Blockade of 1-methyl-4-phenylpyridinium ion (MPP+) nigral toxicity in the rat by prior decortication or MK-801 treatment: a stereological estimate of neuronal loss.
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, (MPTP), produces a parkinsonian syndrome both in man and in experimental animals. Its toxicity is mediated by a metabolite, the 1-methyl-4-phenylpyridinium ion (MPP+). When injected into the striatum, MPP+ is accumulated by dopaminergic nerve terminals and retrogradely transported to the substantia nigra pars compacta (SNc) where it causes neuronal degeneration. MPP+ accumulates in mitochondria and blocks complex I of the electron transport chain. A proposed mechanism of neurotoxicity is excitotoxic neuronal degeneration induced by this energy depletion. We examined whether either prior decortication or administration of the N-methyl-D-aspartate (NMDA) receptor antagonist, (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) could prevent or diminish the selective nigral neuronal degeneration that follows unilateral intrastriatal injection of MPP+. We quantified the extent of neuronal death in the SNc ipsilateral and contralateral to the injections on Nissl-stained sections with unbiased stereological techniques. One week after injection of MPP+, approximately 75% of the SNc neurons were lost on the side of the injection. The loss was a consequence of the reduction in both SNc volume and neuronal density. Both prior decortication or the administration of MK-801 for 2 days nearly completely prevented MPP(+)-induced neuronal loss in the ipsilateral SNc. These results are consistent with an NMDA receptor mediated excitotoxic mechanism for MPP(+)-induced nigral toxicity.
Srivastava
R
R
Massachusetts General Hospital, Boston 02114.
Brouillet
E
E
Beal
M F
MF
Storey
E
E
Hyman
B T
BT
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors; D000818:Animals; D002452:Cell Count; D002541:Cerebral Decortication; D003342:Corpus Striatum; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology*; D015259:Dopamine Agents / Q000008:administration & dosage / Q000037:antagonists & inhibitors* / Q000633:toxicity; D004579:Electron Transport / Q000187:drug effects; D007267:Injections; D007274:Injections, Intraperitoneal; D020267:MPTP Poisoning; D008297:Male; D008853:Microscopy; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000494:pharmacology; D009410:Nerve Degeneration / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000166:cytology* / Q000187:drug effects
D015259:Dopamine Agents; C048977:1-methyl-4-(2'-methylphenyl)-1,2,3,6-tetrahydropyridine; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine