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: Fuhai Bai, Fan Guo, Tao Jiang, Haidong Wei, Heng Zhou, Hong Yin, Haixing Zhong, Lize Xiong, Qiang Wang
• Journal: Molecular neurobiology (Mol Neurobiol) Vol. 54 Issue 2 Pg. 1240-1253 (03 2017) ISSN: 1559-1182 [Electronic] United States
• PMID: 26820679 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Arachidonic Acids
• Receptor, Cannabinoid, CB1
• arachidonyl-2-chloroethylamide
• Glycogen Synthase Kinase 3 beta

Topics

• Animals
• Arachidonic Acids (pharmacology, therapeutic use)
• Brain Ischemia (drug therapy, metabolism, pathology)
• Glycogen Synthase Kinase 3 beta (metabolism)
• Male
• Mitochondria (drug effects, metabolism)
• Organelle Biogenesis
• Rats
• Rats, Sprague-Dawley
• Receptor, Cannabinoid, CB1 (agonists)