Phosphatidylinositol-3-kinase/Protein Kinase B (PI3K/AKT) and Nucleotide-Binding Oligomerization Domain-like Receptor Family Pyrin Domain Containing 3 (NLRP3) Inflammasome Modulation Underlies the Neuroprotective Effects of Vildagliptin in a Rotenone-Induced Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is a chronic neurodegenerative disorder marked by the gradual loss of dopaminergic neurons. Mitochondrial impairment, neuroinflammation, oxidative stress, and abnormal aggregation of α-synuclein are the most prominent features of the pathology. Current therapeutic approaches lack disease-modifying abilities and render only symptomatic relief. It has been observed that increased risk of PD is somehow linked to type 2 diabetes mellitus, and these pathologies share some common signaling cascades. Hence, repurposing hypoglycemic agents targeting specific molecular signaling pathways that mediate α-synuclein aggregation and neuroinflammation can be an effective disease-modifying strategy for PD treatment. This study investigated the neuroprotective potential of the DPP-4 inhibitor, vildagliptin, in a mouse model of chemically induced PD. In silico analyses, including molecular docking as well as molecular dynamics simulation, demonstrate good binding affinity as well as stable interaction of vildagliptin with PI3K (4YKN) and NLRP3 (7ALV) proteins in comparison to other DPP-4 inhibitors (sitagliptin, saxagliptin, linagliptin, and alogliptin). In in vivo studies, it was observed that vildagliptin improved motor coordination, muscle strength, and cognitive abilities. Biochemical assays show a reduction in MDA and restoration of GSH, indicating alleviation of oxidative stress. Moreover, at the molecular level, vildagliptin upregulated neuroprotective markers like PI3K, AKT, CREB, BDNF, and TH and downregulated pathological and inflammatory markers like NLRP3, IL-1β, caspase-1, gasdermin D, and α-syn. Histopathological and immunohistochemistry studies also demonstrate preservation of dopaminergic neurons. These findings collectively suggest that vildagliptin rendered neuroprotection by PI3K/AKT activation and inhibition of NLRP3-mediated neuroinflammation and apoptosis. In conclusion, we can say that vildagliptin possesses definitive neuroprotective potential as a disease-modifying therapy that warrants further clinical exploration.