Dopaminergic cell toxicity of N-substituted derivatives of Parkinsonian toxin 1-Methyl-4-phenylpyridinium (MPP+)

Presented to the 13th Annual Symposium on Graduate Research and Scholarly Projects (GRASP) held at the Rhatigan Student Center, Wichita State University, April 28, 2017.Research completed in the Department of Chemistry, Fairmount College of Liberal Arts and SciencesParkinson's disease (PD) is a neurodegenerative disease whose etiology is unknown but genetics, environmental factors, and mitochondrial mutations may play a role. 1-Methyl-4-phenylpyridinium (MPP+) is a model for PD since it causes PD-like-symptoms in mammals. MPP+ inhibits mitochondrial complex I and increases oxidative stress in dopaminergic neurons. Synaptic accumulation of cytosolic MPP+ through vesicular monoamine transporter-2(VMAT2) has been proposed as an in vivo detoxification mechanism. Our previous studies have shown that N-substituted MPP+ derivatives, [N-(2-phenypropene)-4-phenylpyridinium (MPP-APP)] were potent inhibitors of VMAT, suggesting these should increase MPP+ toxicity. The present studies show that MPP-APP derivatives themselves are more toxic to dopaminergic cells than MPP+. MPP-APP accumulates in cells through diffusion and increases ROS production in dopaminergic cells. The cell death is due to the ROS induced apoptosis similar to MPP+. The implications of these findings to the mechanism of MPP+ toxicity could lead to future treatments for PD.Graduate School, Academic Affairs, University Libraries, Regional Institute on Agin