Amaral Alexandre Umpierrez, Leipnitz Guilhian, Fernandes Carolina Gonçalves, Seminotti Bianca, Zanatta Angela, Viegas Carolina Maso, Dutra-Filho Carlos Severo, Wajner Moacir
Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal de Rio Grande do Sul, Porto Alegre, RS, Brazil.
Int J Dev Neurosci. 2009 Nov;27(7):635-41. doi: 10.1016/j.ijdevneu.2009.08.004. Epub 2009 Aug 13.
Ornithine and homocitrulline are the major metabolites accumulating in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome, a genetic disorder characterized by neurological regression whose pathogenesis is still not understood. The present work investigated the in vitro effects of ornithine and homocitrulline on important parameters of oxidative stress in cerebral cortex from young rats. Ornithine significantly increased chemiluminescence and thiobarbituric acid-reactive substances levels, indicators of lipid peroxidation, while homocitrulline only augmented chemiluminescence values. Furthermore, ornithine-induced increase of thiobarbituric acid-reactive substances levels was attenuated (melatonin and reduced glutathione) or totally prevented (alpha-tocopherol) by free radical scavengers, suggesting that reactive species were involved in the lipid oxidative damage. We also observed that ornithine and homocitrulline significantly decreased the tissue antioxidant defenses, determined by reduced glutathione concentrations, the major non-enzymatic antioxidant defense found in the brain. Homocitrulline reduction of glutathione levels was completely prevented by melatonin and alpha-tocopherol, whereas ornithine-induced decrease of glutathione levels was only attenuated by these free radical scavengers. Ornithine and homocitrulline also induced protein oxidative damage, increasing carbonyl formation and sulfhydryl oxidation. In contrast, these amino acids did not affect nitric oxide production, indicating that nitrogen reactive species were not implicated in the lipid and oxidative damage provoked by ornithine and homocitrulline. Therefore, it is presumed that the major metabolites accumulating in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome elicit oxidative stress and that this pathomechanism may possibly be involved in the brain damage found in patients affected by this disorder.
鸟氨酸和高瓜氨酸是高鸟氨酸血症-高氨血症-高瓜氨酸尿综合征中积累的主要代谢产物，该综合征是一种以神经功能衰退为特征的遗传疾病，其发病机制仍不清楚。本研究调查了鸟氨酸和高瓜氨酸对幼鼠大脑皮质氧化应激重要参数的体外影响。鸟氨酸显著增加了化学发光和硫代巴比妥酸反应性物质水平，这是脂质过氧化的指标，而高瓜氨酸仅增加了化学发光值。此外，自由基清除剂减弱了（褪黑素和还原型谷胱甘肽）或完全阻止了（α-生育酚）鸟氨酸诱导的硫代巴比妥酸反应性物质水平的升高，表明活性物质参与了脂质氧化损伤。我们还观察到，鸟氨酸和高瓜氨酸显著降低了由还原型谷胱甘肽浓度决定的组织抗氧化防御能力，还原型谷胱甘肽是大脑中主要的非酶抗氧化防御物质。褪黑素和α-生育酚完全阻止了高瓜氨酸对谷胱甘肽水平的降低，而这些自由基清除剂仅减弱了鸟氨酸诱导的谷胱甘肽水平的降低。鸟氨酸和高瓜氨酸还诱导了蛋白质氧化损伤，增加了羰基形成和巯基氧化。相比之下，这些氨基酸不影响一氧化氮的产生，表明氮活性物质与鸟氨酸和高瓜氨酸引起的脂质和氧化损伤无关。因此，推测高鸟氨酸血症-高氨血症-高瓜氨酸尿综合征中积累的主要代谢产物会引发氧化应激，并且这种病理机制可能参与了受该疾病影响患者的脑损伤。
