title: Arachidonyl-2-Chloroethylamide Alleviates Cerebral Ischemia Injury Through Glycogen Synthase Kinase-3β-Mediated Mitochondrial Biogenesis and Functional Improvement.
abstract: Arachidonyl-2-chloroethylamide (ACEA), a highly selective agonist of cannabinoid receptor 1 (CB1R), has been reported to protect neurons in ischemic injury. We sought to investigate whether mitochondrial biogenesis was involved in the therapeutic effect of ACEA in cerebral ischemia. Focal cerebral ischemic injury was induced in adult male Sprague Dawley rats. Intraperitoneal injection of 1 mg/kg ACEA improved neurological behavior, reduced infarct volume, and inhibited apoptosis. The volume and numbers of mitochondria were significantly increased after ACEA administration. Expression of mitochondrial transcription factor A (Tfam), nuclear transcription factor-1 (Nrf-1), and cytochrome C oxidase subunit IV (COX IV) were also significantly up-regulated in animals administered ACEA. One thousand nanomoles of ACEA inhibited mitochondrial dysfunction in primary rat cortical neurons exposed to oxygen-glucose deprivation (OGD). Furthermore, ACEA administration increased phosphorylation of glycogen synthase kinase-3β (GSK-3β) after reperfusion. Phosphorylation of GSK-3β induced mitochondrial biogenesis and preserved mitochondrial function whereas inhibition of phosphatidylinositol 3-kinase (PI3K) dampened phosphorylation of GSK-3β and reversed induction of mitochondrial biogenesis and function following ACEA administration. In conclusion, ACEA could induce mitochondrial biogenesis and improve mitochondrial function at the beginning of cerebral ischemia, thus alleviating cerebral ischemia injury. Phosphorylation of GSK-3β might be involved in the regulation of mitochondrial biogenesis induced by ACEA.
authors.affiliation: Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
authors.forename: Fuhai
authors.initials: F
authors.lastname: Bai
authors.affiliation: Department of Radiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Guo
authors.affiliation: Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Department of Anesthesiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710004, China.
authors.forename: Haidong
authors.initials: H
authors.lastname: Wei
authors.affiliation: Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Radiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yin
authors.affiliation: Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China.
authors.forename: Haixing
authors.initials: H
authors.lastname: Zhong
authors.affiliation: Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China. mzkxlz@126.com.
authors.forename: Lize
authors.initials: L
authors.lastname: Xiong
authors.affiliation: Department of Anesthesiology, Xijing Hospital, Fourth Military Medical University, Xi'an, 710032, Shaanxi Province, China. wangqiang@fmmu.edu.cn.|Department of Anesthesiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. wangqiang@fmmu.edu.cn.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Wang
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D000071679:Glycogen Synthase Kinase 3 beta / Q000378:metabolism*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D001678:Organelle Biogenesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists
chemical_list: D001095:Arachidonic Acids; D043884:Receptor, Cannabinoid, CB1; C119325:arachidonyl-2-chloroethylamide; D000071679:Glycogen Synthase Kinase 3 beta
keywords: Arachidonyl-2-chloroethylamide; Cannabinoid receptor 1; Glycogen synthase kinase-3β; Ischemic reperfusion injury; Mitochondrial biogenesis
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