Guidetti Paolo, Bates Gillian P, Graham Rona K, Hayden Michael R, Leavitt Blair R, MacDonald Marcy E, Slow Elizabeth J, Wheeler Vanessa C, Woodman Ben, Schwarcz Robert
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD 21228, USA.
Neurobiol Dis. 2006 Jul;23(1):190-7. doi: 10.1016/j.nbd.2006.02.011. Epub 2006 May 12.
The brain levels of the endogenous excitotoxin quinolinic acid (QUIN) and its bioprecursor, the free radical generator 3-hydroxykynurenine (3-HK), are elevated in early stage Huntington disease (HD). We now examined the status of these metabolites in three mouse models of HD. In R6/2 mice, 3-HK levels were significantly and selectively elevated in the striatum, cortex and cerebellum starting at 4 weeks of age. In contrast, both 3-HK and QUIN levels were increased in the striatum and cortex of the full-length HD models, beginning at 8 months (YAC128) and 15 months (Hdh(Q92) and Hdh(Q111)), respectively. No changes were seen in 13-month-old shortstop mice, which show no signs of motor or cognitive dysfunction or selective neuropathology. These results demonstrate both important parallels and intriguing differences in the progressive neurochemical changes in these HD mouse models and support the hypothesis that QUIN may play a role in the striatal and cortical neurodegeneration of HD.
内源性兴奋性毒素喹啉酸（QUIN）及其生物前体、自由基生成剂3-羟基犬尿氨酸（3-HK）的脑内水平在早期亨廷顿病（HD）中会升高。我们现在研究了这两种代谢物在三种HD小鼠模型中的状态。在R6/2小鼠中，从4周龄开始，纹状体以及皮层和小脑中的3-HK水平显著且选择性升高。相比之下，全长HD模型的纹状体和皮层中3-HK和QUIN水平均升高，分别从8个月（YAC128）和15个月（Hdh(Q92)和Hdh(Q111)）开始。13月龄的短stop小鼠未出现变化，其未表现出运动或认知功能障碍或选择性神经病理学迹象。这些结果表明，这些HD小鼠模型中进行性神经化学变化既存在重要的相似之处，也存在有趣的差异，并支持了QUIN可能在HD的纹状体和皮层神经变性中起作用的假说。
