Cordyceps Polysaccharides Attenuate Post-Ischemic Inflammatory Damage in a Rat Stroke Model with Associated Modulation of the mtDNA/NLRP3 Inflammasome-Related Pyroptosis Pathway

Background: Cordyceps polysaccharides (CSP) have shown neuroprotective potential in models of ischemic stroke, but the underlying mechanisms remain to be clarified. Methods: In this study, the effects of CSP were evaluated in MCAO rats and OGD-exposed BV-2 cells. Results: CSP significantly attenuated ischemic injury and inflammatory responses in both in vivo and in vitro models. Mechanistically, CSP decreased CMPK2 expression, increased TFAM levels, and reduced 8-OHdG expression, suggesting attenuation of oxidative DNA damage and mitochondrial DNA-associated stress. EdU staining further showed that OGD-induced DNA synthesis-related signals were predominantly extranuclear, supporting the possibility of mtDNA-associated alterations under ischemia-like conditions. Moreover, CSP suppressed the upregulation of NLRP3, Caspase-1, N-GSDMD, IL-1β, and IL-18, and reduced LDH release following OGD exposure, suggesting inhibition of inflammasome-associated pyroptotic signaling. Conclusions: These findings suggest that the neuroprotective effects of CSP in ischemic stroke models may be related to the modulation of CMPK2/mtDNA/NLRP3 inflammasome pathway and reduced pyroptosis.