Ribeiro César A, Sgaravatti Angela M, Rosa Rafael B, Schuck Patrícia F, Grando Vanessa, Schmidt Anna L, Ferreira Gustavo C, Perry Marcos L S, Dutra-Filho Carlos S, Wajner Moacir
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600-Anexo, Porto Alegre, RS, CEP 90035-003, Brazil.
Neurochem Res. 2008 Jan;33(1):114-24. doi: 10.1007/s11064-007-9423-9. Epub 2007 Aug 8.
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.
在本研究中，我们调查了枫糖尿症（MSUD）中积累的支链氨基酸（BCAA）对大鼠大脑皮层能量代谢某些参数的体外影响。通过在无（对照）或有亮氨酸（Leu）、缬氨酸（Val）或异亮氨酸（Ile）存在的情况下孵育30日龄大鼠的皮质棱柱体，评估了[1-¹⁴C]乙酸盐、[1-5-¹⁴C]柠檬酸盐和[U-¹⁴C]葡萄糖产生¹⁴CO₂的情况以及大脑对葡萄糖的摄取。与葡萄糖利用情况显著增加高达90%相反，所有氨基酸均使¹⁴CO₂产生显著降低约20 - 55%。此外，Leu显著抑制呼吸链复合体IV的活性，而Val和Ile分别使复合体II - III、III和IV的活性显著抑制高达40%。我们还观察到生育三烯酚（α-生育酚）和肌酸完全阻止了BCAA对呼吸链复合体活性的抑制作用，这表明自由基参与了这些作用。结果表明，MSUD中积累的主要代谢产物通过损害柠檬酸循环和呼吸链中的电子流来干扰大脑有氧代谢。我们推测这些发现可能与理解MSUD患者神经功能障碍的病理生理学相关。
