GW0742 activates miR-17-5p and inhibits TXNIP/NLRP3-mediated inflammation after hypoxic-ischaemic injury in rats and in PC12 cells.

Abstract

This study aimed to investigate the effects of PPAR-β/δ receptor agonist GW0742 on neuroinflammation in a rat model of hypoxia-ischaemia (HI) and in PC12 cells in OGD model. HI was induced by ligating the common carotid artery and inducing hypoxia for 150 minutes. Immunofluorescence was used for quantification of microglia activation and for determining cellular localization of PPAR-β/δ. Expression of proteins was measured by Western blot. Activation of miR-17-5p by GW0742 was assessed in PC12 cells by Dual-Luciferase Reporter Gene Assay. The endogenous expression of TXNIP, NLRP3, cleaved caspase-1 and IL-1β was increased after HI. GW0742 treatment significantly reduced the number of activated pro-inflammatory microglia in ipsilateral hemisphere after HI. Mechanistically, GW0742 significantly decreased the expression of TXNIP, NLRP3, IL-6 and TNF-α. Either PPAR-β/δ antagonist GSK3787, miR-17-5p inhibitor, or TXNIP CRISPR activation abolished the anti-inflammatory effects of GW0742. Activation of PPAR-β/δ by GW0742 activated miR-17-5p expression in PC12 cells and increased cell viability after OGD, which was accompanied by decreased expression of TXNIP and reduced secretion of IL-1β and TNF-α. In conclusion, GW0742 may be a promising neurotherapeutic for the management of HI patients.

• Authors: Marcin Gamdzyk, Desislava Met Doycheva, Ruiqing Kang, Hong Tang, Zackary D Travis, Jiping Tang, John H Zhang
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 24 Issue 21 Pg. 12318-12330 (11 2020) ISSN: 1582-4934 [Electronic] England
• PMID: 33034416 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.

Chemical References

• Blood Glucose
• Cell Cycle Proteins
• Inflammasomes
• MIRN17 microRNA, rat
• MicroRNAs
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, rat
• TXNIP protein, rat
• Thiazoles
• (4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid
• Glucose
• Oxygen

Topics

• Animals
• Blood Glucose (metabolism)
• Cell Cycle Proteins (metabolism)
• Cell Survival
• Female
• Glucose (metabolism)
• Hypoxia (metabolism)
• Inflammasomes
• Inflammation (metabolism)
• Ischemia (metabolism)
• Male
• MicroRNAs (metabolism)
• Microscopy, Fluorescence
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Oxygen (metabolism)
• PC12 Cells
• Rats
• Rats, Sprague-Dawley
• Thiazoles (pharmacology)