The oxidant stress hypothesis in Parkinson's disease: Evidence supporting it

Abstract

Oxidant stress, due to the formation of hydrogen peroxide and oxygen-derived free radicals, can cause cell damage due to chain reactions of membrane lipid peroxidation. Because the substantia nigra is rich in dopamine, which can undergo both enzymatic oxidation via monoamine oxidase and nonenzymatic autoxidation, hydrogen peroxide and oxyradicals (superoxide anion radical and hydroxyl radical) are generated in this midbrain nucleus. Although proof that oxidant stress actually causes the loss of monoaminergic neurons in patients with Parkinson's disease is lacking, there is a considerable body of evidence from studies in both animals and humans that support the concept. (1) Neurotoxins that selectively destroy the dopaminergic neurons in the nigra, such as 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), appear to act via oxidant stress. (2) The substantia nigra of patients with Parkinson's disease reveals evidence of oxidant stress by the findings of increased lipid peroxidation and decreased reduced glutathione. (3) Total iron is increased and ferritin is reduced in the substantia nigra pars compacta in patients with Parkinson's disease. This combination suggests that this transition metal is in a low molecular weight form, capable of catalyzing nonenzymatic oxidative reactions, especially the conversion of hydrogen peroxide to hydroxyl radical, which is the most reactive of the oxygen radicals. (4) Neuromelanin, a product of dopamine autoxidation, can serve as a reservoir for iron, promoting the generation of oxyradicals. (5) Antioxidant defense mechanisms appear to be reduced in the parkinsonian substantia nigra with the findings of decreased activities of glutathione peroxidase and catalase.(ABSTRACT TRUNCATED AT 250 WORDS)

Iron in Chronic Brain Disorders: Imaging and Neurotherapeutic Implications

“…167 A comprehensive open label study in humans with PD suggested that treatment with high doses of both vitamins A and C, putative antioxidants, delayed the need for levodopa or dopamine agonist therapy by 2.5 years. 168 Many antioxidants have been suggested for use in PD, but have not reached human trials. For a more extensive review on antioxidant therapy in PD, the reader is referred to the recent review by Singh et al 169 The EAE models have been attenuated by multiple antioxidants including tirilizad mesylate, 148 n-acetylcysteine, 170 catalase, 171 butylated hydroxyanisole, 172 Euk-8, 173 alpha lipoate, 174 and a green tea analogue.…”

Cytoprotective effects of growth factors: BDNF more potent than GDNF in an organotypic culture model of Parkinson's disease

“…A key player of the excessive oxidative stress seen in dopaminergic cells is DA metabolism itself (152,153). Non-vesicular DA is an unstable molecule and is easily oxidized to produce free radicals, toxic quinones and melanin (154).…”

“…Extensive microgliosis, pro-inflammatory cytokines and oxidative stress-mediated damage is found in post mortem brains of PD patients (120-123, 196, 207, 208) as well as in animal models of PD (124,190,208,209), including upregulated expression of major histocompatibility complex (MHC) molecules and pro-inflammatory cytokines, including TNF-α and IL-1β (120,(122)(123)(124)190) and reactive oxygen-and nitrogen species (190,196,208). These features were co-localized with microglia and were increased in areas most affected by dopaminergic cell death, suggesting a significant role of microglia and inflammation in the degenerative process (153). In mice intoxicated with MPTP, a strong microglial reaction precedes a complete dopaminergic cell death (124,190,208), suggesting a participation of microglia in the neurodegenerative process.…”

“…AQP9 may potentially allow diffusion of this neurotoxin. Finally, DA itself serves as a toxic agent (152,153). In line with high levels of DAT in the SN as a vulnerability factor, AQP9 could potentially facilitate DA uptake and increase cytosolic DA to further escalate the oxidation (40).…”

“…As AQP4 is intimately linked to Kir4.1 (315,316), this could explain the highly expressed perineural pool seen in the SN. The high expression of AQP4 in SN could alternatively be related to the oxidative environment with eminent levels of ROS generated through DA metabolism (152)(153)(154)156) (434). However, its expression pattern in PD is sparse.…”