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

Abstract

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 1 of the electron transport chain. A proposed mechanism of neurotoxicity isexcitotoxic 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.