The prevalence of hyperuricemia (HUA) is climbing worldwide and persistent elevation of serum uric acid impairs cognitive function. This study aimed to explore the mechanisms of Artemisinin (Art) antagonizing cognitive disorder in HUA by suppressing pyroptosis. A mouse model of HUA was established by intraperitoneal injection of 300 mg/kg potassium oxonate (PO) in C57BL/6 mice for 14 days. The mice were simultaneously treated with Art, an agonist of pyroptosis Polyphyllin VI (PPVI), or glutamate receptor-interacting protein 1 (GRIP1) knockdown lentiviral plasmid. After treatment, serum uric acid, IL-6, and TNF-ɑ levels were examined, as well as hippocampal IL-1β and IL-18 levels, and the cognitive function of mice was assessed by the Morris water maze test. Pathological changes in the CA1 of the hippocampus were observed. Cleave-caspase-1, GSDMD-N, and GRIP1 protein level in the hippocampus was quantified by western blot. After PO induction, the escape latency and the time spent in the target quadrant increased in mice, cell arrangement in CA1 hippocampus was loose and disorganized, with obvious inflammatory infiltration and serious damage being observed, and the mouse hippocampus had elevated cleaved-caspase-1, GSDMD-N, IL-1β, and IL-18. Art treatment reduced pyroptosis in the hippocampus and improved cognitive disorder in HUA mice. Administration of PPVI aggravated cognitive disorder in Art-treated HUA mice, and Art improved cognitive dysfunction in HUA mice by inhibiting pyroptosis through upregulation of GRIP1. Art blunts pyroptosis in the hippocampus of HUA mice suffering from cognitive disorder by upregulating GRIP1.

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