Evaluation of the mechanisms involved in leucine-induced oxidative damage in cerebral cortex of young rats

Abstract

Maple syrup urine disease (MSUD) is a metabolic disorder caused by the deficiency of the activity of the mitochondrial enzyme complex branched-chain L-2-keto acid dehydrogenase. The metabolic block results in tissue and body fluid accumulation of the branched-chain amino acids leucine (Leu), isoleucine and valine, as well as of their respective alpha-keto acids. Neurological sequelae are usually present in MSUD, but the pathophysiologic mechanisms of neurotoxicity are still poorly known. It was previously demonstrated that Leu elicits oxidative stress in rat brain. In the present study we investigated the possible mechanisms involved in Leu-induced oxidative damage. We observed a significant attenuation of Leu-elicited increase of thiobarbituric acid-reactive substances (TBA-RS) measurement when cortical homogenates were incubated in the presence of the free radical scavengers ascorbic acid plus trolox, dithiothreitol, glutathione, and superoxide dismutase, suggesting a probable involvement of superoxide and hydroxyl radicals in this effect. In contrast, the use of Nomega-nitro-L-arginine methyl ester or catalase (CAT) did not affect TBA-RS values. We also demonstrated an inhibitory effect of Leu on the activities of the antioxidant enzymes CAT and gluthathione peroxidase, as well as a significant reduction in the membrane-protein thiol content from mitochondrial enriched preparations. Furthermore, dichlorofluorescein levels were increased although not significantly by Leu. Taken together, our present data indicate that an unbalance between free radical formation and inhibition of critical enzyme activities may explain the mechanisms involved in the Leu-induced oxidative damage.

Behavioral Responses in Rats Submitted to Chronic Administration of Branched-Chain Amino Acids

“…Because the metabolites accumulating in MSUD induce oxidative stress (Fontella et al 2002;Bridi et al 2003Bridi et al , 2005Mescka et al 2011), which plays a critical role in the pathophysiology of depressive disorders, we also investigated whether free-radical generation could be involved in reduction in sucrose preference and higher immobility time. Corroborating this hypothesis, antioxidant administration prevented the decreased sweet food intake, increased immobility time, and increased adrenal gland weight.…”

“…Proposed mechanisms of neurotoxicity include energy deprivation and osmotic dysregulation (Howell and Lee 1963;Land et al 1976;Danner and Elsas 1989;Yudkoff et al 1994;Zielke et al 2002;Pilla et al 2003;Sgaravatti et al 2003;Ribeiro et al 2008) and alterations in the concentrations of the neurotransmitters glutamate, aspartate, and aminobutyric in the brain (Dodd et al 1992;Prensky and Moser 1967;Tavares et al 2000;Yudkoff et al 1994;Hutson et al 2001). The brain injury in this disorder may also be related to a reduction of brain uptake of essential amino acids (Araújo et al 2001;Wajner and Vargas 1999;Wajner et al 2000), apoptosis of neural cells (Jouvet et al 2000), oxidative stress (Bridi et al 2003(Bridi et al , 2005Fontella et al 2002;Barschak et al 2006;Mescka et al 2011), increased acetylcholinesterase activity in the brain (Scaini et al 2012), and alterations of neurotrophin levels (Scaini et al 2013a, b).…”

“…Therefore, in this study, we assessed anhedonia, measured by sucrose intake, immobility during the forced swimming test and body and adrenal gland weight in rats submitted to chronic administration of BCAA during development. Because previous observations suggested that oxidative stress may be involved in the pathophysiology of the neurological dysfunction of MSUD (Bridi et al 2003(Bridi et al , 2005Fontella et al 2002;Barschak et al 2006;Mescka et al 2011) and these variables suggest depressive-like symptoms (Katz et al 1981b;Gamaro et al 2003;Lucca et al 2008), we also investigated the influence of the concomitant administration of N-acetylcysteine (NAC) plus deferoxamine (DFX) or imipramine in the behavioral tasks.…”

Differential growth performance, intestinal antioxidant status and relative expression of Nrf2 and its target genes in young grass carp (Ctenopharyngodon idella) fed with graded levels of leucine

“…Abidi and Khan (2007) indicated that excessive leucine leads to the high oxidation to ketones and accumulation of other toxic metabolite. In cerebral cortex of rats, the accumulation of leucine and its metabolite inhibited activities of antioxidant enzymes CAT and GPx, thus leading to oxidative damage (Bridi et al, 2005). These may assist to interpret the depression ) for 8 weeks.…”

Cerebral Oedema, Blood–Brain Barrier Breakdown and the Decrease in Na+,K+-ATPase Activity in the Cerebral Cortex and Hippocampus are Prevented by Dexamethasone in an Animal Model of Maple Syrup Urine Disease

“…Corroborating this hypothesis, our results showed that acute administration of H-BCAA induced a significant increase in IL-1β, IL-6 and TNF-α levels in the hippocampus and cerebral cortex. Moreover, previous studies have shown that the BCAAs cause oxidative stress [56][57][58][59][60][61][62] and inflammation [63,64] and induce mitochondrial dysfunction [65][66][67][68]. Thus, BBB breakdown and a decrease in Na + ,K + -ATPase activity may be a result of excess reactive oxygen species, impaired energy metabolism and the inflammatory response induced by H-BCAA.…”