The toxicity of MPTP to dopamine neurons in culture is reduced at high concentrations.

The toxicity of MPTP to dopamine (DA) neurons was studied in dissociated cell cultures from rat embryo mesencephalon. The cultures were exposed to MPTP (from 0.1 to 200 microM) for 7 days and were analyzed by catecholamine histofluorescence after incubation with alpha-methylnorepinephrine, by tyrosine hydroxylase (T-OH) immunocytochemistry and by [3H]DA uptake. Treatment with MPTP at the lower range of concentrations (between 0.1 and 5 microM) resulted in a dose-dependent reduction of the uptake of [3H]DA, which had a maximum effect at 5 microM. Further increase in the concentration of MPTP (from 10 to 200 microM) resulted in progressive attenuation of the toxic effect. Exposure to 200 microM MPTP did not produce significant reduction in the uptake of [3H]DA. Increased survival of DA neurons at the higher concentrations of MPTP, was documented by catecholamine histofluorescence and by T-OH immunocytochemistry in cultures treated with 10 and 100 microM MPTP. MPTP was shown to be a potent inhibitor of MPP+ uptake by DA neurons in culture. In the presence of 100 or 200 microM MPTP, the uptake of MPP+ was reduced to less than 20% of control levels. Therefore, the reduction of MPTP toxicity at the high concentrations can be explained, at least in part, by the inhibition of the uptake of MPP+ (the toxic metabolite of MPTP oxidation) in the presence of high concentrations of MPTP.