Neuroprotective effects of DPP-4 inhibitors sitagliptin and vildagliptin in Parkinson's disease via autophagy modulation.

This study investigates the neuroprotective potential of the dipeptidyl peptidase-4 (DPP-4) inhibitors sitagliptin and vildagliptin in models of Parkinson's disease (PD). In vitro, sitagliptin (10-80 µM) and vildagliptin (5-40 µM) enhanced mitophagy and modulated autophagy pathway in neuronal cell lines. Sitagliptin (20-80 µM) similarly promoted autophagy in Drosophila larval fat body. In an MPTP (1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine)-induced mouse model of PD, administration of vildagliptin (15 mg/kg/day) mitigated neuronal loss, reduced microglial activation, and increased tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta and striatum. Network pharmacology and molecular docking analyses identified ten key protein targets, with DPP-4, serine/threonine-protein kinase AKT (AKT1) and glycogen synthase kinase-3 beta (GSK3β) emerging as central nodes. These findings indicate that both drugs engage a multi-target network to modulate autophagy and mitophagy, potentially facilitating the clearance of pathogenic protein aggregates and dysfunctional mitochondria. Together, these results position sitagliptin and vildagliptin as promising autophagy-modifying candidates for disease-modifying PD therapy. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-026-04761-8.