Mitofusin-2 mediates cannabidiol-induced neuroprotection against cerebral ischemia in rats  

作　　者：Bing-tian Xu Meng-fan Li Ke-chun Chen Xing Li Ning-bo Cai Jiang-ping Xu Hai-tao Wang 

机构地区：[1]Guangdong Provincial Key Laboratory of New Drug Screening,School of Pharmaceutical Sciences,Southern Medical University,Guangzhou 510515,China [2]Department of Neurology,Guangzhou First People’s Hospital,South China University of Technology,Guangzhou 510180,China [3]Key Laboratory of Mental Health of the Ministry of Education,Southern Medical University,Guangzhou 510515,China [4]Center for Brain Science and Brain-Inspired Intelligence,Guangdong-Hong Kong-Macao Greater Bay Area,Guangzhou 510515,China

出　　处：《Acta Pharmacologica Sinica》2023年第3期499-512,共14页中国药理学报（英文版）

基　　金：National Natural Science Foundation of China(Nos.82173802 and 82273902);Science and Technology Program of Guangzhou(No.202002030494);Guangdong Basic and Applied Basic Research Foundation(No.2022A1515012317).

摘　　要：Cannabidiol(CBD)reportedly exerts protective effects against many psychiatric disorders and neurodegenerative diseases,but the mechanisms are poorly understood.In this study,we explored the molecular mechanism of CBD against cerebral ischemia.HT-22 cells or primary cortical neurons were subjected to oxygen-glucose deprivation insult followed by reoxygenation(OGD/R).In both HT-22 cells and primary cortical neurons,CBD pretreatment(0.1,0.3,1μM)dose-dependently attenuated OGD/R-induced cell death and mitochondrial dysfunction,ameliorated OGD/R-induced endoplasmic reticulum(ER)stress,and increased the mitofusin-2(MFN2)protein level in HT-22 cells and primary cortical neurons.Knockdown of MFN2 abolished the protective effects of CBD.CBD pretreatment also suppressed OGD/R-induced binding of Parkin to MFN2 and subsequent ubiquitination of MFN2.Overexpression of Parkin blocked the effects of CBD in reducing MFN2 ubiquitination and reduced cell viability,whereas overexpressing MFN2 abolished Parkin’s detrimental effects.In vivo experiments were conducted on male rats subjected to middle cerebral artery occlusion(MCAO)insult,and administration of CBD(2.5,5 mg·kg^(−1),i.p.)dose-dependently reduced the infarct volume and ER stress in the brains.Moreover,the level of MFN2 within the ischemic penumbra of rats was increased by CBD treatment,while the binding of Parkin to MFN2 and the ubiquitination of MFN2 was decreased.Finally,short hairpin RNA against MFN2 reversed CBD’s protective effects.Together,these results demonstrate that CBD protects brain neurons against cerebral ischemia by reducing MFN2 degradation via disrupting Parkin’s binding to MFN2,indicating that MFN2 is a potential target for the treatment of cerebral ischemia.

关 键 词：CANNABIDIOL MFN2 PARKIN cerebral ischemia oxidative stress 

分 类 号：R965[医药卫生—药理学]