General mechanisms of neurotoxicity have been investigated over the past several years, principally using the parkinsonian syndrome producing toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydopyridine(MPTP) and its analogues. Studies have been completed assessing the occurrence of compounds structurally related to MPTP or its major metabolite 1-methyl-4-phenylpyridinium (MPP+) in post-mortem brain tissue from patients with idiopathic Parkinson's disease. An immunoassay procedure was developed for the detection of MPP+, and shown to be very sensitive in tissues from animals that had been exposed to MPTP or one of its analogs. Based upon a survey of immunoactivity in extracts of several regions of normal human control brain tissue, there was no evidence for increased immunoactivity in Parkinson's disease patients. Thus, there is no evidence for an environmental neurotoxin chemically related to MPTP in the pathogenesis of idiopathic Parkinson's disease. Several lines of evidence have suggested that hydroxyl radicals generated either by redox cycling a toxin utilizing endogenous enzymes, or as a result of metabolism which has been activated by a toxin, may be involved in the pathogenesis of neurodegenerative disorders. Hydroxyl radical damage may effect many different cell constituents. However, oxidative damage to neuronal DNA could result in impaired neuronal function if the damage remained unrepaired and accumulated. In order to measure oxidative damage to neuronal or mitochondrial DNA, gas chromatographic-mass spectrometric methods are being developed for the detection of thymine glycol, one of the oxidation products of thymine. The method releases methyl 2-methylglycerate from double stranded DNA by several chemical steps, prior to derivatization for mass spectrometric detection.
