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. Graphical Abstract. Overview and signaling pathway of the study. The graphical abstract illustrates the experimental design and findings of the study. Ischemic stroke was induced in SD rats using the tMCAO model. Behavioral assessments included grip strength, rotarod, adhesive tape removal, and neurological scoring to evaluate motor and sensory deficits. Following tMCAO, MCC950, an NLRP3 inflammasome inhibitor, was administered. Post-treatment molecular analyses revealed NLRP3 inflammasome inhibition, SIRT3 upregulation, reduced TUNEL + NSPCs, and decreased cell death. Neurogenesis was enhanced, as indicated by increased expression of SOX2 and Nestin, suggesting MCC950 has potential for mitigating inflammation, reducing cell death, and promoting neurogenesis in post-stroke recovery. • Transient middle cerebral artery occlusion in rats leads to increased levels of NLRP3 and while decreasing SIRT3, highlighting a regulatory connection. • NLRP3-driven inflammation hampers neurogenesis in subventricular zones (SVZ), which is indicated by the low Nestin and Sox2 positive NPSCs. • MCC950 treatment reduces inflammation and restores neurogenesis in ischemic brain regions. • Targeting the SIRT3-NLRP3 pathway with MCC950 may enhance neurogenesis and serve as a therapeutic strategy after ischemic stroke.

Topics & Concepts