Aqueous Extract of Saposhnikoviae Radix Antagonizes Arsenic Neurotoxicity via the NLRP3/Caspase-1/GSDMD Pyroptotic Axis: Translating Environmental Exposure into Neuropathology and Herbal Recalibration.

Chronic arsenic exposure causes neurological damage, but the underlying mechanisms remain incompletely understood. This study investigated whether Saposhnikoviae Radix (SR) aqueous extract protects against arsenic-induced neurotoxicity by modulating pyroptosis. Kunming mice were exposed to NaAsO2 (10 mg/kg) with or without SR (3, 6, 12 g/kg). NaAsO2 exposure induced anxiety-like behaviors and spatial memory deficits, accompanied by widespread neuronal damage (hippocampal pyramidal cell disarray, cerebellar Purkinje cell loss, and cortical vacuolation) and upregulation of pyroptosis-related proteins (NLRP3, Cleaved-Caspase-1, GSDMD-N, IL-1β, IL-18) in brain tissues. SR treatment significantly ameliorated these behavioral and pathological changes. In HT22 cells, NaAsO2 (12.5 μM) reduced cell viability, increased LDH release, induced pyroptotic ultrastructural features (membrane blebbing and pore formation), and upregulated pyroptosis markers; SR (400 μg/mL) effectively reversed these effects. Mechanistically, SR suppressed the NLRP3/Caspase-1/GSDMD axis activation, as confirmed by both protein and mRNA analyses. These findings demonstrate that SR aqueous extract attenuates arsenic-induced central nervous system injury through specific inhibition of the pyroptosis pathway, providing an experimental basis for the potential use of traditional Chinese medicine in preventing environmental metalloid-induced neurotoxicity.