SOURCES OF NEUROTOXIN QUINOLINIC ACID

我们调查了喹啉酸的来源， 色氨酸-犬尿氨酸途径代谢物， HIV感染者和逆转录病毒感染的猕猴在脑中， HIV感染者的喹啉酸浓度升高， 由>300倍的浓度超过CSF的8 9倍 血清喹啉酸水平升高与 酸水平与CSF和脑实质中的酸水平一致， 非逆转录病毒引起的脑炎混淆了对 人类死后数据显示，感染逆转录病毒的恒河猴 用于检查喹啉酸增加的机制 积累，并确定喹啉酸的关系， 脑炎和全身反应最大的犬尿氨酸途径 大脑中的反应与脑炎有关， 不依赖于全身反应，特别是局部喹啉酸 水平和吲哚胺-2，3-双加氧酶活性增加， 大脑皮层，并且在具有皮质的猕猴中最高 脑脑炎皮层犬尿氨酸-3-羟化酶和犬尿氨酸酶 活动只略有增加，在猕猴与当地 脑炎，而3-羟基邻氨基苯甲酸-3，4-双加氧酶活性是 未受影响的CSF喹啉酸水平也升高， 感染的猕猴，特别是那些逆转录病毒诱导的猕猴， 脑炎与脑改变相比，无差异 在患有脑炎的猕猴与 特别是，血浆L-犬尿氨酸和 喹啉酸伴随着增加的活动， 吲哚胺-2，3-双加氧酶，犬尿氨酸-3-羟化酶，犬尿氨酸酶 和3-羟基邻氨基苯甲酸-3，4-双加氧酶， 喹啉酸的尿排泄 色氨酸-2，3-双加氧酶没有变化 在猕猴的血液中， 脑炎显示几乎所有喹啉酸（> 98%） 这些结果证明了一种作用， 用于诱导吲哚胺-2，3-双加氧酶， 在脑组织内形成喹啉酸，特别是在 脑炎的区域，而不是喹啉酸进入 从脑膜或血液中提取大脑减少QUIN产生的策略， 靶向脑内部位是潜在的治疗方法

We investigated the sources of quinolinic acid, a neurotoxic tryptophan - kynurenine pathway metabolite, in brain and blood of HIV-infected patients and retrovirus-infected macaques In brain, quinolinic acid concentrations in HIV-infected patients were elevated by >300-fold to concentrations that exceeded CSF by 8 9-fold There were no significant correlations between elevated serum quinolinic acid levels with those in CSF and brain parenchyma Because non-retrovirus induced encephalitis confounds the interpretation of human post mortem data, rhesus macaques infected with retrovirus were used to examine the mechanisms of increased quinolinic acid accumulations, and determine the relationships of quinolinic acid to encephalitis and systemic responses The largest kynurenine pathway responses in brain were associated with encephalitis and were independent of systemic responses Specifically, local quinolinic acid levels and indoleamine-2,3-dioxygenase activity were increased in cerebral cortex, and were highest in macaques with cortical encephalitis Cerebral cortex kynurenine-3-hydroxylase and kynureninase activities were only increased slightly in macaques with local encephalitis, while 3-hydroxyanthranilate-3,4-dioxygenase activity was unaffected CSF quinolinic acid levels were also elevated in all infected macaques, but particularly those with retrovirus-induced encephalitis In contrast to the brain changes, there was no difference in any systemic measure between macaques with encephalitis versus those without Specifically, increased plasma L-kynurenine and quinolinic acid accompanied increased activities of indoleamine-2,3-dioxygenase, kynurenine-3-hydroxylase, kynureninase and 3-hydroxyanthranilate-3,4-dioxygenase in lung, and increased urinary excretion of quinolinic acid Hepatic tryptophan-2,3-dioxygenase was unchanged Direct measures of the amount of quinolinic acid in brain derived from blood in a macaque with encephalitis showed that almos t all quinolinic acid (>98 %) was synthesized locally within the brain These results demonstrate a role for induction of indoleamine-2,3-dioxygenase in accelerating the local formation of quinolinic acid within the brain tissue, particularly in areas of encephalitis, rather than entry of quinolinic acid into the brain from the meninges or blood Strategies to reduce QUIN production, targeted at intracerebral sites are potential approaches to therapy