Dapagliflozin ameliorates motor deficits in a Parkinson’s disease model induced by 6-OHDA: An integrative in vivo and in silico approach from α-synuclein/A2AAR/TH/TNF-α to APAF-1/caspase-3 modulation

Parkinson’s disease (PD), the second most common neurodegenerative disorder, is characterized by α-synuclein aggregation and loss of dopaminergic neurons, and current treatments are symptomatic. Multiple intricate mechanisms contribute to the pathogenesis, and the effectiveness of single-target approaches is therefore limited. Current approaches highlight therapeutic candidates capable of simultaneously modulating multiple pathways. Recent clinical and experimental studies of sodium-glucose cotransporter inhibitors (SGLT2is), approved for the treatment of type 2 diabetes mellitus, have indicated their pleiotropic and neuroprotective potential. SGLT2i dapagliflozin has several features, including low molecular weight, blood-brain barrier permeability, and tolerability. This study investigated the effects of dapagliflozin on pathways implicated in the pathogenesis of PD in a 6-hydroxydopamine-induced experimental PD model in female Sprague-Dawley rats using in silico, histopathological, immunohistochemical, and biochemical methods. Dapagliflozin was administered by oral gavage at four different doses (2.5 mg/kg, 5 mg/kg, 7.5 mg/kg, and 10 mg/kg) for 14 days. Motor deficits were evaluated by means of behavioral tests, and dapagliflozin was observed to alleviate motor dysfunction. Tyrosine hydroxylase expression increased in brain tissues, whereas A2AAR, TNF-α, and APAF-1 levels, as well as α-synuclein and caspase-3 expression, decreased. In molecular docking analyses, dapagliflozin showed notable binding affinity to PD-associated human target receptors. Our results suggest that dapagliflozin may exert potential neuroprotective effects via modulation of inflammatory, oxidative stress-related, and apoptosis-associated pathways and may represent a promising repurposing candidate for PD.