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). 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.
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