Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, UFRGS, Rua Ramiro Barcelos, 2600, 90035-000, Porto Alegre, Rio Grande do Sul, Brazil.
Serviço de Genética Médica, HCPA, UFRGS, Rua Ramiro Barcelos, 2350, 90035-903, Porto Alegre, Rio Grande do Sul, Brazil.
Mol Neurobiol. 2016 Nov;53(9):6007-6017. doi: 10.1007/s12035-015-9500-z. Epub 2015 Nov 2.
Maple syrup urine disease (MSUD), or branched-chain α-keto aciduria, is an inherited disorder that is caused by a deficiency in branched-chain α-keto acid dehydrogenase complex (BCKAD) activity. Blockade of this pathway leads to the accumulation of the branched-chain amino acids (BCAAs), leucine, isoleucine, and valine, and their respective ketoacids in tissues. The main clinical symptoms presented by MSUD patients include ketoacidosis, hypoglycemia, opisthotonos, poor feeding, apnea, ataxia, convulsions, coma, psychomotor delay, and mental retardation. Although increasing evidence indicates that oxidative stress is involved in the pathophysiology of this disease, the mechanisms of the brain damage caused by this disorder remain poorly understood. In the present study, we investigated the effect of BCAAs on some oxidative stress parameters and evaluated the efficacy of L-carnitine (L-car), an efficient antioxidant that may be involved in the reduction of oxidative damage observed in some inherited neurometabolic diseases, against these possible pro-oxidant effects of a chronic MSUD model in the cerebral cortex and cerebellum of rats. Our results showed that chronic BCAA administration was able to promote both lipid and protein oxidation, impair brain antioxidant defenses, and increase reactive species production, particularly in the cerebral cortex, and that L-car was able to prevent these effects. Taken together, the present data indicate that chronic BCAA administration significantly increased oxidative damage in the brains of rats subjected to a chronic model of MSUD and that L-car may be an efficient antioxidant in this disorder.
枫糖尿症（MSUD），又称支链α-酮酸尿症，是一种遗传性疾病，由支链α-酮酸脱氢酶复合物（BCKAD）活性缺乏引起。该途径的阻断会导致支链氨基酸（BCAAs）、亮氨酸、异亮氨酸和缬氨酸及其各自的酮酸在组织中积累。MSUD 患者的主要临床症状包括酮酸中毒、低血糖、角弓反张、食欲不振、呼吸暂停、共济失调、抽搐、昏迷、精神运动迟缓、智力迟钝。尽管越来越多的证据表明氧化应激参与了这种疾病的病理生理学过程，但这种疾病引起的脑损伤机制仍知之甚少。在本研究中，我们研究了支链氨基酸对一些氧化应激参数的影响，并评估了左旋肉碱（L-car）的疗效，左旋肉碱是一种有效的抗氧化剂，可能参与了一些遗传性神经代谢疾病中观察到的氧化损伤的减少，针对大鼠大脑皮质和小脑慢性 MSUD 模型中这些潜在的促氧化作用。我们的结果表明，慢性支链氨基酸给药能够促进脂质和蛋白质氧化，损害大脑抗氧化防御能力，并增加活性物质的产生，特别是在大脑皮质中，而 L-car 能够预防这些作用。综上所述，这些数据表明，慢性支链氨基酸给药显著增加了慢性 MSUD 模型大鼠大脑中的氧化损伤，而 L-car 可能是这种疾病的有效抗氧化剂。
