Erhardt Sophie, Olsson Sara K, Engberg Göran
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
CNS Drugs. 2009;23(2):91-101. doi: 10.2165/00023210-200923020-00001.
The kynurenine pathway constitutes the main route of tryptophan degradation and generates the production of several neuroactive compounds; quinolinic acid is an excitotoxic NMDA receptor agonist, 3-hydroxykynurenine is a free-radical generator and kynurenic acid (KYNA) is an antagonist at glutamate and nicotinic receptors. In low micromolar concentrations, KYNA blocks the glycine site of the NMDA receptor and the nicotinic alpha(7) acetylcholine receptor. Knowledge regarding kynurenine metabolites and their involvement in neurophysiological processes has increased dramatically in recent years. In particular, endogenous KYNA appears to tightly control firing of midbrain dopamine neurons and to be involved in cognitive functions. Thus, decreased endogenous levels of rat brain KYNA have been found to reduce firing of these neurons, and mice with a targeted deletion of kynurenine aminotransferase II display low endogenous brain KYNA levels concomitant with an increased performance in cognitive tests. It is also suggested that kynurenines participate in the pathophysiology of psychiatric disorders. Thus, elevated levels of KYNA have been found in the CSF as well as in the post-mortem brain of patients with schizophrenia. Advantages in understanding how kynurenines can be pharmacologically manipulated may provide new possibilities in the treatment of psychiatric disorders, such as schizophrenia.
犬尿氨酸途径是色氨酸降解的主要途径，并产生多种神经活性化合物；喹啉酸是一种兴奋性毒性N-甲基-D-天冬氨酸（NMDA）受体激动剂，3-羟基犬尿氨酸是一种自由基生成剂，而犬尿喹啉酸（KYNA）是谷氨酸和烟碱样受体的拮抗剂。在低微摩尔浓度下，KYNA可阻断NMDA受体的甘氨酸位点和烟碱样α(7)乙酰胆碱受体。近年来，关于犬尿氨酸代谢产物及其在神经生理过程中的作用的知识有了显著增加。特别是，内源性KYNA似乎严格控制中脑多巴胺神经元的放电，并参与认知功能。因此，已发现大鼠脑内KYNA的内源性水平降低会减少这些神经元的放电，而靶向缺失犬尿氨酸转氨酶II的小鼠脑内KYNA内源性水平较低，同时在认知测试中的表现有所提高。也有人提出犬尿氨酸参与精神疾病的病理生理学。因此，在精神分裂症患者的脑脊液以及死后大脑中发现KYNA水平升高。了解如何对犬尿氨酸进行药理学调控可能为精神疾病（如精神分裂症）的治疗提供新的可能性。
