Oxidative mechanisms in nigral cell death in Parkinson's disease.
Oxidative stress may contribute to nigral cell death in Parkinson's disease based on postmortem investigations showing increased iron levels, decreased levels of reduced glutathione (GSH), and impaired mitochondrial function. This leads to oxidative damage because lipid peroxidation is increased in substantia nigra and there is a widespread increase in protein and DNA oxidation in the brain in Parkinson's disease. Nitric oxide (NO) may be one of the free radical species involved in nigral degeneration. NO is involved in the production of hydroxyl radicals resulting from MPP+-induced dopamine efflux in striatum. Mice treated with the neuronal nitric oxide synthase (NOS) inhibitor 7-nitroindazole show reduced toxicity to MPTP and knock-out mice lacking neuronal NOS show decreased MPTP susceptibility. In primates, 7-nitroindazole inhibits MPTP toxicity but this remains controversial because no protection is afforded by the nonspecific NOS inhibitor, L-NAME. Indeed, in Parkinson's disease itself, there is little evidence for nitric oxide's involvement in nigral pathology. A susceptibility factor for the development of Parkinson's disease may involve isoforms of cytochrome P450, some of which are found in the brain. CYP2EI, which is associated with free radical production and the formation of endogenous toxins, is selectively localized in nigral dopamine-containing cells. CYP2E1 metabolizes n-hexane leading to the formation of its neurotoxic metabolite 2,5-hexanedione which may explain cases of solvent-induced parkinsonism. Oxidative processes clearly contribute to the pathology of Parkinson's disease but are probably secondary to some other primary unidentified cause, presumably genetic or environmental. Nevertheless, their involvement may allow therapeutic intervention in the cascade of events associated with the progression of Parkinson's disease.
Jenner
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Neurodegenerative Disease Research Centre, Biomedical Science Division, London, United Kingdom.
D000818:Animals; D016923:Cell Death / Q000502:physiology*; D003577:Cytochrome P-450 Enzyme System / Q000502:physiology; D004195:Disease Models, Animal; D005609:Free Radicals; D006801:Humans; D015227:Lipid Peroxidation / Q000502:physiology*; D051379:Mice; D009569:Nitric Oxide / Q000502:physiology; D010300:Parkinson Disease / Q000473:pathology / Q000503:physiopathology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013378:Substantia Nigra / Q000473:pathology / Q000503:physiopathology*
D005609:Free Radicals; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; D003577:Cytochrome P-450 Enzyme System