Stoy N, Mackay G M, Forrest C M, Christofides J, Egerton M, Stone T W, Darlington L G
Royal Hospital for Neuro-Disability, Putney, London, UK.
J Neurochem. 2005 May;93(3):611-23. doi: 10.1111/j.1471-4159.2005.03070.x.
Abnormalities in the kynurenine pathway may play a role in Huntington's disease (HD). In this study, tryptophan depletion and loading were used to investigate changes in blood kynurenine pathway metabolites, as well as markers of inflammation and oxidative stress in HD patients and healthy controls. Results showed that the kynurenine : tryptophan ratio was greater in HD than controls in the baseline state and after tryptophan depletion, indicating increased indoleamine dioxygenase activity in HD. Evidence for persistent inflammation in HD was provided by elevated baseline levels of C-reactive protein, neopterin and lipid peroxidation products compared with controls. The kynurenate : kynurenine ratio suggested lower kynurenine aminotransferase activity in patients and the higher levels of kynurenine in patients at baseline, after depletion and loading, do not result in any differences in kynurenic acid levels, providing no supportive evidence for a compensatory neuroprotective role for kynurenic acid. Quinolinic acid showed wide variations in blood levels. The lipid peroxidation data indicate a high level of oxidative stress in HD patients many years after disease onset. Levels of the free radical generators 3-hydroxykynurenine and 3-hydroxyanthranilic acid were decreased in HD patients, and hence did not appear to contribute to the oxidative stress. It is concluded that patients with HD exhibit abnormal handling of tryptophan metabolism and increased oxidative stress, and that these factors could contribute to ongoing brain dysfunction.
犬尿氨酸途径异常可能在亨廷顿舞蹈症（HD）中起作用。在本研究中，采用色氨酸耗竭和负荷试验来研究HD患者及健康对照者血液中犬尿氨酸途径代谢产物的变化，以及炎症和氧化应激标志物。结果显示，在基线状态和色氨酸耗竭后，HD患者的犬尿氨酸：色氨酸比值高于对照组，表明HD患者体内吲哚胺2,3-双加氧酶活性增加。与对照组相比，HD患者C反应蛋白、新蝶呤和脂质过氧化产物的基线水平升高，提示HD患者存在持续炎症。犬尿酸：犬尿氨酸比值表明患者体内犬尿氨酸转氨酶活性较低，且患者在基线、耗竭和负荷后犬尿氨酸水平较高，但并未导致犬尿酸水平出现差异，这并未为犬尿酸的代偿性神经保护作用提供支持证据。喹啉酸的血液水平变化较大。脂质过氧化数据表明，HD患者在疾病发作多年后存在高水平的氧化应激。HD患者体内自由基生成剂3-羟基犬尿氨酸和3-羟基邻氨基苯甲酸水平降低，因此似乎并未导致氧化应激。研究得出结论，HD患者存在色氨酸代谢异常及氧化应激增加，这些因素可能导致持续的脑功能障碍。
