Melatonin receptor agonist ramelteon attenuates mouse acute and chronic ischemic brain injury  

作　　者：Xiao-li Wu Shou-sheng Lu Meng-ru Liu Wei-dong Tang Jun-zi Chen Yan-rong Zheng Anil Ahsan Ming Cao Lei Jiang Wei-wei Hu Jia-ying Wu Zhong Chen Xiang-nan Zhang 

机构地区：[1]institute of Pharmacology&Toxicology,College of Pharmaceutical Sciences,Key Laboratory of Medical Neurobiology of The Ministry of Health of China,Zhejiang University,Hangzhou 310058,China [2]Department of Pharmacy,First Peopled Hospital of Linhai City,Linhai 317000,China [3]Hangzhou No.4 High school,Hangzhou 310018,China

出　　处：《Acta Pharmacologica Sinica》2020年第8期1016-1024,共9页中国药理学报（英文版）

基　　金：the National Natural Science Foundation of China(81822044,81773703,and 81872844);the Natural Science Foundation of Zhejiang Province(LY19H310007);the Fundamental Research Funds for the Central Universities(2019XZZX004-17).

摘　　要：Melatonin receptors(MTs)are potential drug targets for stroke therapy.Ramelteon is a selective melatonin receptor agonist used to treat insomnia.In this study we investigated whether ramelteon could attenuate cerebral ischemia in mice.Acute focal cerebral ischemia was induced in mice via middle cerebral artery occlusion(MCAO).We found oral administration of ramelteon(3.0 mg/kg)significantly attenuated ischemic injury even when it was given 4 h after the onset of ischemia.We showed that administration of ramelteon(3.0 mg/kg)displayed comparable protective efficacy and length of effective time window as administration of edaravone(10 mg/kg,ip.),which was used in dlinic to treat ischemic stroke.Chronic ischemic brain injury was induced in mice using photothrombosis.Oral administration of ramelteon(3.0 mg·kg^-1·d^-1)for 7 days after ischemia significantly attenuated functional deficits for at least 15 days.The neuroprotection of ramelteon was blocked by 4-P-PDOT,a specific MT antagonist.We further revealed that ramelteon significantly inhibited autophagy in the per-infarct cortex in both the mouse ischemia models via regulating AMPK/mTOR signaling pathway.Intracerebroventricular injection of rapamycin,an autophagy actiator,compromised the neuroprotection of ramelteon,suggesting ramelteon might attenuate ischemic injury by counteracting autophagic cell death.These data demonstrate for the first time the potential benefts of ramelteon in the treatment of both acute and chronic ischemic brain injury and provide the rationale for the application of ramelteon in stroke therapy.

关 键 词：cerebral ischemia ramelteon AUTOPHAGY middle cerebral artery occlusion(MCAO) PHOTOTHROMBOSIS melatonin receptors 

分 类 号：R743[医药卫生—神经病学与精神病学]