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 dopaminergic 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 oNO is an atypical neuroprotective
antioxidant. (.-)NO and
S-nitrosoglutathione (GSNO) protect nigral neurons against oxidative stress caused by
1-methyl-4-phenylpyridinium (MPP(+)),
dopamine,
ferrous citrate,
hemoglobin,
sodium nitroprusside and
peroxynitrite. MPP(+), the toxic metabolite of
1-methyl-4-phenyl-1,2,3,6-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, 17beta-estradiol,
melatonin,
alpha-phenyl-tert-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 neuro-rescue 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.