Parkinson's disease is an age-related neurodegenerative disorder characterized by the progressive degeneration of nigrostriatal dopaminergic neurons. Enavogliflozin, a novel sodium-glucose cotransporter 2 (SGLT2) inhibitor, has recently been demonstrated to exert neuroprotective effects. However, whether enavogliflozin can ameliorate motor behavioral deficits in Parkinson's disease currently remains unclear. To this end, this study aimed to investigate the neuroprotective effects of enavogliflozin on Parkinson's disease and explore its underlying molecular mechanisms. We established a Parkinson's disease model using rotenone-induced C57BL/6 mice (1.5 mg/kg/d, 3 weeks, i.p.) to investigate the neuropharmacological modulation effects of enavogliflozin treatment (0.1 and 1 mg/kg/d, 3 weeks, p.o., 2 h after rotenone injection) on Parkinson's disease from the perspectives of motor behavioral evaluation, pathological changes, oxidative stress, neuroinflammation, and SIRT1/PINK1/Parkin signaling pathways in specific brain regions. The results revealed that enavogliflozin alleviated neuropathological alterations of the substantia nigra, upregulated tyrosine hydroxylase and dopamine transporter expression in nigrostriatal dopaminergic neurons, and improved motor behavioral deficits. Administration of enavogliflozin further significantly reduced the levels of inflammatory cytokines (IL-6 and TNF-α), microglial activation, and oxidative damage in rotenone-induced Parkinson's disease mice. Moreover, we found that enavogliflozin activated PINK1/Parkin-mediated mitophagy by SIRT1 signaling pathway. In conclusion, enavogliflozin ameliorates motor dysfunction in rotenone-induced Parkinson's disease mice by attenuating oxidative stress, inhibiting neuroinflammation, and activating SIRT1/PINK1/Parkin pathway. These findings support a neuroprotective and preventive role for enavogliflozin in Parkinson's disease.
