Ribeiro César Augusto João, Hickmann Fernanda Hermes, Wajner Moacir
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Int J Dev Neurosci. 2011 Feb;29(1):1-7. doi: 10.1016/j.ijdevneu.2010.10.007. Epub 2010 Nov 2.
3-Methylglutaconic aciduria (MGTA) comprehends a group of disorders biochemically characterized by accumulation of 3-methylglutaric acid (MGA), 3-methylglutaconic acid (MGT) and occasionally 3-hydroxyisovaleric acid (OHIVA). Although neurological symptoms are common in the affected individuals, the mechanisms of brain damage are poorly known. In the present study we investigated the in vitro effect MGA, MGT and OHIVA, at concentrations ranging from 0.1 to 5.0mM, on bioenergetics and oxidative stress in synaptosomal preparations isolated from cerebral cortex of young rats. MGA significantly reduced mitochondrial redox potential (25%), as determined by resazurin reduction, and inhibited the activity of Na(+),K(+)-ATPase (30%), whereas MGT and OHIVA did not modify these parameters. Moreover, the inhibitory effect elicited by MGA on Na(+),K(+)-ATPase activity was totally prevented by co-incubation with the scavenging antioxidants creatine and melatonin, implying a role for reactive species in this effect. MGA also increased 2',7'-dichlorofluorescein (DCFH) oxidation (30%), reinforcing that this organic acid induces reactive species production. The present data indicate that MGA compromises mitochondrial function, elicits reactive species production and inhibits the activity of a crucial enzyme implicated in neurotransmission. It is therefore presumed that these deleterious effects may play a role in the pathophysiology of the brain damage observed in patients affected by disorders in which MGA accumulates.
3-甲基戊二酸尿症（MGTA）包括一组生化特征为3-甲基戊二酸（MGA）、3-甲基戊烯二酸（MGT）以及偶尔还有3-羟基异戊酸（OHIVA）蓄积的疾病。尽管神经系统症状在受影响个体中很常见，但脑损伤的机制却知之甚少。在本研究中，我们研究了浓度范围为0.1至5.0mM的MGA、MGT和OHIVA对从幼鼠大脑皮层分离的突触体标本中的生物能量学和氧化应激的体外影响。通过刃天青还原测定，MGA显著降低了线粒体氧化还原电位（25%），并抑制了Na(+)、K(+)-ATP酶的活性（30%），而MGT和OHIVA并未改变这些参数。此外，MGA对Na(+)、K(+)-ATP酶活性的抑制作用通过与清除抗氧化剂肌酸和褪黑素共同孵育而完全被阻止，这意味着活性物质在这种作用中发挥了作用。MGA还增加了2',7'-二氯荧光素（DCFH）的氧化（30%），进一步证明这种有机酸会诱导活性物质的产生。目前的数据表明，MGA损害线粒体功能，引发活性物质的产生，并抑制一种与神经传递有关的关键酶的活性。因此推测，这些有害作用可能在受MGA蓄积疾病影响的患者所观察到的脑损伤病理生理学中起作用。
