Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Rua Ramiro Barcelos, 2600 - Anexo, 90035-003, Porto Alegre, RS, Brazil.
Metab Brain Dis. 2012 Dec;27(4):521-30. doi: 10.1007/s11011-012-9327-5. Epub 2012 Jul 15.
Ornithine, ammonia 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 vivo effects of intracerebroventricular administration of ornithine and homocitrulline in the presence or absence of hyperammonemia induced by intraperitoneal urease treatment on a large spectrum of oxidative stress parameters in cerebral cortex from young rats in order to better understand the role of these metabolites on brain damage. Ornithine increased thiobarbituric acid-reactive substances (TBA-RS) levels and carbonyl formation and decreased total antioxidant status (TAS) levels. We also observed that the combination of hyperammonemia with ornithine resulted in significant decreases of sulfhydryl levels, reduced glutathione (GSH) concentrations and the activities of catalase (CAT) and glutathione peroxidase (GPx), highlighting a synergistic effect of ornithine and ammonia. Furthermore, homocitrulline caused increases of TBA-RS values and carbonyl formation, as well as decreases of GSH concentrations and GPx activity. Hcit with hyperammonemia (urease treatment) decreased TAS and CAT activity. We also showed that urease treatment per se was able to enhance TBA-RS levels. Finally, nitric oxide production was not altered by Orn and Hcit alone or in combination with hyperammonemia. Our data indicate that the major metabolites accumulating in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome provoke lipid and protein oxidative damage and a reduction of the antioxidant defenses in the brain. Therefore, it is presumed that oxidative stress may represent a relevant pathomechanism involved in the brain damage found in patients affected by this disease.
鸟氨酸、氨和同型瓜氨酸是高鸟氨酸血症-高氨血症-同型瓜氨酸尿症综合征中主要积累的代谢物，这是一种遗传性疾病，其特征为神经退行性变，但发病机制尚不清楚。本研究在腹腔内脲酶处理诱导高氨血症的情况下，通过侧脑室给予鸟氨酸和同型瓜氨酸，观察其对幼年大鼠大脑皮质多种氧化应激参数的体内影响，以期更好地理解这些代谢物对脑损伤的作用。鸟氨酸增加了丙二醛（TBA-RS）含量和羰基形成，降低了总抗氧化状态（TAS）水平。我们还观察到，高氨血症与鸟氨酸联合使用导致巯基水平、还原型谷胱甘肽（GSH）浓度和过氧化氢酶（CAT）、谷胱甘肽过氧化物酶（GPx）活性显著降低，表明鸟氨酸和氨具有协同作用。此外，同型瓜氨酸导致 TBA-RS 值和羰基形成增加，GSH 浓度和 GPx 活性降低。高氨血症（脲酶处理）与同型瓜氨酸联合使用降低了 TAS 和 CAT 活性。我们还表明，脲酶处理本身就能够增强 TBA-RS 水平。最后，鸟氨酸和同型瓜氨酸单独或与高氨血症联合使用均不改变一氧化氮的产生。我们的数据表明，高鸟氨酸血症-高氨血症-同型瓜氨酸尿症综合征中积累的主要代谢物会引起大脑中的脂质和蛋白质氧化损伤，并降低抗氧化防御能力。因此，可以推测氧化应激可能是这种疾病患者脑损伤的相关发病机制之一。
