SOURCES OF NEUROTOXIN QUINOLINIC ACID

我们调查了喹啉酸的来源，一种神经毒性 脑组织和血液中的色氨酸-犬尿氨酸途径代谢物 HIV感染患者和大脑中感染逆转录病毒的猕猴， HIV感染者体内喹啉酸浓度升高 比CSF300倍的浓度高出8.9倍 血清喹啉浓度升高之间没有显著相关性 脑脊液和脑实质中的酸度，因为 非逆转录病毒引起的脑炎混淆了对 人类尸检数据显示，感染逆转录病毒的恒河猴 用于研究喹啉酸增加的机制 积累，并确定喹啉酸与 脑炎和全身反应最大的犬尿氨酸途径 脑部的反应与脑炎有关，并且 与全身反应无关，特别是局部喹啉酸 水平和吲哚-2，3-双加氧酶活性增加 大脑皮层，并在有皮质的猕猴中最高 脑炎大脑皮层犬尿氨酸-3-羟基酶和犬尿氨酸酶 只有局部感染的猕猴的活动略有增加。 脑炎，而3-羟基邻氨基苯甲酸-3，4-双加氧酶活性 未受影响的脑脊液喹啉酸水平也在所有患者中升高。 被感染的猕猴，特别是那些由逆转录病毒诱导的猕猴 脑炎与脑部的变化对比，没有差别 在患有脑炎的猕猴和 无特异性者，血浆L-犬尿氨酸和 喹啉酸伴随着酶活性的增加 吲哚-2，3-双加氧酶、犬尿氨酸-3-羟基酶、犬尿氨酸酶 和3-羟基邻氨基苯甲酸-3，4-双加氧酶，并增加 喹啉酸肝的尿液排泄 色氨酸-2，3-双加氧酶不变直接测定量 从血液中提取的一种猕猴脑中的喹啉酸 脑炎显示，几乎所有的喹啉酸(&gt；98%)是 这些结果在大脑内的局部合成显示了一个作用 用于诱导吲哚胺-2，3-双加氧酶加速局部 在脑组织内形成喹啉酸，特别是在 脑炎的区域，而不是喹啉酸进入脑部 大脑从脑膜或血液中减少奎宁产生的策略， 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