Reduction of zinc accumulation in mitochondria contributes to decreased cerebral ischemic injury by normobaric hyperoxia treatment in an experimental stroke model.

Abstract

Cerebral ischemia interrupts oxygen supply to the affected tissues. Our previous studies have reported that normobaric hyperoxia (NBO) can maintain interstitial partial pressure of oxygen (pO2) in the penumbra of ischemic stroke rats at the physiological level, thus affording significant neuroprotection. However, the mechanisms that are responsible for the penumbra rescue by NBO treatment are not fully understood. Recent studies have shown that zinc, an important mediator of intracellular and intercellular neuronal signaling, accumulates in neurons and leads to ischemic neuronal injury. In this study, we investigate whether NBO could regulate zinc accumulation in the penumbra and prevent mitochondrial damage in penumbral tissue using a transient cerebral ischemic rat model. Our results showed that NBO significantly reduced zinc-staining positive cells and zinc-staining intensity in penumbral tissues, but not in the ischemic core. Moreover, ischemia-induced zinc accumulation in mitochondria, isolated from penumbral tissues, was greatly attenuated by NBO or a zinc-specific chelator, N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN). NBO or TPEN administration stabilized the mitochondrial membrane potential in the penumbra after cerebral ischemia. Finally, ischemia-induced cytochrome c release from mitochondria in penumbral tissues was significantly reduced by NBO or TPEN treatment. These findings demonstrate a novel mechanism for NBO's neuroprotection, especially to penumbral tissues, providing further evidence for the potential clinical benefit of NBO for acute ischemic stroke.

• Authors: Wen Dong, Zhifeng Qi, Jia Liang, Wenjuan Shi, Yongmei Zhao, Yumin Luo, Xunming Ji, Ke Jian Liu
• Journal: Experimental neurology (Exp Neurol) Vol. 272 Pg. 181-9 (Oct 2015) ISSN: 1090-2430 [Electronic] United States
• PMID: 25891441 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Inc. All rights reserved.

Chemical References

• Cholinesterase Inhibitors
• Ethylenediamines
• RhodZin-3
• Xanthenes
• Cytochromes c
• Phosphopyruvate Hydratase
• Zinc
• N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine
• Oxygen

Topics

• Analysis of Variance
• Animals
• Brain (drug effects, ultrastructure)
• Cholinesterase Inhibitors (therapeutic use)
• Cytochromes c (metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Ethylenediamines (therapeutic use)
• Functional Laterality
• Infarction, Middle Cerebral Artery (metabolism, pathology, therapy)
• Male
• Membrane Potential, Mitochondrial (physiology)
• Mitochondria (drug effects, metabolism)
• Oxygen (therapeutic use)
• Phosphopyruvate Hydratase (metabolism)
• Rats
• Rats, Sprague-Dawley
• Xanthenes (metabolism)
• Zinc (metabolism)