In a rotenone rat model of Parkinson's disease, oral empagliflozin improved motor behavior, preserved substantia nigra and striatal dopaminergic markers and dopamine levels, reduced α-synuclein aggregation and microglial activation, replenished glutathione, and suppressed…

Provides actionable preclinical evidence that an FDA‑approved SGLT2 inhibitor can target NLRP3-driven neuroinflammation and pyroptosis—supporting repurposing potential for disease-modifying PD therapy—while translation is limited by reliance on a single rotenone toxin model and absence of CNS…

The NLRP3 inflammasome is a crucial booster of pyroptosis and neuroinflammation in Parkinson's disease (PD). Although empagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, has shown neuroprotective ability, its impact on NLRP3 inflammasome stimulation in PD remains undefined. This study examined the neuroprotective properties of empagliflozin in the PD rat model induced by rotenone, with an emphasis on its modulation of NLRP3 inflammasome-mediated pyroptosis. PD was induced via daily subcutaneous administration of rotenone for 14 consecutive days. During this period, animals received daily oral empagliflozin treatment. Empagliflozin significantly improved motor performance, preserved the histoarchitecture of both substantia nigra and striatum, and restored tyrosine hydroxylase immunoreactivity and dopamine levels. It also reduced α-synuclein aggregation, suppressed microglial activation, and replenished glutathione content. Mechanistically, empagliflozin downregulated the NLRP3/caspase-1/IL-1β signaling cascade and reduced gasdermin D (GSDMD) expression, thereby inhibiting pyroptotic cell death. In conclusion, these findings highlight empagliflozin as a promising neuroprotective agent capable of mitigating rotenone-induced PD pathology by targeting NLRP3 inflammasome-mediated pyroptosis, supporting its prospective repurposing as a disease-modifying therapy for PD and related neurodegenerative disorders.