A chemically-induced acute model of maple syrup urine disease in rats for neurochemical studies

Bridi, Raquel; Fontella, Fernanda U.; Pulrolnik, Vánia; Braun, César A.; Zorzi, Giovanni K.; Coelho, Daniella de Moura; Wajner, Moaçir; Vargas, Carmen Regla; Dutra-Filho, Carlos Severo

doi:10.1016/j.jneumeth.2006.01.005

Cited by 29 publications

(18 citation statements)

References 22 publications

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“…The animals received two subcutaneous injections per day of the BCAA pool (15.8 mL/g body weight at 12-h intervals) containing 190 mmol/L Leu, 59 mmol/L Ile, and 69 mmol/L Val in saline solution, administered for 21 days starting at postnatal day (PD) 7 (last injection at PD 27) (n ¼ 12, per group) (Bridi et al 2006). Immediately after administration of the first injection of the BCAA pool, NAC was administered subcutaneously twice a day (at 12-h intervals) and DFX was administered once every two days for a total of 21 days (Di-Pietro et al 2008).…”

Section: Animalsmentioning

confidence: 99%

“…Twelve hours after the last injection of BCAA, the animals were submitted to behavioral testing. The choice of the administered doses and the ages of the rats were based on a previous study (Bridi et al 2006), which showed that the administration of the BCAA pool to rats (similar doses and ages to those used in this study) resulted in increased levels of Leu, Ile, and Val in the blood and brain. Importantly, the dose of the BCAA pool mimicked the biochemical events observed in MSUD patients during crises, but in this model leucine levels in plasma and brain returned to basal values after 12 h the final BCAA injection, thus, we evaluate the chronic effects of daily episodes of metabolic decompensation.…”

Section: Animalsmentioning

confidence: 99%

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

et al. 2013

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Maple syrup urine disease (MSUD) is an inborn metabolism error caused by a deficiency of branched-chain a-keto acid dehydrogenase complex activity. This blockage leads to an accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, as well as their corresponding a-keto and a-hydroxy acids. Previous reports suggest that MSUD patients are at high risk for chronic neuropsychiatric problems. Therefore, in this study, we assessed variables that suggest depressive-like symptoms (anhedonia as 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. Furthermore, we determined if these parameters were sensitive to imipramine and N-acetylcysteine/deferoxamine (NAC/DFX). Our results demonstrated that animals subjected to chronic administration of branched-chain amino acids showed a decrease in sucrose intake without significant changes in body weight. We also observed an increase in adrenal gland weight and immobility time during the forced swimming test. However, treatment with imipramine and NAC/DFX reversed these changes in the behavioral tasks. In conclusion, this study demonstrates a link between MSUD and depression in rats. Moreover, this investigation reveals that the antidepressant action of NAC/DFX and imipramine might be associated with their capability to maintain pro-/anti-oxidative homeostasis.

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Section: Animalsmentioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

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

et al. 2013

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“…However, Leu and KIC are considered the main neurotoxins in this disorder since increased plasma concentrations of these compounds (up to 5.0 mM) are associated with the appearance of neurological symptoms [1,[6][7][8]. In addition, it has been postulated that demyelination [3,9,10], neurotransmitter disturbances [11][12][13][14], reduced brain uptake of essential amino acids [15], induction of oxidative stress [16][17][18], apoptosis [19] and energetic deficit [8,[20][21][22][23][24] may be related to the brain injury of MSUD.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Brain Energy Metabolism by the Branched-chain Amino Acids Accumulating in Maple Syrup Urine Disease

et al. 2007

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In the present work we investigated the in vitro effect of the branched-chain amino acids (BCAA) accumulating in maple syrup urine disease (MSUD) on some parameters of energy metabolism in cerebral cortex of rats. 14CO2 production from [1-14C]acetate, [1-5-14C]citrate and [U-14C]glucose, as well as glucose uptake by the brain were evaluated by incubating cortical prisms from 30-day-old rats in the absence (controls) or presence of leucine (Leu), valine (Val) or isoleucine (Ile). All amino acids significantly reduced 14CO2 production by around 20-55%, in contrast to glucose utilization, which was significantly increased by up to 90%. Furthermore, Leu significantly inhibited the activity of the respiratory chain complex IV, whereas Val and Ile markedly inhibited complexes II-III, III and IV by up to 40%. We also observed that trolox (alpha-tocopherol) and creatine totally prevented the inhibitory effects provoked by the BCAA on the respiratory chain complex activities, suggesting that free radicals were involved in these effects. The results indicate that the major metabolites accumulating in MSUD disturb brain aerobic metabolism by compromising the citric acid cycle and the electron flow through the respiratory chain. We presume that these findings may be of relevance to the understanding of the pathophysiology of the neurological dysfunction of MSUD patients.

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“…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).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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Leucine accumulates in fluids and tissues of patients affected by maple syrup urine disease, an inherited metabolic disorder, predominantly characterized by neurological dysfunction. Although, a variable degree of cognition/psychomotor delay/mental retardation is found in a considerable number of individuals affected by this deficiency, the mechanisms underlying the neuropathology of these alterations are still not defined. Therefore, the aim of this study was to investigate the effect of acute intra-hippocampal leucine administration in the step-down test in rats. In addition, the leucine effects on the electrophysiological parameter, long-term potentiation generation, and on the activities of the respiratory chain were also investigated. Male Wistar rats were bilaterally administrated with leucine (80 nmol/hippocampus; 160 nmol/rat) or artificial cerebrospinal fluid (controls) into the hippocampus immediately post-training in the behavioral task. Twenty-four hours after training in the step-down test, the latency time was evaluated and afterwards animals were sacrificed for assessing the ex vivo biochemical measurements. Leucine-treated animals showed impairment in memory consolidation and a complete inhibition of long-term potentiation generation at supramaximal stimulation. In addition, a significant increment in complex IV activity was observed in hippocampus from leucine-administered rats. These data strongly indicate that leucine compromise memory consolidation, and that impairment of long-term potentiation generation and unbalance of the respiratory chain may be plausible mechanisms underlying the deleterious leucine effect on cognition.

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A chemically-induced acute model of maple syrup urine disease in rats for neurochemical studies

Cited by 29 publications

References 22 publications

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

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

Inhibition of Brain Energy Metabolism by the Branched-chain Amino Acids Accumulating in Maple Syrup Urine Disease

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

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