L-tryptophan-kynurenim pathway enzymes are a therapeutic target for various neurological disorders

Changes in L-Tryptophan (TRP)-kynurenine (KYN) pathway metabolism play an important role (s) in various neurological disorders such as depressive symptoms associated with cytokine therapy. Indoleamine 2, 3-dioxygenase (IDO) 1 is the rate-limiting and the inflammatory cytokine inducible enzyme of the TRP-KYN pathway and plays a role in immune regulation. Here, the physiological significance of TRP-Kyn pathway metabolism in CNS is summarized. About 90% of total plasma L-TRP is bound to albumin, forming a complex that cannot cross the blood-brain barrier (BBB), but free form L-TRP is available for transport across the BBB into the brain. An important interface exists with the CNS since L-TRP, KYN and 3-hydroxykinurenine (3-HK) can cross the BBB quite readily. On the other hand, QUIN, KYNA and 3-hydroxyanthranilic acid (3-HAA) do not cross the BBB, but their concentrations are elevated markedly after systemic administration of KYN. The altered TRP/KYN ratio in the blood can produce significant secondary changes in the amount of KYNs in the CNS, contributing no doubt to the effects of immune activity and stress. This relationship may be of special significance for understanding the cognitive and neurodegenerative effects of inflammatory CNS diseases. The manipulation of TRP-KYN pathway metabolism through the administration of an enzyme modulator can serve as a novel therapeutic strategy for various neurological disorders.