Mechanism of Accumulation of the 1‐methyl‐4‐Phenylpyridinium Species into Mouse Brain Synaptosomes

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Abstract
The mechanism of accumulation of 1‐methyl‐4‐phenylpyridinium ion (MPP+), the toxic metabolite of 1‐methyl‐4‐phenyl‐l,2,3,6‐tetrahydropyridine, into neuronal terminals was studied using mouse brain synaptosomes as an in vitro model. Addition of MPP+ to synaptosomal preparations, essentially devoid of contamination by extrasynap‐tosomal mitochondria, resulted in its time‐ and concentration‐dependent accumulation. Intrasynaptosomal concentrations of 79 and 106 μM were reached 10 and 30 min, respectively, after addition of 50 μM MPP+. The accumulation of 50 μM MPP+ into synaptosomes was only slightly affected by the catecholamine uptake blockers mazindol and nomifensine; in contrast, it was markedly enhanced by tetra‐phenylborate, a lipophilic anion that increases the rate of accumulation of permeant cations via a Nernstian concentration gradient. MPP+ accumulation was significantly increased or decreased as a consequence of hyperpolarization or depolarization, respectively, of the plasma membrane of synaptosomes. This effect was evident after incubation for 10 min. Changes in mitochondrial membrane potential also affected MPP+ accumulation, although only after 30 min of incubation. Data indicate that polarization of neuronal membranes may significantly contribute to the accumulation of MPP+ into nerve terminals.

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