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

Abstract

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.

Alteration of dopamine uptake into rat striatal vesicles and synaptosomes caused by an in vitro exposure to atrazine and some of its metabolites

“…Increased cytosolic DA is in turn easily oxidized and reactive oxygen species (ROS), including DA quinones, are produced (LaVoie and Hastings, 1999). Such increase in cytosolic DA will therefore result in decreased DA in the vesicles and ROS-mediated toxicity to DA neurons (Chiueh et al, 2000). Of the 3 metabolites examined, only DACT was found to be ineffective in alteriong synaptosomal or vesicular uptake of DA.…”

Novel mechanisms and approaches in the study of neurodegeneration and neuroprotection. A review

“…In Parkinson's disease (PD) the role of neuromelanin as either an accelerant to neurotoxicity or as a neuroprotectant for pars compacta dopaminergic neurons is unresolved (Wilczok et al, 1999;Chiueh et al, 2000;Gerlach et al, 2000;Kostrzewa, 2000;Solano et al, 2000;Sulzer and Zecca, 2000;Double et al, 2003). Neuromelanin-containing neurons are apparently more susceptible to cell death (Marsden, 1983).…”

Curcumin and the cellular stress response in free radical‐related diseases

“…Considerable insights into the pathogenesis of PD, indeed, have been achieved by use of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is commonly used to induce an experiment model of PD [105,107]. Excessive free radical formation or antioxidant deficiency and the resulting oxidative stress are all mechanisms involved in MPTP neurotoxicity [108]. Rajeswari [109] has shown that curcumin protects rat brain from MPTP-induced neurotoxicity by virtue of its scavenger activity.…”