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.

中文翻译：

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花生四烯酸-2-氯乙酰胺通过糖原合酶激酶3β介导的线粒体生物发生和功能改善来减轻脑缺血。

据报道，大麻素受体1（CB1R）的高度选择性激动剂花生四基-2-氯乙酰胺（ACEA）在缺血性损伤中保护神经元。我们试图研究线粒体的生物发生是否参与ACEA在脑缺血中的治疗作用。成年雄性Sprague Dawley大鼠诱发局灶性脑缺血损伤。腹膜内注射1 mg / kg ACEA可改善神经行为，减少梗塞体积并抑制细胞凋亡。施用ACEA后线粒体的体积和数量显着增加。施用ACEA的动物中，线粒体转录因子A（Tfam），核转录因子-1（Nrf-1）和细胞色素C氧化酶亚基IV（COX IV）的表达也显着上调。一千纳摩尔的ACEA抑制暴露于缺氧-葡萄糖剥夺（OGD）的原代大鼠皮层神经元的线粒体功能障碍。此外，ACEA给药可增加再灌注后糖原合酶激酶3β（GSK-3β）的磷酸化。GSK-3β的磷酸化诱导了线粒体的生物发生并保持了线粒体的功能，而抑制磷脂酰肌醇3-激酶（PI3K）抑制了GSK-3β的磷酸化并逆转了ACEA给药后线粒体的生物发生和功能的诱导。综上所述，ACEA可在脑缺血开始时诱导线粒体生物发生并改善线粒体功能，从而减轻脑缺血损伤。GSK-3β的磷酸化可能参与了ACEA诱导的线粒体生物发生的调控。