Activation of mitochondrial KATP channels mediates neuroprotection induced by chronic morphine preconditioning in hippocampal CA-1 neurons following cerebral ischemia

Purpose: Pharmacologic preconditioning, through activating several mechanisms and mediators, can increase the tolerance of different tissues against ischemia/reperfusion (I/R) injury. Recent studies have shown that morphine preconditioning has protective effects in different organs, especially in the heart. Nevertheless, its mechanisms are not well elucidated in the brain. The present study aimed to clarify whether the activation of mitochondrial KATP (mKATP) channels in chronic morphine (CM) preconditioning could decrease hippocampus damage following I/R injury. Materials and methods: CM preconditioning was performed by the administration of additive doses of morphine for 5 days before I/R injury induction. I/R injury was induced by the occlusion of bilateral common carotid arteries. The possible role of mKATP channels was evaluated by the injection of 5hydroxydecanoate (5-HD) before I/R injury. Terminal deoxynucleotidyl transferase-mediated dUTP nickend labeling (TUNEL) was performed to detect apoptosis in hippocampal neurons. The expressions of Bcell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (BAX) and levels of malondialdehyde (MDA) and catalase (CAT) enzymes were assessed. Results: CM attenuated apoptosis in the hippocampal CA1 neurons (P < 0.001 vs I/R), and mKATP channel blocking with 5-HD significantly increased apoptosis (P < 0.001 vs CM + I/R). CM increased CAT activity (P <0.05 vs I/R) and Bcl-2 protein expression (P <0.01 vs I/R), while it decreased MDA level (P <0.05 vs I/R) and BAX protein expression (P <0.05 vs I/R). Pretreatment with 5-HD abolished all the above-mentioned effects of CM. Conclusions: These findings describe novel evidence whereby CM preconditioning in hippocampal CA1 neurons can improve oxidative stress and apoptosis through the activation of mKATP channels and eventually protect the hippocampal tissue against I/R injury. (C) 2017 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.