ON THE MECHANISMS UNDERLYING 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE NEUROTOXICITY - THE EFFECT OF PERINIGRAL INFUSION OF 1-METHYL-4-PHENYL-1,2,3,6-TETRAHYDROPYRIDINE, ITS METABOLITE AND THEIR ANALOGS IN THE RAT

  • 1 May 1987
    • journal article
    • research article
    • Vol. 241  (2) , 669-676
Abstract
The discovery that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism in humans and other primates by selective destruction of substantia nigra dopaminergic neurons has spurred research to define the mechanisms underlying its toxicity. To avoid variables such as tissue distribution, extracerebral metabolism and blood-brain barrier permeability, the authors studied the neurochemical and morphologic effects of direct perinigral infusions of various concentrations of MPTP, its metabolites and analogs in the rat. MPTP, in the highest dose used, 1000 nmol, decreased dopamine and its metabolites in ipsilateral striatum by .apprx. 75%, whereas 3,3-dimethyl-MPTP (which is oxidized to 1,3,3-trimethyl-4-phenyl-2,3-dihydropyridinium cation but not to a pyridinium species) had no effect. The 2,2 and 3,3-dimethyl analogs of 1-methyl-4-phenyl-2,3-dihydropyridinium cation which also cannot be oxidized to pyridium species, reduced striatial dopamine, suggesting that these compounds are toxic in their own right. 1-Methyl-4-phenylpyridinium cation (MPP+) and its 4-(4-fluorophenyl) and 4-(2-pyridyl) analogs that have less negative reduction potentials than MPP+, were most potent in decreasing stritial dopamine and metabolites, with MPP+ being 5 to 10 times more effective than its two analogs and .apprx. 100 times more potent that MPTP and the two dimethyl 1-methyl-4-phenyl-2,3-dihydropyridinium cation analogs. These findings suggest that MPP+ is ultimately responsible for MPTP toxicity but does not act via oxidant stress mechanisms. All compounds tested except MPTP produced large lesions around the infusion site, which nonselectively destroyed the entire substantia nigra and adjacent ascending noradrenergic and serotonergic pathways. MPTP produced smaller nonspecific lesions at the center of the infusion site but caused selective loss of dopamine neurons in distant regions of substantia nigra, suggesting that it alone, among the compounds tested, is selectively toxic. The lack of a similar selective effect by MPP+ can be explained by its high local concentrations leading to severe local damage before significant diffusion can take place.