Salvinorin A moderates postischemic brain injury by preserving endothelial mitochondrial function via AMPK/Mfn2 activation.

Abstract

Salvinorin A (SA) is a highly selective kappa opioid receptor (KOR) agonist that has significant protective effects on cerebrovascular function after ischemic stroke, but its underlying mechanism is still unclear. This study aimed to investigate whether KOR activation improves the morphology and function of intracellular mitochondria to protect endothelial cells after cerebral ischemia. A transient ischemic brain damage was generated by establishing middle cerebral artery occlusion (MCAO) model in male Sprague-Dawley rats and oxygen glucose deprivation (OGD) model in human brain microvascular endothelial cells (HBMECs). In vivo findings revealed that SA significantly reduced the infarct size, brain edema and Evans blue effusion after MCAO. In vitro findings revealed that SA improved the cell viability and decreased the apoptotic rates in HBMECs OGD model. SA also protected membrane potential and morphology of mitochondria, reduced the ROS level after OGD. SA function was blocked by KOR inhibitor norbinaltorphimine (NB). SA upregulated the phosphorylation levels of AMPK, and Mfn2 expression. Our findings suggest that SA effectively mitigated focal cerebral ischemic injury by activating KOR which potentially preserved mitochondrial function by up-regulating AMPK/Mfn2 in endothelial cells.

• Authors: Haiping Dong, Wei Zhou, Jihua Xin, Haiyan Shi, Xueya Yao, Zhenzhou He, Zhenhong Wang
• Journal: Experimental neurology (Exp Neurol) Vol. 322 Pg. 113045 (12 2019) ISSN: 1090-2430 [Electronic] United States
• PMID: 31461637 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 Elsevier Inc. All rights reserved.

Chemical References

• Diterpenes, Clerodane
• Mitochondrial Proteins
• Neuroprotective Agents
• Receptors, Opioid, kappa
• Adenylate Kinase
• GTP Phosphohydrolases
• salvinorin A

Topics

• Adenylate Kinase (metabolism)
• Animals
• Brain Ischemia (metabolism, pathology)
• Cell Survival (drug effects)
• Diterpenes, Clerodane (pharmacology)
• Endothelial Cells (drug effects, metabolism)
• GTP Phosphohydrolases (metabolism)
• Humans
• Male
• Mitochondria (drug effects, metabolism)
• Mitochondrial Proteins (metabolism)
• Neuroprotective Agents (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Receptors, Opioid, kappa (agonists)
• Signal Transduction (drug effects)