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 microM. Non-specific 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 gamma-[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 microM. 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.
Sanchez-Ramos
J R
JR
Department of Neurology, University of Miami School of Medicine, Florida 33136.
Song
S
S
Mash
D C
DC
Weiner
W J
WJ
D015655:1-Methyl-4-phenylpyridinium / Q000037:antagonists & inhibitors*; D000818:Animals; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000502:physiology*; D003342:Corpus Striatum / Q000378:metabolism; D004298:Dopamine / Q000493:pharmacokinetics; D050483:Dopamine Plasma Membrane Transport Proteins; D004347:Drug Interactions; D005021:Ethylamines / Q000494:pharmacology; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D009498:Neurotoxins / Q000037:antagonists & inhibitors*; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D013256:Steroids / Q000737:chemistry / Q000494:pharmacology*
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D005021:Ethylamines; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D010879:Piperazines; D011725:Pyridines; D013256:Steroids; C072017:U 78518F; D015655:1-Methyl-4-phenylpyridinium; D004298:Dopamine