Lycorine ameliorates astrocytic apoptosis and inflammation in cerebral ischemia/reperfusion injury via inhibiting mitochondrial dysfunction via SIRT1-mediated SIRT3/PRDX3 activation

Abstract

Lycorine (LYC) exerts anti-inflammation, antioxidation, and anti-apoptosis effects on many diseases. However, its impact on cerebral ischemia/reperfusion injury (CI/RI) has not been comprehensively examined yet. Using a murine model of middle cerebral artery occlusion/reperfusion (MCAO/R), we found that LYC administration significantly reduced neurological deficits, cerebral infarction, and cerebral edema, and provided long-term benefits in MCAO/R mice. In vitro studies using oxygen-glucose deprivation/reoxygenation (OGD/R)-induced primary astrocytes demonstrated that LYC enhanced cell viability while simultaneously reducing inflammation and apoptosis. Besides, LYC also alleviated OGD/R-induced mitochondrial dysfunction. Further analysis revealed that LYC enhanced SIRT3-mediated deacetylation of peroxiredoxin 3 (PRDX3), which is crucial for mitochondrial protection. SIRT3 inhibition with 3-TYP or shRNA significantly hindered PRDX3 deacetylation and abated the beneficial effects of LYC on OGD/R-induced astrocytes. Intriguingly, LYC increased SIRT1 expression and activity. Furthermore, the promoting effects of LYC on the deacetylation of PRDX3 mediated by SIRT3, as well as its protective capabilities against OGD/R-induced mitochondrial dysfunction, apoptosis, and inflammation in astrocytes, were abrogated by SIRT1 inhibition with EX527. These results indicate that LYC safeguards against CI/RI-induced apoptosis and inflammation in astrocytes by enhancing mitochondrial function via the SIRT1/SIRT3/PRDX3 pathway.