Cordyceps Polysaccharides Attenuate Experimental Ischemic Stroke Injury: Association with IL-17/NF-κB Signaling

Cordyceps polysaccharides (CSP) have shown protective potential in ischemic stroke, but their central inflammatory mechanisms remain unclear. This study examined whether the effects of CSP are associated with interleukin-17 (IL-17)/nuclear factor kappa B (NF-κB)-related signaling. Publicly available human transcriptomic datasets were integrated and analyzed to identify inflammation-related pathways in ischemic stroke, and a public mouse middle cerebral artery occlusion (MCAO) single-cell RNA sequencing (RNA-seq) dataset was analyzed to identify relevant brain cell populations. IL-17 receptor A (IL-17RA) knockdown was performed in oxygen–glucose deprivation (OGD)-exposed SH-SY5Y cells. The effects of CSP were further evaluated in MCAO rats and OGD-exposed BV-2 cells. Bioinformatics analyses showed enrichment of IL-17 and NF-κB signaling in ischemic stroke datasets, and single-cell module-score analysis showed that microglia exhibited the largest MCAO-associated increase in IL-17/NF-κB-related module scores. IL-17RA knockdown improved the viability of OGD-exposed SH-SY5Y cells. In MCAO rats, CSP improved neurological and behavioral outcomes, increased cerebral blood flow, and reduced cerebral edema, infarct volume, neuronal loss, microglial responses, and IL-17A/IL-17RA expression. In OGD-exposed BV-2 cells, CSP reduced IL-17A, IL-17RA, NF-κB activator 1 (ACT1), tumor necrosis factor receptor-associated factor 6 (TRAF6), IL-1β, IL-6, and the phosphorylated p65/total p65 ratio. These findings suggest that the protective effects of CSP in ischemic stroke models are associated with attenuation of IL-17/NF-κB-related neuroinflammation.