Promotion of oxidative stress by 3-hydroxyglutaric acid in rat striatum
Promotion of oxidative stress by 3-hydroxyglutaric acid in rat striatum
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DOI：
10.1007/s10545-005-3677-7
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发表时间：
2005-01-01
影响因子：
4.2
通讯作者：
Wajner, M
中科院分区：
文献类型：
--
作者：
Latini, A;Scussiato, K;Wajner, M
遗传性神经代谢紊乱戊二酰辅酶A脱氢酶缺乏症（GDD）（也称为1型谷氨酸尿症）患者的纹状体变性特征的病理生理学仍在争论中。我们之前曾报道过，3-羟基戊二酸（3-OH-GA）被认为是这种疾病的主要神经毒素，会诱导大鼠大脑皮质的氧化应激。在目前的工作中，我们扩展了这些研究，通过测量总自由基捕获抗氧化潜力（TRAP），总抗氧化反应性（TAR）和谷胱甘肽（GSH）水平，以及过氧化氢（H2 O2）的产生，研究浓度范围为0.01至1.0 mmol/L的3-OH-GA对脑抗氧化防御的体外作用，纹状体匀浆中一氧化氮（NO）和丙二醛。我们观察到，当纹状体匀浆用3-OH-GA处理时，TRAP、TAR和GSH水平显著降低（高达50%）。相比之下，3-OH-GA显着增加了H2 O2（高达44%）、NO（高达95%）和丙二醛水平（高达28%）。这些数据表明，总的非酶抗氧化剂防御（TRAP）和组织的能力，以处理增加的反应物种（TAR）减少了3-OH-GA在纹状体。此外，结果还反映了脂质过氧化作用的增加，可能继发于3-OH-GA诱导的自由基产生。因此，可以推测氧化应激参与了GDD的神经病理学过程。
The pathophysiology of the striatum degeneration characteristic of patients affected by the inherited neurometabolic disorder glutaryl-CoA dehydrogenase deficiency (GDD), also known as glutaric aciduria type 1, is still in debate. We have previously reported that 3-hydroxyglutaric acid (3-OH-GA) considered the main neurotoxin in this disorder, induces oxidative stress in rat cerebral cotex. In the present work, we extended these studies by investigating the in vitro effect of 3-OH-GA, at concentrations ranging from 0.01 to 1.0 mmol/L on the brain antioxidant defences by measuring total radical-trapping antioxidant potential (TRAP), total antioxidant reactivity (TAR) and glutathione (GSH) levels, and on the production of hydrogen peroxide (H2O2), nitric oxide (NO) and malondialdehyde in striatum homogenates from young rats. We observed that TRAP, TAR and GSH levels were markedly reduced (by up to 50%) when striatum homogenates were treated with 3-OH-GA. In contrast, H2O2 (up to 44%), NO (up to 95%) and malondialdehyde levels (up to 28%) were significantly increased by 3-OH-GA. These data indicate that total nonenzymatic antioxidant defences (TRAP) and the tissue capacity to handle an increase of reactive species (TAR) were reduced by 3-OH-GA in the striatum. Furthermore, the results also reflect an increase of lipid peroxidation, probably secondary to 3-OH-GA-induced free radical production. Thus, it may be presumed that oxidative stress is involved in the neuropathology in GDD.