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

Abstract

Background Inflammation 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. Methods Male 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). Results Cerebral 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. Conclusions Light 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 Information This 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.

Protective Role of Low Ethanol Administration Following Ischemic Stroke via Recovery of KCC2 and p75NTR Expression

“…Several recent studies show that in the adult, there are indications that ethanol could have positive effects particularly for the traumatized brain [3][4][5][6][7][8][9][10]50]. Some of the mechanisms proposed to mediate this positive effect of low concentrations of ethanol are to suppress apoptosis and inflammation.…”

“…Strikingly, these studies found a strong correlation between low intake and lower risk and severity of post-ischemic injury. Both effects in apoptosis and inflammation are proposed to be involved in the mechanism in rodents [9,10].…”

Chronic Low-Dose Alcohol Consumption Attenuates Post-Ischemic Inflammation via PPARγ in Mice

“…Our recent studies found that 8-week gavage feeding with 0.7 g/kg/day ethanol prior to the ischemia significantly decreased infarct size and neurological deficits in a mouse model of transient focal cerebral ischemia [ 21 , 22 ]. The peak blood alcohol concentration was about 9 mM [ 21 ].…”

“…To measure the infarct size, sections from eight levels (between 2.9 mm rostral and 4.9 mm caudal to bregma) were selected for Nissl staining as described previously [ 22 ]. The sections were incubated in 0.01% cresyl violet acetate (Sigma, St. Louis, MO, USA) solution for 14 min at 60 °C, rinsed in distilled water, dehydrated in ethanol, cleaned in xylene, and covered with xylene-a based mounting media (VWR).…”

“…It affects the incidence and prognosis of ischemic stroke [ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. Experimentally, we found that chronic alcohol consumption dose-dependently alters cerebral ischemia/reperfusion (I/R) injury in rodents [ 20 , 21 , 22 ]. Furthermore, the beneficial effect of low-dose alcohol consumption (LAC) may be related to an increased nuclear PPARγ expression/DNA-binding activation [ 23 ].…”