Neuroprotective strategies in parkinson's disease: protection against progressive nigral damage induced by free radicals

Brain undergoes neurodegeneration when excess free radicals overwhelm antioxidative defense systems during senescence, head trauma and/or neurotoxic insults. A site-specific accumulation of ferrous citrate-iron complexes in the substantia nigra dopa-minergic neurons could lead to exaggerated dopamine turnover, dopamine auto-oxidation, free radical generation, and oxidant stress. Eventually, this iron-catalyzed dopamine auto-oxidation results in the accumulation of neuromelanin, a progressive loss of nigral neurons, and the development of Parkinson's disease when brain dopamine depletion is greater than 80%. Emerging evidence indicates that free radicals such as hydroxyl radicals (*OH) and nitric oxide (*NO) may play opposite role in cell and animal models of parkinsonism. *OH is a cytotoxic oxidant whereas *NO is an atypical neuroprotective antioxidant. *NO and S-nitrosoglutathione (GSNO) protect nigral neurons against oxidative stress caused by l-methyl-4-phenylpyridinium (MPP+), dopamine, ferrous citrate, hemoglobin, sodium nitroprusside and peroxynitrite. MPP+ the toxic metabolites of l-methyl-4-phenyl-l,2,3,6-tetrahydropyridine(MPTP) increases the nigral uptake of iron complexes and dopamine overflow leading to the generation of *OH, protein oxidation, lipid peroxidation, and associated retrograde degeneration. In addition to GSNO, MPP+-induced oxidative neurotoxicity can be prevented by antioxidants including selegiline, 7-nitroindazole, 17 beta -estradiol, melatonin, alpha -phenyltert-butylnitrone and U78517F. Similar to selegiline, 7-nitroindazole is a MAO-B inhibitor, which blocks the bio-activation of MPTP and oxidative stress. Freshly prepared but not light exposed, *NO-exhausted GSNO is about 100 times more potent than the classic antioxidant glutathione. Via S-nitrosylation, GSNO also inhibits proteolysis and cytotoxicity caused by caspases and HIV-1 protease. Furthermore, in addition to protection against serum deprivation stress, the induction of neuronal NOS1 in human cells increases tolerance to MPP+-induced neuro-toxicity since newly synthesized *NO prevents apoptosis possibly through up-regulation of bcl-2 and down regulation of p66(shc). In conclusion, reactive oxygen species are unavoidable by-products of iron-catalyzed dopamine auto-oxidation, which can initiate lipid peroxidation, protein oxidation, DNA damage, and nigral loss, all of which can be prevented by endogenous and exogenous *NO. Natural and man-made antioxidants can be employed as part of preventative or neuroprotective treatments in Parkinson's disease and perhaps dementia complexes as well. For achieving neuroprotection and neurorescue in early clinical parkinsonian stages, a cocktail therapy of multiple neuroprotective agents may be more effective than the current treatment with extremely high doses of a single antioxidative agent.