Oxidative DNA Damage in the Parkinsonian Brain: An Apparent Selective Increase in 8‐Hydroxyguanine Levels in Substantia Nigra

Abstract

Abstract:Oxidative damage has been implicated in the pathology of Parkinson's disease (PD), eg., rises in the level of the DNA damage product, 8-hydroxy-2 '-deoxyguanosine, have been reported. However, many other products result from oxidative DNA damage, and the pattern of products can be diagnostic of the oxidizing species. Gas chromatography/mass spectrometry was used to examine products of oxidation and deamination of all four DNA bases in control and PD brains. Products were detected in all brain regions examined, both normal and PD. Analysis showed that levels of 8-hydroxyguanine (8-OHG) tended to be elevated and levels of 2,6-diamino-4-hydroxy-5-formamidopyrimidine (FAPy guanine) tended to be decreased in PD. The most striking difference was a rise in 8-OHG in PD substantia nigra (p = 0.0002); rises in other base oxidation/deamination products were not evident, showing that elevation in 8-OHG is unlikely to be due to peroxynitrite (0N00) or hydroxyl radicals (0H), or to be a prooxidant effect of treatment with L-Dopa. However, some or all of the rise in 8-OHG could be due to a change in 8-OHG/FAPy guanine ratios rather than to an increase in total oxidative guanine damage. Key Words: Parkinson's diseaseOxidative damage-8-Hydroxyguanosine-Substantia nigra.

Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease—resemblance to the effect of amphetamine drugs of abuse

“…is also elevated in the neurons affected in the disease, compared to surrounding brain regions in the PD brain, as well as in comparison to the SN of ageͲmatched controls [87,88]. Lipid and DNA oxidation were also found to be systemically elevated in PD [82].…”

Potent induction of total cellular GSH and NQO1 as well as mitochondrial GSH by 3H-1,2-dithiole-3-thione in SH-SY5Y neuroblastoma cells and primary human neurons: Protection against neurocytotoxicity elicited by dopamine, 6-hydroxydopamine, 4-hydroxy-2-nonenal, or hydrogen peroxide

“…Dopaminergic neurons are particularly prone to oxidative and electrophilic stress due to oxidation of dopamine, resulting in the generation of ROS as well as the electrophilic quinone molecules (Spina and Cohen, 1989). ROS-induced alteration of macromolecules including polyunsaturated fatty acids in membrane lipids, proteins, and DNA has been observed in the substantia nigra of the parkinsonian patients and animal models (Alam et al, 1997a;Alam et al, 1997b;Selley, 1998).…”

Protective effect of erythropoietin against 1-methyl-4-phenylpyridinium-induced neurodegenaration in PC12 cells

“…MPTP produces reactive oxygen species (ROS) in vivo via the active metabolite 1-methyl-4-phenyl pyridinium ion (MPP + ), which stimulates the superoxide radical production in vitro and induces cell death in PC12 cells [2] . Moreover, MPTP generates hydroxyl radicals to cause membrane lipid peroxidation or DNA damage, which is thought to be a mechanism of dopaminergic neuron degeneration [3] . Hence, chemicals that reduce the oxidative stress induced by MPP + are supposed to be neuroprotective in Parkinson's disease.…”