Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Rua Ramiro Barcelos, 2600, Building 21111, Porto Alegre, RS, 90035-003, Brazil.
Departamento de Ciências Biológicas, Universidade Regional Integrada do Alto Uruguai e das Missões, Avenida Sete de Setembro, 1621, Erechim, RS, 99709-910, Brazil.
Neurotox Res. 2020 Dec;38(4):1024-1036. doi: 10.1007/s12640-020-00291-0. Epub 2020 Oct 1.
We investigated redox homeostasis in cerebral and peripheral tissues of wild type (WT) and glutaryl-CoA dehydrogenase knockout mice (Gcdh) submitted to inflammation induced by lipopolysaccharide (LPS) since patients with glutaric aciduria type I (GA I) manifest acute encephalopathy during catabolic events triggered by inflammation. WT and Gcdh mice fed a low (0.9%) or high (4.7%) Lys chow were euthanized 4 h after LPS intraperitoneal injection. Cerebral cortex of Lys-restricted Gcdh animals presented no alterations of redox homeostasis, whereas those fed a high Lys chow showed increased malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity, compared to WT mice. Furthermore, Gcdh mice receiving low Lys and injected with LPS presented elevated MDA levels and decreased reduced glutathione (GSH) concentrations, glutathione peroxidase (GPx), and glutathione reductase (GR) activities in cerebral cortex. LPS administration also decreased GSH values, as well as GPx and GR activities in cerebral cortex of Gcdh mice receiving Lys overload. Further experiments performed in WT and Gcdh mice injected with LPS and receiving either a low or high Lys chow revealed increased MDA levels and decreased GSH concentrations in cerebral cortex and striatum, but not in hippocampus, liver and heart of Gcdh mice, suggesting a selective vulnerability of these cerebral structures to oxidative stress during an inflammatory process. LPS administration also increased S100B and NF-κF protein levels in brain of Gcdh mice receiving high Lys. These data support the hypothesis that low Lys diet is beneficial in GA I by preventing redox imbalance, whereas a high Lys diet or systemic inflammation per se or combined induce oxidative stress in striatum and cerebral cortex that are mainly damaged in this disorder.
我们研究了野生型（WT）和戊二酰辅酶 A 脱氢酶敲除（Gcdh）小鼠在脂多糖（LPS）诱导的炎症状态下脑和外周组织中的氧化还原平衡，因为 1 型戊二酸血症（GA I）患者在炎症引起的分解代谢事件中会出现急性脑病。WT 和 Gcdh 小鼠分别喂食低（0.9%）或高（4.7%）赖氨酸饲料，LPS 腹腔注射 4 小时后处死。赖氨酸限制的 Gcdh 动物的大脑皮层没有氧化还原平衡的改变，而那些喂食高赖氨酸饲料的动物则表现出丙二醛（MDA）水平升高和超氧化物歧化酶（SOD）活性增加，与 WT 小鼠相比。此外，给予低赖氨酸并注射 LPS 的 Gcdh 小鼠表现出大脑皮层 MDA 水平升高和还原型谷胱甘肽（GSH）浓度、谷胱甘肽过氧化物酶（GPx）和谷胱甘肽还原酶（GR）活性降低。LPS 处理还降低了 Gcdh 小鼠大脑皮层的 GSH 值，以及 GPx 和 GR 活性。在给予 LPS 并分别给予低或高赖氨酸饲料的 WT 和 Gcdh 小鼠中进行的进一步实验表明，Gcdh 小鼠大脑皮层和纹状体 MDA 水平升高，GSH 浓度降低，但海马、肝脏和心脏没有变化，这表明在炎症过程中这些大脑结构对氧化应激具有选择性易感性。LPS 处理还增加了 Gcdh 小鼠高赖氨酸饮食中大脑 S100B 和 NF-κF 蛋白水平。这些数据支持这样一种假设，即低赖氨酸饮食通过防止氧化还原失衡对 GA I 有益，而高赖氨酸饮食或全身性炎症本身或两者结合会在纹状体和大脑皮层中诱导氧化应激，而这些区域在这种疾病中主要受到损害。
