D-2-hydroxyglutaric acid induces oxidative stress in cerebral cortex of young rats - PubMed (original) (raw)
D-2-hydroxyglutaric acid induces oxidative stress in cerebral cortex of young rats
Alexandra Latini et al. Eur J Neurosci. 2003 May.
Abstract
Large amounts of d-2-hydroxyglutaric acid (DGA) accumulate in d-2-hydroxyglutaric aciduria (D-2-OHGA), an inherited neurometabolic disorder characterized by severe neurological dysfunction and cerebral atrophy. Despite the significant brain abnormalities, the neurotoxic mechanisms of brain injury in this disease are virtually unknown. In this work, the in vitro effect of DGA on various parameters of oxidative stress was investigated; namely chemiluminescence, thiobarbituric acid-reactive substances (TBA-RS), total radical-trapping antioxidant potential (TRAP), total antioxidant reactivity (TAR) and the activities of the antioxidant enzymes catalase, glutathione peroxidase and superoxide dismutase in cerebral cortex from 30-day-old-rats. DGA significantly increased chemiluminescence and TBA-RS and decreased TAR values in the cortical supernatants. In contrast, TRAP and the antioxidant enzyme activities were not altered by the metabolite. Furthermore, the DGA-induced increase of TBA-RS was fully prevented by the free radical scavengers ascorbic acid plus Trolox (water-soluble alpha-tocopherol) and attenuated by the inhibitor of nitric oxide synthase Nomega-nitro-L-arginine methyl ester (L-NAME), suggesting the role of superoxide, hydroxyl and nitric oxide radicals in this action. The data indicate a stimulation of lipid peroxidation through the production of free radicals and a reduction of the brain capacity to efficiently modulate the damage associated with the enhanced generation of free radicals by DGA. In the case that these findings also occur in human D-2-OHGA, it is feasible that oxidative stress may be involved in the pathophysiology of the brain injury observed in patients with this disease.
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