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

Chun Li,Sumitra Miriyala,Hong Sun,Manikandan Panchatcharam,Ethyn G Loreno,Jiyu Li,Xiaohong Lu

doi:10.3390/ijms22105121

Abstract

Ischemic stroke is one of the leading causes of death and permanent disability in adults. Recently, we found that light alcohol consumption (LAC) suppresses post-ischemic inflammatory response, which plays an important role in ischemic brain damage. Our goal was to determine the role of peroxisome proliferator-activated receptor-gamma (PPARγ) in the anti-inflammatory effect of LAC against transient focal cerebral ischemia. In in vivo study, male C57BL/6J wild type (WT) and endothelial-specific conditional PPARγ knockout mice were gavage fed with 0.7 g/kg/day ethanol or volume-matched water daily for 8 weeks. From the 7th week, 3 mg/kg/day GW9662 (a selective PPARγ antagonist) was intraperitoneally given for two weeks. Cerebral ischemia/reperfusion (I/R) injury and expression of manganese superoxide dismutase (MnSOD) and adhesion molecules, neutrophil infiltration, and microglial activation in the cerebral cortex before and following a 90 min unilateral middle cerebral artery occlusion (MCAO)/24 h reperfusion were evaluated. In in vitro study, the impact of chronic alcohol exposure on expression of PPARγ and MnSOD in C57BL/6J mouse brain microvascular endothelial cells (MBMVECs) was measured. PPARγ and MnSOD were significantly upregulated in the cerebral cortex of ethanol-fed WT mice and low-concentration ethanol-exposed C57BL/6J MBMVECs. GW9662 significantly inhibited alcohol-induced upregulation of MnSOD. Eight-week ethanol feeding significantly reduced cerebral I/R injury and alleviated the post-ischemic inflammatory response (upregulation of intercellular adhesion molecule-1 (ICAM-1) and E-selectin, microglial activation, and neutrophil infiltration). Treatment with GW9662 and endothelial-specific conditional knockout of PPARγ did not alter cerebral I/R injury and the inflammatory response in the control mice but abolish the neuroprotective effect in ethanol-fed mice. In addition, GW9662 and endothelial-specific conditional knockout of PPARγ diminished the inhibitory effect of LAC on the post-ischemic expression of adhesion molecules and neutrophil infiltration. Our findings suggest that LAC may protect against cerebral I/R injury by suppressing the post-ischemic inflammation via activation of PPARγ.

Highlights

One of the leading causes of permanent disability and mortality in adults is ischemic stroke, which occurs when an artery supplying blood to the brain gets obstructed [1,2]
Eight weeks of daily feeding with 0.7 g/kg/day ethanol, two weeks of daily treatment with 3 mg/kg/day GW9662, and 3 weeks of daily treatment with 0.5 mg/kg/day tamoxifen did not significantly change body weight, mean arterial blood pressure (MABP), heart rate, and fasting glucose level when compared to the water group (Table 1)
Eight-week feeding with 0.7 g/kg/day significantly increased protein expression of manganese superoxide dismutase (MnSOD) and nuclear protein expression/DNA-binding activity of PPARγ in the cerebral cortex

Summary

Introduction

One of the leading causes of permanent disability and mortality in adults is ischemic stroke, which occurs when an artery supplying blood to the brain gets obstructed [1,2]. The post-ischemic inflammatory response is a double-edged sword. It produces secondary brain injury in the acute stage of stroke [6]. The initial post-ischemic inflammatory response is characterized by upregulation of adhesion molecules on brain microvascular endothelial cells, inflammatory activation of microglia, recruitment of leukocytes, and accumulation of cytokines and chemokines in the ischemic area. The activation of microglia and recruitment of leukocytes appear to be central features after transient focal cerebral ischemia [7,8]. The recruitment of leukocytes into the ischemic area is facilitated by the upregulation of adhesion molecules on endothelial cells prior to and during reperfusion [11]. The recruitment of leukocytes is associated with inflammatory activation of microglia and subsequent production of inflammatory mediators

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