α-Keto Acids Accumulating in Maple Syrup Urine Disease Stimulate Lipid Peroxidation and Reduce Antioxidant Defences in Cerebral Cortex From Young Rats

Bridi, Raquel; Braun, César A.; Zorzi, Giovanni K.; Wannmacher, Clóvis Milton Duval; Wajner, Moaçir; Lissi, Eduardo; Dutra-Filho, Carlos Severo

doi:10.1007/s11011-005-4152-8

Cited by 71 publications

(44 citation statements)

References 36 publications

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“…Otherwise, the nitric oxide synthase inhibitor L-NAME fully prevented the inhibitory effect of the BCKA on CK activity from C6 glioma cells indicating that NO is probably involved in those effects. The previous findings that the BCKA induce oxidative stress in the brain corroborates with our findings (Fontella et al, 2002;Bridi et al, 2005).…”

Section: Discussionsupporting

confidence: 93%

The Human Serotonin 1A Receptor Expressed in Neuronal Cells: Toward a Native Environment for Neuronal Receptors

Paila¹,

Chattopadhyay²

2006

Cell Mol Neurobiol

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Accumulation of the branched-chain alpha-keto acids (BCKA), alpha-ketoisocaproic acid (KIC), alpha-keto-beta-methylvaleric acid (KMV), and alpha-ketoisovaleric acid (KIV) and their respective branched-chain alpha-amino acids (BCAA) in tissues and biological fluids is the biochemical hallmark of patients affected by the neurometabolic disorder known as maple syrup urine disease (MSUD). Considering that brain energy metabolism is possibly altered in MSUD, the objective of this study was to determine creatine kinase (CK) activity, a key enzyme of energy homeostasis, in C6 glioma cells exposed to BCKA. The cells were incubated with 1, 5, or 10 mM BCKA for 3 h and the CK activity measured afterwards. The results indicated that the BCKA significantly inhibited CK activity at all tested concentrations. Furthermore, the inhibition caused by the BCKA on CK activity was totally prevented by preincubation with the energetic substrate creatine and by coincubation with the N-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase inhibitor, indicating that deficit of energy and nitric oxide (NO) are involved in these effects. In contrast, other antioxidants such as glutathione (GSH) and trolox (soluble Vitamin E) were not able to prevent CK inhibition. In addition, we observed that the C6 cells changed their usual rounded morphology when exposed for 3 h to 10 mM BCKA and that creatine and L-NAME prevented these morphological alterations. Considering the importance of CK for brain metabolism homeostasis, it is conceivable that inhibition of this enzyme by increased levels of BCKA may contribute to the neurodegeneration of MSUD patients.

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Section: Discussionsupporting

confidence: 93%

The Human Serotonin 1A Receptor Expressed in Neuronal Cells: Toward a Native Environment for Neuronal Receptors

Paila¹,

Chattopadhyay²

2006

Cell Mol Neurobiol

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“…Oxidative stress was also demonstrated in disorders of amino acid metabolism, such as maple syrup urine disease (MSUD), tyrosinemia type I, and homocystinuria (Barschak et al , 2007(Barschak et al , and 2008Bridi et al 2005;Bird et al 1995;Streck et al 2001 andWyse et al 2002). Now, we will focus the role of oxidative stress in PKU.…”

Section: Oxidative Stress and Neurodegenerationmentioning

confidence: 99%

Oxidative Stress in Phenylketonuria: What is the Evidence?

et al. 2011

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Phenylketonuria (PKU) is an inborn error of amino acid metabolism caused by severe deficiency of phenylalanine hydroxylase activity, leading to the accumulation of phenylalanine and its metabolites in blood and tissues of affected patients. Phenylketonuric patients present as the major clinical feature mental retardation, whose pathomechanisms are poorly understood. In recent years, mounting evidence has emerged indicating that oxidative stress is possibly involved in the pathology of PKU. This article addresses some of the recent developments obtained from animal studies and from phenylketonuric patients indicating that oxidative stress may represent an important element in the pathophysiology of PKU. Several studies have shown that enzymatic and non-enzymatic antioxidant defenses are decreased in plasma and erythrocytes of PKU patients, which may be due to an increased free radical generation or secondary to the deprivation of micronutrients which are essential for these defenses. Indeed, markers of lipid, protein, and DNA oxidative damage have been reported in PKU patients, implying that reactive species production is increased in this disorder. A considerable set of data from in vitro and in vivo animal studies have shown that phenylalanine and/or its metabolites elicit reactive species in brain rodent. These findings point to a disruption of pro-oxidant/antioxidant balance in PKU. Considering that the brain is particularly vulnerable to oxidative attack, it is presumed that the administration of appropriate antioxidants as adjuvant agents, in addition to the usual treatment based on restricted diets or supplementation of tetrahydrobiopterin, may represent another step in the prevention of the neurological damage in PKU.

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“…They conclude that this mechanism might contribute to neurological damage in MSUD, as Na-K ATPase pump is a critical enzyme for normal brain development and functioning. Bridi et al (2005) also report that alpha keto acids accumulating in MSUD stimulate lipid peroxidation and reduce antioxidant defense in cerebral cortex.…”

Section: Review Of Literaturementioning

confidence: 89%

Inborn Errors of Metabolism and Brain Involvement - 5 Years Experience from a Tertiary Care Center in South India

Vaidyanathan¹,

Narayanan²,

Vasudevan³

2012

Brain Damage - Bridging Between Basic Research and Clinics

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α-Keto Acids Accumulating in Maple Syrup Urine Disease Stimulate Lipid Peroxidation and Reduce Antioxidant Defences in Cerebral Cortex From Young Rats

Cited by 71 publications

References 36 publications

The Human Serotonin 1A Receptor Expressed in Neuronal Cells: Toward a Native Environment for Neuronal Receptors

The Human Serotonin 1A Receptor Expressed in Neuronal Cells: Toward a Native Environment for Neuronal Receptors

Oxidative Stress in Phenylketonuria: What is the Evidence?

Inborn Errors of Metabolism and Brain Involvement - 5 Years Experience from a Tertiary Care Center in South India

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