Ellagitannin Component Punicalin Ameliorates Cognitive Dysfunction, Oxidative Stress, and Neuroinflammation via the Inhibition of cGAS‐STING Signaling in the Brain of an Aging Mouse Model

ABSTRACT Despite remarkable breakthroughs in pharmacotherapy, many potential therapies for aging remain unexplored. Punicalin (PUN), an ellagitannin component, exerts anti‐inflammatory, antioxidant, and anti‐apoptotic effects. This study investigated the beneficial effects of PUN against age‐related brain damage in mice and explored the underlying mechanisms. We validated the protective effects of PUN against D‐galactose (D‐gal)‐induced neuroinflammation and subsequent neuronal damage in BV2 microglia and N2a cells, respectively, in vitro. In vivo experiments were conducted on mice that were administered an 8‐week regimen of intraperitoneal injections of D‐gal at a dosage of 150 mg/kg/day, concurrently with oral gavage of PUN at the same dose. PUN inhibited the production of D‐gal‐induced inflammatory cytokines ( iNOS , COX2, TNF‐α, IL‐6, IL‐2, and IL‐1β) in BV2 cells and conferred protection to N2a cells against synaptic damage mediated by BV2 microglia‐induced neuroinflammation. The in vivo findings revealed that PUN considerably improved memory and learning deficits, reduced MDA levels, enhanced GSH‐Px, CAT, and SOD activities, and modulated the expression of inflammatory proteins such as iNOS , COX‐2, IL‐1β, IL‐2, IL‐6, and TNF‐α. Furthermore, PUN inhibited the secretion of SASP factors (ICAM‐1, PAI‐1, MMP‐3, and MMP‐9), decreased microglial activation, and reduced astrocytosis. Additionally, PUN suppressed the expression of cGAS, p‐STING, p‐TBK1, p‐p65, and p‐IRF3 in aging mouse brains and cultured BV2 microglia. In conclusion, PUN improved cognitive dysfunction in aging mice through antioxidant and anti‐inflammatory mechanisms via inhibition of the cGAS‐STING pathway, suggesting that it can be a promising therapeutic agent for brain aging and aging‐related diseases.