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. 2019 Feb 12:13:6.
doi: 10.3389/fncel.2019.00006. eCollection 2019.

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

Guodong Xu  1   2 , Chun Li  1 , Anne L Parsiola  1 , Jiyu Li  1 , Kimberly D McCarter  1 , Runhua Shi  3 , William G Mayhan  4 , Hong Sun  1
Affiliations

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

Guodong Xu et al. Front Cell Neurosci. .

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.

Keywords: adhesion molecule; cytokine/chemokine; ethanol; ischemic stroke; matrix metalloproteinase; microglia; neutrophil infiltration.

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Figures

Figure 1
Figure 1
Influence of ethanol on brain injury following a 90-min middle cerebral artery occlusion (MCAO)/24-h reperfusion. (A) Representative brain sections stained with 2,3,5-triphenyltetrazolium chloride (TTC). (B) Total infarct volume (n = 6). (C) Neurological score (n = 15). Values are means ± SE. *P < 0.05 vs. Vehicle.
Figure 2
Figure 2
Dynamic change of plasma ethanol concentration in the 0.7 g/kg/day (A) and 2.8 g/kg/day (B) ethanol groups at the beginning and end of an 8-week feeding period. Values are means ± SE for four mice in each group. *P < 0.05 vs. Beginning of 8-week.
Figure 3
Figure 3
Influence of ethanol on expression of intercellular adhesion molecule-1 (ICAM-1; A), vascular cell adhesion molecule-1 (VCAM-1; B), E-selectin (C) and P-selectin (D) following a 90-min MCAO/24-h reperfusion. Values are means ± SE for five mice in each group. Data shown are representative blots for each group. Ischemic side and contralateral side were run on separate gels with two samples from the vehicle group as internal control. **P < 0.05 vs. Vehicle without ischemia/reperfusion (I/R). *P < 0.05 vs. Without I/R. #P < 0.05 vs. Vehicle with I/R.
Figure 4
Figure 4
Influence of ethanol on microglial activation following a 90-min MCAO/24-h reperfusion. (A) Representative lba1 staining. (B) Values are mean ± SE for five mice in each group. *P < 0.05 vs. Vehicle.
Figure 5
Figure 5
Influence of ethanol on neutrophil infiltration following a 90-min MCAO/24-h reperfusion. (A) Representative MPO staining. (B) Values are mean ± SE for five mice in each group. *P < 0.05 vs. Vehicle.
Figure 6
Figure 6
Influence of ethanol on expression of interleukin-1β (IL-1β; A), IL-1ra (B), CCL-12 (C), IL-27 (D) and TIMP-1 (E) following a 90-min MCAO/24-h reperfusion. Values are means ± SE for four mice in each group. **P < 0.05 vs. Vehicle without I/R. *P < 0.05 vs. Without I/R. #P < 0.05 vs. Vehicle with I/R.
Figure 7
Figure 7
Influence of ethanol on blood-brain barrier (BBB) permeability following a 90-min MCAO/24-h reperfusion. (A) Representative IgG staining. (B) Values are means ± SE for five mice in each group. (C) Values are means ± SE for six mice in each group. (D) Representative gelatin zymography. (E) Values are means ± SE for five mice in each group. *P < 0.05 vs. Vehicle. **P < 0.05 vs. Vehicle without I/R. #P < 0.05 vs. Without I/R.
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