Departamento de Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil.
Mol Genet Metab. 2013 Jan;108(1):30-9. doi: 10.1016/j.ymgme.2012.11.001. Epub 2012 Nov 9.
Deficiency of glutaryl-CoA dehydrogenase (GCDH) activity or glutaric aciduria type I (GA I) is an inherited neurometabolic disorder biochemically characterized by predominant accumulation of glutaric acid and 3-hydroxyglutaric acid in the brain and other tissues. Affected patients usually present acute striatum necrosis during encephalopathic crises triggered by metabolic stress situations, as well as chronic leukodystrophy and delayed myelination. Considering that the mechanisms underlying the brain injury in this disease are not yet fully established, in the present study we investigated important parameters of oxidative stress in the brain (cerebral cortex, striatum and hippocampus), liver and heart of 30-day-old GCDH deficient knockout (Gcdh(-/-)) and wild type (WT) mice submitted to a normal lysine (Lys) (0.9% Lys), or high Lys diets (2.8% or 4.7% Lys) for 60 h. It was observed that the dietary supplementation of 2.8% and 4.7% Lys elicited noticeable oxidative stress, as verified by an increase of malondialdehyde concentrations (lipid oxidative damage) and 2-7-dihydrodichlorofluorescein (DCFH) oxidation (free radical production), as well as a decrease of reduced glutathione levels and alteration of various antioxidant enzyme activities (antioxidant defenses) in the cerebral cortex and the striatum, but not in the hippocampus, the liver and the heart of Gcdh(-/-) mice, as compared to WT mice receiving the same diets. Furthermore, alterations of oxidative stress parameters in the cerebral cortex and striatum were more accentuated in symptomatic, as compared to asymptomatic Gcdh(-/-) mice exposed to 4.7% Lys overload. Histopathological studies performed in the cerebral cortex and striatum of these animals exposed to high dietary Lys revealed increased expression of oxidative stress markers despite the absence of significant structural damage. The results indicate that a disruption of redox homeostasis in the cerebral cortex and striatum of young Gcdh(-/-) mice exposed to increased Lys diet may possibly represent an important pathomechanism of brain injury in GA I patients under metabolic stress.
谷氨酸酰辅酶 A 脱氢酶（GCDH）活性缺乏或 1 型戊二酸尿症（GA I）是一种遗传性神经代谢疾病，其生化特征为大脑和其他组织中戊二酸和 3-羟基戊二酸的主要积累。受影响的患者通常在代谢应激情况下发生脑病危象时出现急性纹状体坏死，以及慢性脑白质营养不良和髓鞘形成延迟。考虑到该疾病中脑损伤的机制尚未完全确定，本研究我们研究了 30 天大的 GCDH 缺陷敲除（Gcdh(-/-)）和野生型（WT）小鼠大脑（大脑皮层、纹状体和海马体）、肝脏和心脏中的氧化应激重要参数，这些小鼠接受正常赖氨酸（Lys）（0.9% Lys）或高 Lys 饮食（2.8%或 4.7% Lys）60 小时。观察到 2.8%和 4.7% Lys 的饮食补充引起了明显的氧化应激，这可以通过增加丙二醛浓度（脂质氧化损伤）和 2-7-二氢二氯荧光素（DCFH）氧化（自由基产生）来验证，以及降低还原型谷胱甘肽水平和改变各种抗氧化酶活性（抗氧化防御）在大脑皮层和纹状体中，但不在海马体、肝脏和心脏中，与接受相同饮食的 WT 小鼠相比，Gcdh(-/-)小鼠。此外，与无症状 Gcdh(-/-)小鼠相比，症状性 Gcdh(-/-)小鼠暴露于 4.7% Lys 过载时，大脑皮层和纹状体中的氧化应激参数改变更为明显。在这些动物的大脑皮层和纹状体中进行的组织病理学研究表明，尽管没有明显的结构损伤，但氧化应激标志物的表达增加。结果表明，暴露于高 Lys 饮食的年轻 Gcdh(-/-)小鼠大脑皮层和纹状体中氧化还原平衡的破坏可能代表 GA I 患者在代谢应激下脑损伤的重要病理机制。
