Department of Neurology, Faculty of Medicine, Albert Szent-Györgyi Clinical Centre, University of Szeged, Semmelweis u. 6, Szeged, 6725, Hungary.
J Neural Transm (Vienna). 2012 Feb;119(2):225-34. doi: 10.1007/s00702-012-0765-3. Epub 2012 Jan 19.
Tryptophan is one of the essential amino acids, 80% of which is catabolised in the extrahepatic tissues by indoleamine-2,3-dioxygenase (IDO), the rate-limiting enzyme of the kynurenine pathway. Metabolites along the kynurenine pathway have been implicated to play a role in the pathomechanism of neuroinflammatory and neurodegenerative disorders. Changes in the concentration levels of kynurenines can shift the balance to pathological conditions. The ability to influence the metabolism towards the neuroprotective branch of the kynurenine pathway, i.e. towards kynurenic acid (KYNA) synthesis, may be one option in preventing neurodegenerative diseases. Three potential therapeutic strategies could be feasible to develop drugs to live up to expectations: (1) chemically related drugs with better bioavailability and higher affinity to the binding sites of excitatory receptors; (2) prodrugs of KYNA, which easily cross the blood-brain barrier combined with an inhibitor of organic acid transport for enhancement of the brain KYNA concentration; (3) inhibitors of enzymes of the kynurenine pathway. In this review, we focus on aspects of the pathomechanism and therapeutic possibilities of amyotrophic lateral sclerosis and multiple sclerosis that may be influenced by kynurenines.
色氨酸是必需氨基酸之一，其中 80%在肝外组织中通过吲哚胺 2,3-双加氧酶 (IDO) 代谢，IDO 是犬尿氨酸途径的限速酶。犬尿氨酸途径的代谢产物被认为在神经炎症和神经退行性疾病的发病机制中发挥作用。犬尿氨酸浓度的变化可能会使平衡向病理状态倾斜。影响代谢向犬尿氨酸途径的神经保护分支（即向犬尿酸 (KYNA) 合成）的能力可能是预防神经退行性疾病的一种选择。有三种潜在的治疗策略可以开发出符合预期的药物：(1) 具有更好生物利用度和更高亲和力的化学相关药物，与兴奋性受体的结合位点；(2) KYNA 的前药，易透过血脑屏障，结合有机酸转运抑制剂，以提高脑 KYNA 浓度；(3) 犬尿氨酸途径的酶抑制剂。在这篇综述中，我们重点介绍了肌萎缩侧索硬化症和多发性硬化症的发病机制和治疗可能性，这些都可能受到犬尿氨酸的影响。
