Sapko Michael T, Guidetti Paolo, Yu Ping, Tagle Danilo A, Pellicciari Roberto, Schwarcz Robert
Maryland Psychiatric Research Center, University of Maryland School of Medicine, P.O. Box 21247, Baltimore, MD 21228, USA.
Exp Neurol. 2006 Jan;197(1):31-40. doi: 10.1016/j.expneurol.2005.07.004. Epub 2005 Aug 15.
Excessive activation of NMDA receptors results in excitotoxic nerve cell loss, which is believed to play a critical role in the pathophysiology of Huntington's disease (HD) and several other catastrophic neurodegenerative diseases. Kynurenic acid (KYNA), a neuroinhibitory tryptophan metabolite, has neuroprotective properties and may serve as an endogenous anti-excitotoxic agent. This hypothesis was tested in the striatum, using mice with a targeted deletion of kynurenine aminotransferase II (KAT II), a major biosynthetic enzyme of KYNA in the mammalian brain. On post-natal day (PND) 14, the striatum of mkat-2-/- mice showed a reduction in KYNA levels but contained normal concentrations of the metabolically related neurotoxins 3-hydroxykynurenine and quinolinic acid (QUIN). Intrastriatal injections of QUIN, a NMDA receptor agonist, caused significantly larger lesions in these immature mutant mice than in age-matched wild-type animals. This lesion enlargement was not observed when mkat-2-/- mice were acutely pre-treated with the kynurenine 3-hydroxylase inhibitor UPF 648, which counteracted the striatal KYNA deficit. Moreover, no increased vulnerability to QUIN was observed in 2-month-old mkat-2-/- mice, which present with normal brain KYNA levels. Intrastriatal injections of the non-NMDA receptor agonist kainate caused similar lesion sizes in both genotypes regardless of age. These results indicate that endogenous KYNA preferentially controls the vulnerability of striatal neurons to QUIN. Our data suggest that timely pharmacological interventions resulting in an up-regulation of brain KYNA levels may benefit patients suffering from HD or other neurodegenerative diseases.
N-甲基-D-天冬氨酸（NMDA）受体的过度激活会导致兴奋性毒性神经细胞丢失，这被认为在亨廷顿舞蹈病（HD）及其他几种严重神经退行性疾病的病理生理学过程中起关键作用。犬尿喹啉酸（KYNA）是一种具有神经抑制作用的色氨酸代谢产物，具有神经保护特性，可能作为一种内源性抗兴奋性毒性因子。本研究以哺乳动物脑内KYNA的主要生物合成酶犬尿氨酸转氨酶II（KAT II）靶向缺失的小鼠为实验对象，在纹状体中对这一假说进行了验证。在出生后第14天（PND 14），mkat-2-/-小鼠纹状体中的KYNA水平降低，但代谢相关神经毒素3-羟基犬尿氨酸和喹啉酸（QUIN）的浓度正常。向纹状体内注射NMDA受体激动剂QUIN后，这些未成熟的突变小鼠所产生的损伤明显大于年龄匹配的野生型动物。当用犬尿氨酸3-羟化酶抑制剂UPF 648对mkat-2-/-小鼠进行急性预处理以抵消纹状体中KYNA的缺乏时，未观察到这种损伤扩大现象。此外，在2月龄脑KYNA水平正常的mkat-2-/-小鼠中，未观察到对QUIN的易感性增加。无论年龄大小，向纹状体内注射非NMDA受体激动剂海藻酸在两种基因型小鼠中所造成的损伤大小相似。这些结果表明，内源性KYNA优先控制纹状体神经元对QUIN的易感性。我们的数据表明，及时进行导致脑KYNA水平上调的药物干预可能会使HD或其他神经退行性疾病患者受益。
