Dose-Dependent Influences of Ethanol on Ischemic Stroke: Role of Inflammation

Abstract

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.

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

“…Epidemiological studies have found that heavy ethanol consumption increases the morbidity of ischemic stroke and worsens the prognosis of ischemic stroke, whereas mild-moderate ethanol consumption may reduce the morbidity of ischemic stroke and decrease infarct volume and mortality from ischemic stroke [11][12][13][14][15][16] . Consistently, we recently found that ethanol consumption dose-dependently alters cerebral I/R injury in rodents 17 . Increasing evidence indicates that chronic ethanol consumption alters apoptosis and autophagy in many tissues and organs, such as liver, pancreas, heart, and brain [18][19][20][21][22] .…”

“…The control group was gavage fed with 10 ml/kg water. At the end of 8 weeks of feeding, blood pressure, heart rate, and fasting blood glucose were measured similarly as described previously 17 . Blood pressure and heart rate were measured using a CODA mouse tail-cuff system (Kent Scientific, Torrington, CT, USA).…”

“…Transient focal cerebral ischemia. All mice were subjected to transient focal cerebral ischemia, which was induced by unilateral MCAO for 90 minutes as described previously 17 . To avoid a possible effect of acute ethanol, ethanol was not given on the day before the experiment.…”

“…Animals were allowed to recover for 24 hours. A 24-point scoring system was used to evaluate sensorimotor deficits as described previously 17 . Six tests (spontaneous activity, symmetry of movement, floor walking, beam walking, symmetry of forelimbs, and climbing wall of wire cage) for motor function and two tests (response to vibrissae touch and reaction to touch on either side of trunk) for sensory function were graded on a scale of 0 to 3 each.…”

Ischemic stroke with a preceding Trans ischemic attack(TIA) less than 24 hours and thrombolytic therapy

“…The identified comorbidities associated with exclusion from thrombolytic therapy are comparable to existing prospective and retrospective studies, such as increasing age associated with worse outcomes [32], female gender corresponding with significantly higher percentages of cardioembolic strokes [33], and severe carotid artery stenosis, which predicts poor outcome [34]. Other identified comorbidities reported in previous studies are diabetes; due to hyperglycemia, which increases the risk of cerebral hemorrhage with rtPA treatment [35], and chronic alcohol use; which increases excitotoxic/ischemic damage, leading to poor outcomes [36].…”