Guidetti Paolo, Luthi-Carter Ruth E, Augood Sarah J, Schwarcz Robert
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD 21228, USA.
Neurobiol Dis. 2004 Dec;17(3):455-61. doi: 10.1016/j.nbd.2004.07.006.
Huntington's disease (HD), an inherited neurodegenerative disorder, is caused by an abnormal polyglutamine expansion in the huntingtin protein. This genetic defect may result in heightened neuronal susceptibility to excitotoxic injury, a mechanism that has been postulated to play a critical role in HD. Quinolinate (QUIN) and kynurenate (KYNA), two endogenous neuroactive metabolites of the kynurenine pathway of tryptophan degradation, have been proposed to modulate excitotoxic neuronal death in HD. A third kynurenine pathway metabolite, the free radical generator 3-hydroxykynurenine (3-HK), has also been hypothesized to play a causal role in the pathogenesis of HD. We show here that the brain levels of both 3-HK and QUIN are increased three to four-fold in low-grade (grade 0/1) HD brain. These changes were seen in the neocortex and in the neostriatum, but not in the cerebellum. In contrast, brain 3-HK and QUIN levels were either unchanged or tended to decrease in grade 2 and advanced grade (grades 3-4) HD brain. Brain kynurenine and KYNA levels fluctuated only modestly as the illness progressed. These results support a possible involvement of 3-HK and QUIN in the early phases of HD pathophysiology and indicate novel therapeutic strategies against the disease.
亨廷顿舞蹈症（HD）是一种遗传性神经退行性疾病，由亨廷顿蛋白中异常的多聚谷氨酰胺扩增引起。这种基因缺陷可能导致神经元对兴奋性毒性损伤的易感性增加，这一机制被认为在HD中起关键作用。喹啉酸（QUIN）和犬尿喹啉酸（KYNA）是色氨酸降解的犬尿氨酸途径的两种内源性神经活性代谢产物，已被提出可调节HD中兴奋性毒性神经元死亡。犬尿氨酸途径的第三种代谢产物，自由基生成剂3-羟基犬尿氨酸（3-HK），也被假设在HD的发病机制中起因果作用。我们在此表明，在低度（0/1级）HD脑中，3-HK和QUIN的脑内水平均增加了三到四倍。这些变化在新皮层和新纹状体中可见，但在小脑中未见。相比之下，在2级和晚期（3-4级）HD脑中，脑内3-HK和QUIN水平要么没有变化，要么有下降趋势。随着疾病进展，脑内犬尿氨酸和KYNA水平仅略有波动。这些结果支持3-HK和QUIN可能参与HD病理生理学的早期阶段，并表明针对该疾病的新治疗策略。
