Chronic ethanol consumption dose-dependently affects both incidence and prognosis of ischemic stroke. Our goal was to determine whether the influence of chronic ethanol consumption on ischemic stroke is related to an altered inflammatory profile in the brain. Male C57BL/6J mice were divided into six groups and gavage fed with 0.175, 0.35, 0.7, 1.4, 2.8 g/kg/day ethanol or volume-matched water once a day for 8 weeks. Adhesion molecules, microglial activation, neutrophil infiltration, pro- and anti-inflammatory cytokines/chemokines, blood-brain barrier (BBB) permeability, and matrix metallopeptidases (MMPs) in the cerebral cortex before and following a 90-min unilateral middle cerebral artery occlusion (MCAO)/24-h reperfusion were evaluated. Brain ischemia/reperfusion (I/R) injury was significantly reduced in 0.7 g/kg/day ethanol group (peak blood ethanol concentration: 9 mM) and worsened in 2.8 g/kg/day ethanol group (peak blood ethanol concentration: 37 mM). Baseline E-selectin was downregulated in all ethanol groups, whereas baseline intercellular adhesion molecule-1 (ICAM-1) was only downregulated in 0.35 and 0.7 g/kg/day ethanol groups. Interestingly, baseline vascular cell adhesion molecule-1 (VCAM-1) was upregulated in 0.35, 0.7, and 1.4 g/kg/day ethanol groups. Post-ischemic upregulation of ICAM-1 and E-selectin were suppressed in all ethanol groups. Post-ischemic neutrophil infiltration and microglial activation were significantly less in the low-moderate (0.175–1.4 g/kg/day) ethanol groups but greater in the 2.8 g/kg/day ethanol group compared to the vehicle group. At basal conditions, ethanol increased one pro- and two anti-inflammatory cytokines/chemokines at the 0.7 g/kg/day dose, and 13 pro- and eight anti-inflammatory cytokines/chemokines at the 2.8 g/kg/day dose. After ischemia, 0.7 g/kg/day ethanol suppressed post-ischemic pro-inflammatory cytokines/chemokines and enhanced post-ischemic anti-inflammatory cytokines/chemokines. Moreover, 0.7 g/kg/day ethanol significantly reduced baseline MMP-9 activity and alleviated post-ischemic BBB breakdown. On the other hand, 2.8 g/kg/day ethanol worsened post-ischemic BBB breakdown. Our findings suggest that low-moderate ethanol consumption may prevent ischemic stroke and reduce brain I/R injury by suppressing inflammation, whereas heavy alcohol consumption may induce ischemic stroke and worsen brain I/R injury by aggravating inflammation.

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BackgroundInflammation and apoptosis are two key elements involved in cerebral ischemia/reperfusion (I/R) injury. Ethanol is one of the most commonly and regularly used chemical substances. We determined the influences of chronic ethanol consumption on inflammation and apoptosis following transient focal cerebral ischemia.MethodsMale C57/BL6J mice were divided into 6 groups and gavage fed with 0.175, 0.35, 0.7, 1.4, 2.8 g/kg/d ethanol or volume‐matched water once a day for eight weeks. Cerebral I/R injury, adhesion molecules, microglial activation, neutrophil infiltration, pro‐ and anti‐inflammatory cytokines/chemokines, MMPs, cleaved caspase‐3‐positive neurons, and TUNEL‐positive neurons were evaluated at 24 hours after a 90‐minute unilateral middle cerebral artery occlusion (MCAO).ResultsCerebral I/R injury was only significantly reduced in 0.7 g/kg/d ethanol group (peak blood ethanol concentration: 9 mM) and increased in 2.8 g/kg/d ethanol group (peak blood ethanol concentration: 37 mM). Baseline and post‐ischemic upregulation of ICAM‐1 and E‐selectin were suppressed in all ethanol groups. Post‐ischemic microglial activation and neutrophil infiltration were significantly alleviated in 0.175–1.4 g/kg/d ethanol groups but dramatically exacerbated in 2.8 g/kg/d ethanol group. Ethanol tends to dose‐dependently increase both baseline pro‐ and anti‐inflammatory cytokines/chemokines, but dose‐dependently suppressed post‐ischemic increase in pro‐inflammatory cytokines/chemokines. Surprisingly, 2.8 g/kg/d ethanol strengthened post‐ischemic increase in anti‐inflammatory cytokines/chemokines. Furthermore, although baseline MMP‐9 activity was reduced in 0.7 g/kg/d ethanol group, the magnitude of post‐ischemic increase in MMP‐9 activity was significantly less in 2.8 g/kg/d ethanol group. Both cleaved caspase‐3‐positive neurons and TUNEL‐positive neurons were significantly less in 0.7 g/kg/d ethanol group.ConclusionsLight alcohol consumption protects against cerebral I/R injury by suppressing post‐ischemic inflammation and apoptosis, whereas heavy alcohol consumption may exacerbate cerebral I/R injury via an inflammation‐ and apoptosis‐independent mechanism.Support or Funding InformationThis study was supported by a National Institutes of Health Grant (AA023610) and funds from Louisiana State University Health Sciences Center‐Shreveport to HS, a postdoctoral fellowship to CL and a predoctoral fellowship to KDM from the Center for Cardiovascular Diseases and Sciences, Louisiana State University Health Science Center‐Shreveport.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.