MCC950 mitigates SIRT3-NLRP3-driven inflammation and rescues post-stroke neurogenesis

Abstract

Sustained activation of the SIRT3-NLRP3 inflammasome has been associated with worse outcomes after ischemic stroke. The objective of this study was to examine the potential mechanism by which the SIRT3-NLRP3 inflammasome affects neural stem and progenitor cells (NSPCs) after transient middle cerebral artery occlusion (tMCAO) in rats. Following tMCAO, significantly elevated levels of NLRP3, ASC, cleaved caspase 1, IL-1β, and IL-18 were observed in the ischemic subventricular zone. Moreover, tMCAO increased NLRP3 expression while decreasing SIRT3 levels, suggesting a connection between these two processes. Furthermore, we discovered that inflammation induced by the NLRP3 inflammasome impaired post-stroke hippocampal and subventricular neurogenesis, while nestin (a marker for NSPCs) and Sox2 (a marker for stem cell pluripotency) were downregulated after tMCAO. However, systemic administration of MCC950 reduced inflammatory signaling and effectively restored neurogenesis. Overall, our results suggest that protecting NSPCs and neurogenesis in the ischemically damaged brain by mitigating the impact of the SIRT3-NLRP3 inflammasome may be a feasible treatment strategy for ischemic stroke.

Keywords: Ischemic stroke; NLRP3 inflammasome; Neural stem and progenitor cells; Neurogenesis; SIRT3; Subventricular zone; Transient middle cerebral artery occlusion.