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Active uptake of MPP+, a metabolite of MPTP, by brain synaptosomes

K Chiba, A J Trevor, N Castagnoli

    Biochemical and Biophysical Research Communications
    |May 16, 1985
    PubMed

    Insights

    This study shows that mouse brain synaptosomes selectively take up N-methyl-4-phenylpyridine (MPP+), a neurotoxin metabolite. This selective MPP+ uptake may explain MPTP

    Area of Science:

    • Neuroscience
    • Neurotoxicology
    • Biochemistry

    Background:

    • The neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) causes Parkinsonism.
    • MPP+ (N-methyl-4-phenylpyridine) is a toxic metabolite of MPTP implicated in neuronal damage.

    Purpose of the Study:

    • To investigate the selective uptake of MPP+ in mouse brain synaptosomes.
    • To understand the mechanism and regional specificity of MPP+ accumulation.

    Main Methods:

    • Utilized mouse brain synaptosomal preparations.
    • Measured the uptake of radiolabeled [3H]-MPP+ and [3H]-MPTP.
    • Assessed the influence of ions, inhibitors, and different brain regions on MPP+ uptake.

    Main Results:

    • MPP+ uptake by striatal synaptosomes was significantly higher (approx. 25x) than MPTP uptake.
    • MPP+ uptake demonstrated Michaelis-Menten kinetics (KM=0.48 µM, Vmax=5.3 nmol/g/min).
    • Uptake was dependent on Na+ and inhibited by ouabain, cocaine, and dopamine (Ki=0.12 µM).
    • Corpus striatum synaptosomes showed 5-10 times greater [3H]-MPP+ accumulation compared to other regions.

    Conclusions:

    • MPP+ exhibits selective and active transport into mouse brain synaptosomes.
    • The corpus striatum shows a particular high capacity for MPP+ accumulation.
    • Selective MPP+ uptake likely contributes to the neurotoxic specificity of MPTP on nigrostriatal dopaminergic neurons.

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