Prevention of the nigrostriatal toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine by inhibitors of 3,4-dihydroxyphenylethylamine transport.
The 3,4-dihydroxyphenylethylamine (DA, dopamine) uptake inhibitors GBR 13,069, amfonelic acid, WIN-35,065-2, WIN-35,428, nomifensine, mazindol, cocaine, McN-5908, McN-5847, and McN-5292 were effective in preventing [3H]DA and [3H]1-methyl-4-phenylpyridinium (MPP+) uptake in rat and mouse neostriatal tissue slices. These DA uptake inhibitors also were effective in attenuating the MPP+-induced release of [3H]DA in vitro. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration to mice (6 X 25 mg/kg i.p.) resulted in a large (70-80%) decrement in neostriatal DA. WIN-35,428 (5 mg/kg), GBR 13,069 (10 mg/kg), McN-5292 (5 mg/kg), McN-5908 (2 mg/kg), and amfonelic acid (2 mg/kg), when administered intraperitoneally 30 min prior to each MPTP injection, fully protected against MPTP-induced neostriatal damage. Other DA uptake inhibitors showed partial protection in vivo at the doses selected. Desmethylimipramine did not prevent [3H]MPP+ uptake or MPP+-induced release of [3H]DA in vitro, and did not protect against MPTP neurotoxicity in vivo. These results support the hypothesis put forth previously by others that the active uptake of MPP+ by dopaminergic neurons is necessary for toxicity.
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D015655:1-Methyl-4-phenylpyridinium; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D003042:Cocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D018492:Dopamine Antagonists; D005444:Flunarizine / Q000031:analogs & derivatives*; D008297:Male; D051379:Mice; D009268:Nalidixic Acid / Q000031:analogs & derivatives; D009287:Naphthyridines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000633:toxicity; D011726:Pyridinium Compounds / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism
D018492:Dopamine Antagonists; D009287:Naphthyridines; D010879:Piperazines; D011725:Pyridines; D011726:Pyridinium Compounds; D011758:Pyrroles; C050005:McN 5292; C050006:McN 5908; D009268:Nalidixic Acid; C021279:(1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester; C043424:GBR 13069; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D003042:Cocaine; D005444:Flunarizine; D015655:1-Methyl-4-phenylpyridinium; C006486:amfonelic acid; D004298:Dopamine