Neuroprotective effects of empagliflozin and metformin combined therapy on rotenone induced Parkinsonism in Wistar rats via PI3K and PPARγ modulation

Abstract

Parkinsonism is a progressive neurodegenerative disorder characterized by dopaminergic neuronal loss and α-synuclein aggregation within the substantia nigra pars compacta (SNc). We investigated the potential neuroprotective effects of metformin and empagliflozin, individually and combined, in a rotenone-induced Parkinsonism in rats. Rats were assigned to control, rotenone (ROT), metformin + ROT, empagliflozin + ROT, and combined metformin+empagliflozin + ROT groups. Motor function was assessed using the open field test, static rod test, and inverted grid test. Both metformin and empagliflozin monotherapies significantly improved motor deficits, while the combination therapy demonstrated superior efficacy compared to either treatment alone (p < 0.05). Histopathological and immunohistochemical findings further showed that the combined therapy markedly attenuated neuronal degeneration and α-synuclein deposition relative to monotherapies (p < 0.001). Biochemically, metformin was more effective than empagliflozin in preserving dopamine levels, with a significant difference observed between the two treatments (p < 0.001). Notably, the combination therapy achieved the greatest overall improvement, significantly surpassing both the ROT group and empagliflozin (p < 0.001) and showing comparable effects to metformin (p > 0.05). Additionally, the combined treatment restored PI3K/AKT signaling activity and significantly upregulated PPAR-γ expression (p < 0.001 vs. ROT). Collectively, these findings suggest that combined metformin and empagliflozin therapy exerts enhanced neuroprotective effects through modulation of protein aggregation pathways, highlighting a promising drug-repositioning strategy for Parkinsonism.