Obrenovitch T P, Urenjak J
Pharmacology, School of Pharmacy, University of Bradford, United Kingdom.
Amino Acids. 2000;19(1):299-309. doi: 10.1007/s007260070061.
Three complementary questions related to the kynurenine pathway and excitotoxicity were addressed in this study: (i) Which extracellular levels of quinolinic acid (QUIN) may be neurotoxic? (ii) Which extracellular levels of kynurenic acid (KYNA) may control excessive NMDA-receptor function? (iii) Can "anti-excitotoxic" levels of KYNA be reached by inhibition of kynurenine-3-hydroxylase (i.e. inhibition of QUIN synthesis and shunts of kynurenine metabolism toward KYNA)? Multifunctional microdialysis probes were used in halothane anaesthetised rats to apply NMDA or QUIN directly to the brain, with or without co-perfusion of KYNA, to record the resulting local depolarisations, and to monitor changes in dialysate KYNA after kynurenine-3-hydroxylase inhibition. QUIN produced concentration-dependent depolarisations with an estimated EC50 (i.e. concentration in the perfusion medium) of 1.22mM. The estimated ED50 for KYNA inhibition of NMDA-responses was 181microM. Kynurenine-3-hydroxylase inhibition (Ro-61-8048, 100mg/kg i.p.) increased dialysate KYNA 11 times (to 33.8nM) but without any reduction of NMDA-responses. These data challenge the notion that extracellular accumulation of endogenous QUIN may contribute to excessive NMDA-receptor activation in some neurological disorders, and the suitability of kynurenine-3-hydroxylase inhibition as an effective anti-excitotoxic strategy.
（i）喹啉酸（QUIN）的哪些细胞外水平可能具有神经毒性？（ii）犬尿喹啉酸（KYNA）的哪些细胞外水平可能控制过度的NMDA受体功能？（iii）通过抑制犬尿氨酸-3-羟化酶（即抑制QUIN合成并使犬尿氨酸代谢转向KYNA）能否达到“抗兴奋毒性”水平的KYNA？在氟烷麻醉的大鼠中使用多功能微透析探针，直接向脑内施加NMDA或QUIN，同时或不同时共灌注KYNA，记录由此产生的局部去极化，并监测犬尿氨酸-3-羟化酶抑制后透析液中KYNA的变化。QUIN产生浓度依赖性去极化，估计的EC50（即灌注介质中的浓度）为1.22mM。KYNA抑制NMDA反应的估计ED50为181μM。犬尿氨酸-3-羟化酶抑制（Ro-61-8048，100mg/kg腹腔注射）使透析液中KYNA增加了11倍（至33.8nM），但并未降低NMDA反应。这些数据对以下观点提出了挑战，即内源性QUIN的细胞外积累可能在某些神经系统疾病中导致NMDA受体过度激活，以及犬尿氨酸-3-羟化酶抑制作为一种有效的抗兴奋毒性策略的适用性。
