Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, UFRGS, Porto Alegre, RS, Brazil.
Brain Res. 2011 Jan 19;1369:235-44. doi: 10.1016/j.brainres.2010.10.112. Epub 2010 Nov 5.
Hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome is an autosomal recessive disorder caused by a defect in the mitochondrial ornithine transporter, leading to accumulation of ornithine (Orn), homocitrulline (Hcit) and ammonia. Progressive neurological regression whose pathogenesis is not well established is common in this disease. The present work investigated the in vivo effects of intracerebroventricular administration of Orn and Hcit on important parameters of oxidative stress and energy metabolism in cerebral cortex from young rats. Orn and Hcit significantly increased thiobarbituric acid-reactive substances values and carbonyl formation, indicators of lipid and protein oxidative damage, respectively. Furthermore, N-acetylcysteine and the combination of the free radical scavengers ascorbic acid plus α-tocopherol attenuated the lipid oxidation and totally prevented the protein oxidative damage provoked by Orn and Hcit, suggesting that reactive species were involved in these effects. Hcit, but not Orn administration, also decreased glutathione concentrations, as well as the activity of catalase and glutathione peroxidase, indicating that Hcit provokes a reduction of brain antioxidant defenses. As regards to the parameters of energy metabolism, we verified that Orn and Hcit significantly inhibited the citric acid cycle function (inhibition of CO(2) synthesis from [1-(14)C] acetate), the aerobic glycolytic pathway (reduced CO(2) production from [U-(14)C] glucose) and complex I-III activity of the respiratory chain. Hcit also inhibited the activity of aconitase, an enzyme very susceptible to free radical attack. Taken together, our data indicate that mitochondrial homeostasis is disturbed by Orn and especially by Hcit. It is presumed that the impairment of brain bioenergetics and the oxidative damage induced by these metabolites may possibly contribute to the brain deterioration and neurological symptoms affecting patients with HHH syndrome.
高鸟氨酸血症-高血氨-同型瓜氨酸血症（HHH）综合征是一种常染色体隐性遗传疾病，由线粒体鸟氨酸转运蛋白缺陷引起，导致鸟氨酸（Orn）、同型瓜氨酸（Hcit）和氨的积累。这种疾病的共同特点是神经退行性病变进展，但其发病机制尚未完全确定。本研究旨在研究脑室内给予 Orn 和 Hcit 对幼年大鼠大脑皮质重要氧化应激和能量代谢参数的体内影响。Orn 和 Hcit 显著增加了丙二醛反应产物和羰基形成，分别为脂质和蛋白质氧化损伤的指标。此外，N-乙酰半胱氨酸和自由基清除剂抗坏血酸加α-生育酚的组合减轻了脂质氧化，并完全阻止了由 Orn 和 Hcit 引起的蛋白质氧化损伤，表明活性物质参与了这些作用。Hcit 给药而不是 Orn 给药还降低了谷胱甘肽浓度以及过氧化氢酶和谷胱甘肽过氧化物酶的活性，表明 Hcit 引发了脑抗氧化防御的减少。关于能量代谢参数，我们发现 Orn 和 Hcit 显著抑制柠檬酸循环功能（抑制 [1-(14)C] 乙酸盐合成 CO2）、有氧糖酵解途径（减少 [U-(14)C] 葡萄糖合成 CO2）和呼吸链复合物 I-III 活性。Hcit 还抑制了 aconitase 的活性，该酶极易受到自由基攻击。总之，我们的数据表明，线粒体稳态受到 Orn 的干扰，特别是受到 Hcit 的干扰。据推测，这些代谢物引起的脑能量代谢障碍和氧化损伤可能有助于 HHH 综合征患者的脑恶化和神经症状。
