3-Hydroxyglutaric and glutaric acids are neurotoxic through NMDA receptors in vitro
3-Hydroxyglutaric and glutaric acids are neurotoxic through NMDA receptors in vitro
复制标题
3-羟基戊二酸和戊二酸在体外通过 NMDA 受体具有神经毒性
DOI：
10.1023/a:1005577920954
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发表时间：
1999
影响因子：
4.2
通讯作者：
G. Hoffmann
中科院分区：
文献类型：
--
作者：
S. Kölker;B. Ahlemeyer;J. Krieglstein;G. Hoffmann
戊二酰辅酶A脱氢酶缺乏症（GDD; McKusick 231670）导致体液和脑组织中3-羟基谷氨酸（30 H-GA）和谷氨酸（GA）蓄积（Baric et al 1998; Goodman et al 1977）。通常在6至18个月大之间，并发疾病甚至常规免疫接种都可能引发急性脑炎样脑病危象，导致不可逆转的双侧纹状体破坏，从而导致严重的张力障碍-运动障碍，并丧失先前获得的运动技能（Hoffmann et al 1991，1996）。虽然GDD的生化和临床特征已被很好地描述，但年龄和区域特异性神经元损伤的机制仍不清楚。大量证据表明GDD中存在兴奋性毒性序列：GA和30 H-GA显示出与兴奋性毒性氨基酸谷氨酸的结构相似性，GDD患者脑组织的尸检显示纹状体和皮质中的突触后空泡化与谷氨酸介导的损伤相似（Goodman et al 1977）。先前使用器官型大鼠脑切片培养物的研究显示了30 H-GA的神经毒性作用，尽管在高浓度（> 1.5mmol/L）下，但GA没有，这表明30 H-GA是GDD中的主要兴奋性毒素（Flott-Rahmel等1997）。我们推测GDD的年龄和区域特异性脑损伤可能是由过度刺激NMDA受体和随后的兴奋性毒性细胞死亡引起的。因此，我们研究了主要的病理代谢产物GA和30 H-GA对神经元培养的影响，以及NMDA和非NMDA受体拮抗剂是否可以预防神经毒性作用。
Glutaryl-CoA dehydrogenase deficiency (GDD; McKusick 231670) causes an accumulation of 3-hydroxyglutaric (30H-GA) and glutaric (GA) acids in body fluids as well as brain tissue (Baric et al 1998; Goodman et al 1977). Typically between the 6th and 18th months of age, intercurrent illness or even a routine immunization can trigger an acute encephalitis-like encephalopathic crisis that leads to an irreversible bilateral striatal destruction and consequently to a severe dystonic-dyskinetic disorder with loss of previously acquired motor skills (Hoffmann et al 1991, 1996). Although the biochemical and clinical features of GDD are well described, the mechanism of age- and regional-specific neuronal damage remains unclear. Substantial evidence points to an excitotoxic sequence in GDD: GA and 30H-GA exhibit structural similarities to the excitotoxic amino acid glutamate, and post-mortem examination of brain tissue of GDD patients revealed postsynaptic vacuolation in striatum and cortex similar to that of glutamate-mediated damage (Goodman et al 1977). A previous study using organotypic rat brain slice cultures showed a neurotoxic effect of 30H-GA, though at high concentrations (> 1.5 mmol/L), but not for GA, suggesting that 30H-GA is the main excitotoxin in GDD (Flott-Rahmel et al 1997). We hypothesized that the age- and regional specific brain damage in GDD could be caused by overstimulation of NMDA receptors and subsequent excitotoxic cell death. We therefore investigated the effects of the main pathological metabolites GA and 30H-GA on neuronal cultures and whether neurotoxic effects could be prevented by NMDA and non-NMDA receptor antagonists.