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

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 p...

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Autores principales: Li, Chun, Li, Jiyu, Loreno, Ethyn G., Miriyala, Sumitra, Panchatcharam, Manikandan, Lu, Xiaohong, Sun, Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150922/
https://www.ncbi.nlm.nih.gov/pubmed/34066125
http://dx.doi.org/10.3390/ijms22105121
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author Li, Chun
Li, Jiyu
Loreno, Ethyn G.
Miriyala, Sumitra
Panchatcharam, Manikandan
Lu, Xiaohong
Sun, Hong
author_facet Li, Chun
Li, Jiyu
Loreno, Ethyn G.
Miriyala, Sumitra
Panchatcharam, Manikandan
Lu, Xiaohong
Sun, Hong
author_sort Li, Chun
collection PubMed
description 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.
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spelling pubmed-81509222021-05-27 Chronic Low-Dose Alcohol Consumption Attenuates Post-Ischemic Inflammation via PPARγ in Mice Li, Chun Li, Jiyu Loreno, Ethyn G. Miriyala, Sumitra Panchatcharam, Manikandan Lu, Xiaohong Sun, Hong Int J Mol Sci Article 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. MDPI 2021-05-12 /pmc/articles/PMC8150922/ /pubmed/34066125 http://dx.doi.org/10.3390/ijms22105121 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Li, Chun
Li, Jiyu
Loreno, Ethyn G.
Miriyala, Sumitra
Panchatcharam, Manikandan
Lu, Xiaohong
Sun, Hong
Chronic Low-Dose Alcohol Consumption Attenuates Post-Ischemic Inflammation via PPARγ in Mice
title Chronic Low-Dose Alcohol Consumption Attenuates Post-Ischemic Inflammation via PPARγ in Mice
title_full Chronic Low-Dose Alcohol Consumption Attenuates Post-Ischemic Inflammation via PPARγ in Mice
title_fullStr Chronic Low-Dose Alcohol Consumption Attenuates Post-Ischemic Inflammation via PPARγ in Mice
title_full_unstemmed Chronic Low-Dose Alcohol Consumption Attenuates Post-Ischemic Inflammation via PPARγ in Mice
title_short Chronic Low-Dose Alcohol Consumption Attenuates Post-Ischemic Inflammation via PPARγ in Mice
title_sort chronic low-dose alcohol consumption attenuates post-ischemic inflammation via pparγ in mice
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150922/
https://www.ncbi.nlm.nih.gov/pubmed/34066125
http://dx.doi.org/10.3390/ijms22105121
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