21‐Aminosteroids Interact with the Dopamine Transporter to Protect Against 1‐Methyl‐4‐Phenylpyridinium‐Induced Neurotoxicity

Abstract: 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 K_i 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.