SOURCES OF QUINOLINIC ACID

喹啉酸的来源

• 批准号: 2449928
• 负责人: P F MORRISON
• 金额: --
• 依托单位: NATIONAL CENTER FOR RESEARCH RESOURCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2449928
• 关键词: brain metabolism; gerbil /jird; inflammation; laboratory rat; mass spectrometry; method development; neuroprotectants; neurotoxicology; neurotransmitter metabolism; quinolinate

Methods were developed for quantifying the source fluxes of the excitotoxin quinolinic acid (QUIN) in normal and inflamed tissue. The issue of sources of QUIN is important, because potential therapeutic strategies to reduce QUIN accumulations and neurotoxicity may target different potential sources. We developed an isotope ratio assay in which unlabeled QUIN:labeled QUIN concentration ratios, for individual tissues and plasma in animals infused to steady state with labeled QUIN, could be related to the fraction f of QUIN produced endogenously, in relation to that obtained from all sources. We performed experiments on control, cerebral ischemic, and LPS-inoculated gerbils and rats infused with labeled QUIN via osmotic minipumps. We employed a highly sensitive mass spectrometry assay for determination of labeled and unlabeled QUIN levels in brain and other tissues, plasma, whole blood, and urine. A major finding is that endogenous production of QUIN is the dominant source of this agent during brain inflammation, since nearly all hippocampus and striatal QUIN is synthesized endogenously at peak response to ischemia (f=95%); even 30% of QUIN present in control brain is synthesized endogenously. This finding implies that agents that act at the terminal step of QUIN synthesis, such as 6-chlorohydroxyanthranilate, should be effective in reducing QUIN production and related toxicity during brain inflammation. In addition, microdialysis has been introduced to determine absolute fluxes of QUIN production in tissue. Modeling of the kynurenine pathway combined with microdialysis has shown that depletion of QUIN precursors by dialysis does not significantly alter the rate of production of QUIN in brain tissue.

方法被开发用于量化的源通量的 兴奋毒素喹啉酸（QUIN）在正常和发炎组织。 的 QUIN来源问题很重要，因为潜在的治疗 减少QUIN蓄积和神经毒性的策略可能靶向 不同的潜在来源。 我们开发了一种同位素比测定法， 未标记的QUIN：标记的QUIN浓度比，对于个体 用标记的QUIN输注至稳态的动物组织和血浆， 可能与内源性产生的QUIN的分数f有关， 与从所有来源获得的有关。 我们对 对照、脑缺血和LPS接种的沙鼠和大鼠输注 与标记的QUIN通过渗透微型泵。 我们雇佣了一个高度敏感的 用于测定标记和未标记QUIN的质谱分析 脑和其他组织、血浆、全血和尿液中的水平。 一 主要发现是QUIN的内源性产生占主导地位 在大脑炎症期间，这种药物的来源，因为几乎所有 海马和纹状体QUIN在峰值时内源性合成 对缺血的反应（f=95%）;对照脑中甚至存在30%的QUIN 是内源性合成的。 这一发现意味着， 在QUIN合成的最终步骤，例如 6-氯羟基邻氨基苯甲酸酯，应能有效降低QUIN 在脑炎症期间产生和相关毒性。 此外，本发明还提供了一种方法， 微透析已被引入到测定QUIN的绝对通量 组织中的生产。 犬尿氨酸途径的建模与 微透析已经表明，通过透析消耗QUIN前体 不会显著改变大脑中QUIN的产生速率 组织.