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

Authors


Address correspondence and reprint requests to Prof. B. Halliwell at Neurodegenerative Diseases Research Centre, Pharmacology Group, King's College, Manresa Road, London, SW3 6LX U.K.

Abstract

Abstract: Oxidative damage has been implicated in the pathology of Parkinson's disease (PD), e.g., 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 (ONOO) or hydroxyl radicals (OH), 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.

Abbreviations used: ANCOVA, analysis of covariance; BSTFA + 1% TMS, N,O-bis(trimethylsilyl)trifluoroacetamide + 1% trimethylchlorosilane; FAPy adenine, 4,6-diamino-5-formamidopyrimidine; FAPy guanine, 2,6-diamino-4-hydroxy-5-formamidopyrimidine; GC/MS, gas chromatography/mass spectrometry; I.S., internal standard; MDA, malondialdehyde; 8-OHdG, 8-hydroxy-2′-deoxyguanosine; 8-OHG, 8-hydroxyguanine; PD, Parkinson's disease; PMI, postmortem interval.

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