Danshensu sodium attenuates pyroptosis in ischemic stroke by targeting the HMGB1/RAGE axis and downstream NLRP3/GSDMD/ASC/Caspase-1 pathway.

BACKGROUND

Danshensu Sodium (DSS-S), the sodium salt of a principal water-soluble active compound from Salvia miltiorrhiza, was investigated for its effects on cerebral ischemic-reperfusion (I/R) injury and the underlying molecular mechanisms.

METHODS

Neuroprotection by DSS-S was evaluated in vivo using a transient middle cerebral artery occlusion (tMCAO) model in male C57BL/6J mice and in vitro using an oxygen-glucose deprivation/reperfusion (OGD/R) model in Neuro-2a mouse neuroblastoma cells.

RESULTS

High-mobility group box 1 (HMGB1) was identified as a key target of DSS-S. Following I/R or OGD/R, levels of IL-1β, IL-6, TNF-α, IL-18, and HMGB1 were significantly elevated in both mouse serum and cell culture supernatant, and these increases were substantially attenuated by DSS-S treatment. DSS-S reduced cytoplasmic HMGB1 accumulation, promoted its nuclear retention, down-regulated the receptor for advanced glycation end-products (RAGE), and weakened the HMGB1-RAGE interaction. Pyroptosis was activated in both tMCAO and OGD/R models, and DSS-S intervention effectively inhibited pyroptosis by suppressing the HMGB1/RAGE signaling pathway and NLRP3 inflammasome activation.

CONCLUSION

DSS-S exerts neuroprotective effects against cerebral I/R injury in vivo and reduces OGD/R-induced injury in vitro. The protection is mediated through inhibition of pyroptosis, achieved by targeting the HMGB1/RAGE axis and suppressing NLRP3 inflammasome activation.