Resveratrol Alleviates Ischemia-Reperfusion-Induced Neuronal Damage by Inhibiting NR3C2-Mediated TRIM28 Expression.

Abstract

Background: Cerebral ischemia-reperfusion injury (CIRI) exacerbates neuronal damage through mechanisms including apoptosis and autophagy dysregulation. Resveratrol (Res), a natural polyphenol with neuroprotective properties, may alleviate CIRI-induced damage by modulating key signaling pathways. This study investigates the therapeutic effects of Res on CIRI, focusing on its role in balancing apoptosis and autophagy via regulation of nuclear receptor subfamily 3 group C member 2 (NR3C2) and tripartite motif containing 28 (TRIM28).

Method: In vivo, cognitive impairment, neurological dysfunction, cerebral infarction, neuronal damage, and inflammatory response were assessed in Sprague Dawley (SD) rats subjected to middle cerebral artery occlusion/reperfusion (MCAO/R) using the morris water maze, Longa and Bederson scores, 2,3,5-tripheny ltetrazolium chloride (TTC) staining, hematoxylin and eosin staining, Nissl staining, and enzyme-linked immunosorbent assay (ELISA). The expression of NR3C2 and TRIM28 were analyzed by real time quantitative polymerase chain reaction (RT-qPCR) and western blot (WB). In vitro, Res effects on oxygen-glucose deprivation/reperfusion (OGD/R)-treated PC12 cells were evaluated using cell counting kit-8 (CCK-8), ELISA, terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) staining, and WB. The relationship between NR3C2 and TRIM28 was validated using dual luciferase and chromatin immunoprecipitation followed by quantitative polymerase chain reaction (ChIP-qPCR).

Result: Res treatment significantly improved cognitive performance in the morris water maze test, and the infarct area was reduced by 16.736%. It was accompanied by downregulation of NR3C2 and TRIM28 expression. In vitro, Res enhanced cell viability, reduced inflammatory responses and apoptosis (with a 17.70% decrease in cell apoptosis rate), and restored autophagy balance. Mechanistically, NR3C2 was shown to directly regulate TRIM28 transcription, mediating the observed neuroprotective effects.

Conclusion: Res inhibits NR3C2 expression, which in turn directly regulates the transcription of TRIM28 through NR3C2, alleviating apoptosis and autophagy dysregulation induced by CIRI. This mechanism clearly demonstrates the important role of NR3C2 in CIRI and reveals its regulatory relationship with TRIM28. By uncovering the neuroprotective effects of Res, we provide new insights for the treatment of CIRI and lay the foundation for future targeted therapeutic strategies involving NR3C2 and TRIM28.