MPP⁺-induced pathophysiology demonstrates advantages of neurotoxicology studies in brain slices

Since MPTP and its metabolite MPP⁺ produce nigrostriatal lesions and symptoms similar to Parkinson's disease, recent studies have aimed toward defining their selectivity and neurotoxic mechanisms. In mitochondria in vitro, MPP⁺ blocked electron transport and decreased oxygen consumption. However, these effects were not selective to striatal mitochondria or even to mitochondria from brain, they required concentrations of MPP⁺ much greater than those found in vivo, and physiological actions could not be related to intramitochondrial changes. Lower doses of MPP⁺ did produce highly selective degeneration of dopaminergic (DA) neurons in cell cultures. We report here that MPP⁺ provoked large (80%) oxidations of cytochrome b and large K_o⁺ increments (approximately 30 mM) in rat striatal slices. These effects were slowed by mazindol, which inhibits DA uptake, and were markedly attenuated in rat hippocampal slices which have little DA input. Since DA terminals comprise only 2-4% of the striatal mass, the large MPP⁺-induced changes suggest that while MPP⁺ neurotoxicity in brain requires the presence of functioning DA terminals, effects are not confined to these terminals. Such studies illustrate the complexity of MPP⁺ neurotoxicity and demonstrate the importance of investigations in models such as brain slices with an extracellular space and intercellular relationships as in intact brain.