice.Beneficial therapeutic effects have been obtained in ALS model mice using cyclooxygenase-2 inhibitors to inhibit the biosynthesis of PGE_(2),but the usefulness of this inhibitor has not yet been proven in clinical trials.In this review,we present current evidence on the involvement of PGE_(2)in the progression of ALS and discuss the potential of microsomal prostaglandin E syn-thase(mPGES)and the prostaglandin receptor E-prostanoid(EP)2 as therapeutic targets for ALS.Signaling pathways involving prostaglandin receptors mediate toxic effects in the central nervous system.In some situations,however,the receptors mediate neuroprotective effects.Our recent studies demonstrated that levels of mPGES-1,which catalyzes the final step of PGE_(2)biosynthesis,are increased at the early-symptomatic stage in the spinal cords of transgenic ALS model mice carrying the G93A variant of superoxide dismutase-1.In addition,in an experimental motor-neuron model used in studies of ALS,PGE_(2)induces the production of reactive oxygen species and subsequent caspase-3-de-pendent cytotoxicity through activation of the EP2 receptor.Moreover,this PGE_(2)-induced EP2 up-regulation in motor neurons plays a role in the death of motor neurons in ALS model mice.Further understanding of the pathophysiologi-cal role of PGE_(2)in neurodegeneration may provide new insights to guide the development of novel therapies for ALS.

关 键 词：Prostaglandin E_(2) Amyotrophic lateral sclerosis Motor neuron death E-prostanoid receptor Microsomal prostaglandin E synthetase-1 

分 类 号：R746.4[医药卫生—神经病学与精神病学]