SOURCES OF NEUROTOXIN QUINOLINIC ACID

神经毒素喹啉酸的来源

• 批准号: 6591315
• 负责人: MELVYN P HEYES
• 金额: $ 11.11万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6591315
• 关键词: AIDS; Mammalia; bioimaging /biomedical imaging; communicable diseases; immunology; inflammation; infrared radiation; lymphatic system; nervous system; virus

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

我们研究了一种神经毒性的喹啉酸来源 色氨酸-Kynurenine途径代谢物，在大脑和血液中 HIV感染的患者和大脑逆转录病毒感染的猕猴， HIV感染患者的喹啉酸浓度升高 在那里超过CSF的浓度高300倍 升高的血清喹啉之间没有显着相关性 与CSF和大脑实质中的酸性水平，因为 非返回病毒引起的脑炎混淆了解释 人类验尸数据，感染逆转录病毒的恒河猕猴为 用于检查喹啉酸增加的机制 积累，并确定喹啉酸与 脑炎和全身反应是最大的Kynurenine途径 大脑的反应与脑炎有关，是 独立于全身反应，特别是局部喹啉酸 水平和吲哚胺-2,3-二加氧酶活性在 脑皮质，在猕猴中最高 脑炎脑皮层kynurenine-3-羟化酶和雌激酶 与本地的猕猴仅略微增加了活动 脑炎，而3-羟基雄酸-3,4-二氧酶活性是 未受影响的CSF喹啉酸水平也升高 感染的猕猴，尤其是那些逆转录病毒引起的 脑炎与大脑变化相反，没有差异 在任何脑脑炎与脑炎之间的全身度量中 那些没有具体的，血浆L-京难是增加和 喹啉酸伴随着增加的活性 吲哚胺-2,3-二氧酶，kynurenine-3-羟化酶，kynureninase 肺中的3-羟基氰酸-3,4-二氧酶，并增加 喹啉酸肝尿液排泄 色氨酸-2,3-二加氧酶是数量不变的直接度量 在猕猴中衍生出血液中的喹啉酸的 脑炎表明所有喹啉酸（> 98％）的almos t 在大脑中局部合成的结果表明了作用 用于诱导吲哚胺-2,3-二加氧酶在加速局部 脑组织内的喹啉酸形成，特别是在 脑炎区域，而不是将喹啉酸进入 来自脑膜或血液策略以减少奎因产量的大脑， 针对脑内部位的目标是治疗的潜在方法