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Influence of Chronic Ethanol Consumption on Apoptosis and Autophagy Following Transient Focal Cerebral Ischemia in Male Mice.

ABSTRACT: Stroke remains one of the leading causes of permanent disability and death worldwide. Apoptosis and autophagy are two key elements involved in ischemic brain damage. Ethanol is a commonly used and abused chemical substance that affects the prognosis of ischemic stroke. We determined the influence of chronic ethanol consumption on apoptosis and autophagy following transient focal cerebral ischemia. Male C57BL/6?J mice were randomly divided into three groups and gavage fed with 0.7 and 2.8?g/kg/day ethanol or volume-matched water daily for 8 weeks. DNA fragmentation, TUNEL-positive neurons, cleaved caspase-3-positive neurons, translocation of mitochondrial cytochrome C and apoptosis inducing factor (AIF), LC3B-positive neurons, and expression of LC3B, Beclin-1 and Bcl-2 in peri-infarct cortex were evaluated at 24?hours of reperfusion after a 90-minute unilateral middle cerebral artery occlusion (MCAO). Cerebral ischemia/reperfusion (I/R) injury was significantly improved in the 0.7?g/kg/d ethanol group but worsened in the 2.8?g/kg/d ethanol group. DNA fragmentation was significantly increased at 24?hours of reperfusion in all groups. However, the magnitude of the increase was significantly less in the 0.7?g/kg/d ethanol group. In addition, both cleaved caspase-3-positive neurons and TUNEL-positive neurons were significantly less in 0.7?g/kg/d ethanol group. Furthermore, translocation of mitochondrial cytochrome C and AIF was significantly alleviated in the 0.7?g/kg/d ethanol group. On the other hand, baseline expression of LC3B was significantly reduced in the 2.8?g/kg/d ethanol group. Post-ischemic expression of LC3B and LC3B-positive neurons were significantly attenuated in both 0.7 and 2.8?g/kg/d ethanol groups. Moreover, although post-ischemic expression of Beclin-1 was not altered in the ethanol groups, post-ischemic expression of Bcl-2 was significantly greater in both 0.7 and 2.8?g/kg/d ethanol groups. Our findings suggest that light ethanol consumption may protect against cerebral I/R injury by suppressing post-ischemic apoptosis, whereas heavy ethanol consumption may exacerbate cerebral I/R injury by suppressing autophagy.

SUBMITTER: Li C

PROVIDER: S-EPMC7145844 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Influence of Chronic Ethanol Consumption on Apoptosis and Autophagy Following Transient Focal Cerebral Ischemia in Male Mice.

Li Chun C Li Jiyu J Xu Guodong G Sun Hong H

Scientific reports 20200409 1

Stroke remains one of the leading causes of permanent disability and death worldwide. Apoptosis and autophagy are two key elements involved in ischemic brain damage. Ethanol is a commonly used and abused chemical substance that affects the prognosis of ischemic stroke. We determined the influence of chronic ethanol consumption on apoptosis and autophagy following transient focal cerebral ischemia. Male C57BL/6 J mice were randomly divided into three groups and gavage fed with 0.7 and 2.8 g/kg/da ...[more]

PMID: 32273547

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Project description:One of the major players in the pathophysiology of cerebral ischemia is disrupted homeostasis of glutamatergic neurotransmission, resulting in elevated extracellular glutamate (Glu) concentrations and excitotoxicity-related cell death. In the brain, Glu concentrations are regulated by Glu transporters, including Glu transporter-1 (GLT-1) and cystine/Glu antiporter (system xc-). Modulation of these transporters by administration of ceftriaxone (CEF, 200 mg/kg, i.p.) or N-acetylcysteine (NAC, 150 mg/kg, i.p.) for 5 days before focal cerebral ischemia may induce brain tolerance to ischemia by significantly limiting stroke-related damage and normalizing Glu concentrations. In the present study, focal cerebral ischemia was induced by 90-minute middle cerebral artery occlusion (MCAO). We compared the effects of CEF and NAC pretreatment on Glu concentrations in extracellular fluid and cellular-specific expression of GLT-1 and xCT with the effects of two reference preconditioning methods, namely, ischemic preconditioning and chemical preconditioning in rats. Both CEF and NAC significantly reduced Glu levels in the frontal cortex and hippocampus during focal cerebral ischemia, and this decrease was comparable with the Glu level achieved with the reference preconditioning strategies. The results of immunofluorescence staining of GLT-1 and xCT on astrocytes, neurons and microglia accounted for the observed changes in extracellular Glu levels to a certain extent. Briefly, after MCAO, the expression of GLT-1 on astrocytes decreased, but pretreatment with CEF seemed to prevent this downregulation. In addition, every intervention used in this study seemed to reduce xCT expression on astrocytes and neurons. The results of this study indicate that modulation of Glu transporter expression may restore Glu homeostasis. Moreover, our results suggest that CEF and NAC may induce brain tolerance to ischemia by influencing GLT-1 and system xc- expression levels. These transporters are presumably good targets for the development of novel therapies for brain ischemia.

Dataset Information

Influence of Chronic Ethanol Consumption on Apoptosis and Autophagy Following Transient Focal Cerebral Ischemia in Male Mice.

Publications

Influence of Chronic Ethanol Consumption on Apoptosis and Autophagy Following Transient Focal Cerebral Ischemia in Male Mice.

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