AA-2βG attenuates nigrostriatal degeneration and related dopaminergic, redox, and inflammatory alterations in experimental parkinsonism.

Parkinson's disease (PD) is characterized by progressive nigrostriatal degeneration, dopamine depletion, and interactions among neuronal vulnerability, oxidative imbalance, and neuroinflammatory responses. AA-2βG is a chemically stable ascorbate derivative; however, its protective profile in experimental parkinsonism remains incompletely defined. We prioritized in vivo phenotyping using a subacute MPTP-induced mouse model, followed by complementary cellular analyses and exploratory transcriptomic profiling. AA-2βG was administered orally at 75, 150, or 300 mg/kg for 17 days, starting 3 days before MPTP administration. Under this pre-exposure paradigm, AA-2βG attenuated body-weight loss and motor deficits, reduced the decline in tyrosine hydroxylase immunoreactivity, and preserved Nissl-positive neuronal populations in the substantia nigra pars compacta. AA-2βG partially preserved striatal dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid levels and attenuated alterations in dopamine turnover indices. AA-2βG attenuated glial activation markers, central and peripheral inflammatory changes, and redox disturbances in MPTP-exposed mice, accompanied by improvements in total antioxidant capacity, antioxidant enzyme activities, and glutathione redox status. Complementary experiments in SH-SY5Y neuroblastoma cells, BV2 microglia, and SVGP12 astrocytes showed selected neuronal injury, inflammatory, and trophic responses associated with the in vivo phenotype. Transcriptomic profiling identified AA-2βG-associated changes involving Drd2, Spp1, Lamp5, and Slc39a10; RT-qPCR and protein analyses supported selected expression changes but did not establish causal mediation. No overt histopathological abnormalities or elevations in serum liver enzymes were observed under the tested regimen. Collectively, these findings show that AA-2βG attenuates MPTP-associated neuronal, neurochemical, redox, glial, and inflammatory alterations and support evaluation in progressive and post-lesion models of parkinsonian neurodegeneration.