Induction of oxidative stress by the metabolites accumulating in 3-methylglutaconic aciduria in cerebral cortex of young rats.

Abstract:

:3-methylglutaconic (MGT), 3-methylglutaric (MGA) and occasionally 3-hydroxyisovaleric (OHIVA) acids accumulate in a group of diseases known as 3-methylglutaconic aciduria (MGTA). Although the clinical presentation of MGTA is mainly characterized by neurological symptoms, the mechanisms of brain damage in this disease are poorly known. In the present study we investigated the in vitro effect of MGT, MGA and OHIVA on various parameters of oxidative stress in cerebral cortex from young rats. Thiobarbituric acid-reactive substances (TBA-RS) and chemiluminescence were significantly increased by MGT, MGA and OHIVA, indicating that these metabolites induce lipid oxidative damage. Furthermore, the addition of melatonin, alpha-tocopherol and superoxide dismutase plus catalase fully prevented MGT-induced increase on TBA-RS, suggesting that free radicals were involved in this effect. These metabolites also provoked protein oxidative damage determined by increased carbonyl formation and sulfhydryl oxidation, but did not induce superoxide generation in submitochondrial particles. It was also verified that MGA and MGT significantly decreased the non-enzymatic antioxidant defenses in cerebral cortex supernatants and that melatonin and alpha-tocopherol totally blocked MGA-induced GSH reduction. The data indicate that the metabolites accumulating in MGTA elicit oxidative stress in vitro in the cerebral cortex. It is therefore presumed that this pathomechanism may be involved in the brain damage observed in patients affected by MGTA.

journal_name

Life Sci

journal_title

Life sciences

authors

Leipnitz G,Seminotti B,Amaral AU,de Bortoli G,Solano A,Schuck PF,Wyse AT,Wannmacher CM,Latini A,Wajner M

doi

10.1016/j.lfs.2007.12.024

subject

Has Abstract

pub_date

2008-03-12 00:00:00

pages

652-62

issue

11-12

eissn

0024-3205

issn

1879-0631

pii

S0024-3205(08)00010-6

journal_volume

82

pub_type

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