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

TL;DR

This study evaluates new N-benzylpyrrolidine compounds that inhibit MAO enzymes and shows they can reduce motor deficits in a Parkinson's disease mouse model.

Contribution

The study introduces novel N-benzylpyrrolidine derivatives with MAO-B inhibitory activity and demonstrates their efficacy in an experimental Parkinson’s model.

Findings

The compounds ameliorated MPTP-induced motor deficits in mice without altering basal dopamine levels.

Compound 3e partially restored striatal dopamine levels, similar to a known positive control.

Compound 3e increased hippocampal levels of pro-inflammatory cytokines IL-1β and TNF-α.

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 (3e, 3f, and 3i), 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. Compounds 3f and 3i improved motor function without detectable changes in striatal DA levels, whereas compound 3e partially 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) following 3e administration. 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.

Figures