Pharmacological profiling of Thiamet-G inhibitor in MPTP induced Parkinson’s disease: Evidence from behavioral, biochemical, and histological studies

Abstract

Parkinson's disease (PD) is a progressive neurodegenerative disease marked by the loss of dopaminergic neurons, oxidative stress, mitochondrial dysfunction, and neuroinflammation. Growing evidence suggests that the dysregulation of O-GlcNAcylation, a dynamic post-translational modification regulated by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), plays a role in the pathogenesis of PD. Disrupted O-GlcNAcylation leads to mitochondrial dysfunction, oxidative stress, and abnormal inflammatory signaling, which in turn accelerates the degeneration of dopaminergic neurons. This research examined the neuroprotective effects of Thiamet-G (10 and 20 mg/kg, i.p.), a selective inhibitor of OGA, in a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The administration of MPTP resulted in significant motor deficits, heightened oxidative stress, and increased levels of inflammatory mediators, alongside neuronal damage in the substantia nigra pars compacta. Treatment with Thiamet-G significantly (p < 0.0001) enhanced locomotor activity, motor coordination, and grip strength when compared to disease controls. Biochemical assessments indicated a decrease in lipid peroxidation and a restoration of antioxidant enzymes (GSH, CAT, SOD). ELISA analysis revealed a significant reduction in pro-inflammatory mediators (TNF-α, IL-1β, NF-κB) and a notable (p < 0.0001) increase in neuronal survival proteins MEF2D and SRPK3, along with a decrease in OGA expression, confirming improved O-GlcNAcylation. Histopathological evaluations supported these results, showing less neuronal degeneration, reduced astrocytic proliferation, and increased neuronal density in the groups treated with Thiamet-G. Thus, the research indicates that Thiamet-G provides neuroprotection in Parkinson's disease by influencing SRPK3 and MEF2D, while also preventing motor dysfunction, oxidative stress, and neuroinflammation.