21-AMINOSTEROIDS INTERACT WITH THE DOPAMINE TRANSPORTER TO PROTECT AGAINST 1-METHYL-4-PHENYLPYRIDINIUM-INDUCED NEUROTOXICITY

U-78518F, a 21-aminosteroid from the novel family of lipid peroxidation inhibitors (lazaroids), increased survival of dopamine (DA) neurons in mesencephalic cell cultures incubated with the neurotoxin 1-methyl-4-phenylpyridinium (MPP+). Protection against DA neuron death occurred with increasing concentrations of U-78518F up to 30-mu-M. Nonspecific toxicity produced with higher concentrations of MPP+ was not affected by the lazaroid. U-78518F inhibited cellular uptake of [H-3]MPP+ and [H-3]DA, but not that of gamma-[H-3]aminobutyric acid. In human striatal membrane preparations, U-78518F competed with [H-3]mazindol for binding to the DA transporter, with a calculated K(i) value of 10-mu-M. Two of four lazaroids tested inhibited [H-3]DA uptake in the cell culture system. The protective effects of 21-aminosteroids in MPP+-induced neurotoxicity are, in part, a function of the interaction of these agents with the DA transporter.