SOURCES OF QUINOLINIC ACID

开发了定量测定土壤中的 正常组织和炎症组织中的兴奋性毒素喹啉酸(Quin)。这个 Quin的来源问题很重要，因为潜在的治疗作用 减少奎宁蓄积和神经毒性的策略可能针对 不同的潜在来源。我们开发了一种同位素比率分析方法， 哪个未标记的Quin：标记的Quin浓度比率，对于个人 给动物体内的组织和血浆注入标记奎宁使其处于稳定状态， 可能与内源产生的Quin的分数f有关，在 与从所有来源获得的关系。我们进行了一系列实验 对照组、脑缺血和脂多糖接种沙土鼠和大鼠 用标记的奎因通过渗透压小泵。我们雇佣了一个高度敏感的 质谱法测定标记和未标记的喹啉 脑和其他组织、血浆、全血和尿液中的含量。一个 主要发现是Quin的内源生产占主导地位 这种物质的来源在脑部发炎期间，因为几乎所有 海马体和纹状体Quin在内源性合成高峰期 对缺血的反应(f=95%)；对照脑组织中甚至存在30%的Quin 是内源性合成的。这一发现表明，行动的代理人 在Quin合成的最后一步，如 6-氯羟基邻氨基苯甲酸酯，应该是有效的减少Quin 在脑部炎症过程中产生和相关的毒性。此外, 采用微透析法测定喹啉的绝对通量 生产纸巾。犬尿氨酸途径的模拟 微透析法已表明，通过透析法耗尽Quin前体 不会显著改变大脑中Quin的产生速度 组织。

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.