-Benzylpyrrolidine Compounds with MAO-B Inhibitory Activity in an Experimental Model of Parkinson's Disease.

Abstract

The pathogenesis of Parkinson's disease (PD) is characterized by progressive degeneration of nigrostriatal dopaminergic signaling, resulting in motor dysfunction. Although monoamine oxidase (MAO) inhibitors are clinically used in PD, their long-term efficacy and safety remain limited. In the present study, three novel N-benzylpyrrolidine derivatives (,, and), previously identified as dual MAO-A/B inhibitors in silico and in vitro, were pharmacologically evaluated in an acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. The compounds were administered intraperitoneally starting 2 days prior to MPTP exposure and continuing for 6 days thereafter. Repeated administration of the compounds did not alter striatal dopamine (DA) levels under basal conditions, indicating no detectable modulation of dopaminergic tone in vivo. All three derivatives ameliorated MPTP-induced motor deficits. Compoundsandimproved motor function without detectable changes in striatal DA levels, whereas compoundpartially restored striatal DA levels, similar to the positive control. In addition, compound-specific alterations in hippocampal pro-inflammatory cytokines were observed, including increased levels of interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) followingadministration. Together, these findings provide in vivo pharmacological characterization of novel MAO-targeting derivatives and reveal differential behavioral, neurochemical, and cytokine profiles among the tested compounds, supporting further mechanistic investigation.