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 l‐methyl‐4‐phenylpyridinium (MPP+). Protection against DA neuron death occurred with increasing concentrations of U‐78518F up to 30 μM. Nonspecific toxicity produced with higher concentrations of MPP+ was not affected by the lazaroid. U‐78518F inhibited cellular uptake of [3H]MPP+ and [3H]DA, but not that of γ‐[3H]aminobutyric acid. In human striatal membrane preparations, U‐78518F competed with [3H]mazindol for binding to the DA transporter, with a calculated Ki value of 10 μM. Two of four lazaroids tested inhibited [3H]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.