Induction of oxidative stress in rat brain by the metabolites accumulating in maple syrup urine disease

Abstract

Maple syrup urine disease (MSUD) is an inherited disorder caused by deficiency of branched-chain L-2-keto acid dehydrogenase complex activity. Affected patients present severe brain dysfunction manifested as convulsions, coma, psychomotor delay and mental retardation. However, the underlying mechanisms of these neurological findings are virtually unknown. In this study, we tested the in vitro effect of L-leucine, L-isoleucine and L-valine, the amino acids accumulating in MSUD, on the lipid peroxidation parameters chemiluminescence and thiobarbituric acid-reactive substances (TBA-RS), as well as on total radical-trapping antioxidant potential (TRAP) and total antioxidant reactivity (TAR) in cerebral cortex from 30-day-old rats. L-Leucine significantly increased chemiluminescence and TBA-RS measurements and markedly decreased TRAP and TAR values. L-Isoleucine increased chemiluminescence and decreased TRAP measurements, but TAR and TBA-RS levels were not altered by the amino acid. Finally, TRAP measurement was diminished by L-valine. The results indicate a stimulation of lipid peroxidation and a reduction of brain capacity to efficiently modulate the damage associated with an increased production of free radicals by the branched-chain amino acids (BCAAs) accumulated in MSUD. It is therefore tempting to speculate that oxidative stress may be implicated in the brain damage found in MSUD patients.

The Intra-Hippocampal Leucine Administration Impairs Memory Consolidation and LTP Generation in Rats

“…In addition, compensatory increased respiratory chain activity has also been involved with oxidative stress induction (Shigenaga et al 1994;Witte et al 2009). This is in agreement with the studies performed by Fontella et al (2002) and Bridi et al (2003) demonstrating LEU-induced oxidative stress in rat brain, and with the putative role of ROS in the coordination of the mitochondrial genome and the expression of nuclearencoded mitochondrial genes (Li et al 1995).…”

“…In this context, a large body of in vitro and in vivo studies has pointed out LEU accumulation as the main toxic condition in MSUD. In this context, it has been demonstrated that high LEU concentrations alter brain energy metabolism (Howell and Lee 1963;Halestrap et al 1974;Pilla et al 2003a, b;Sgaravatti et al 2003;Ribeiro et al, 2008;Zinnati et al 2009;Amaral et al 2010), glutamatergic neurotransmission system (Tashian 1961;Tavares et al 2000;Zinnanti et al 2009), brain uptake of essential amino acids (Araujo et al 2001), and induces oxidative stress and apoptosis (Jouvet et al, 2000;Fontella et al, 2002;Bridi et al, 2003;Bridi et al 2006). In addition, behavioral deficits induced by LEU administration or its cognate a-ketoacid and a-hydroxyisocaproate, have also been reported (Mello et al 1999;Vasques et al 2005;Zinnanti et al 2009).…”

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.…”