The kynurenine pathway (KP)
The KP is a major degradative pathway of tryptophan (TRP) that ultimately leads to the production of NAD (Figure right). Within the brain, approximately 95% of the tryptophan absorbed in the human diet is processed by this pathway and the remaining 5% serves as a precursor to the synthesis of the neurotransmitter serotonin. Recent findings have shown that the KP is one of the major regulatory mechanisms of the immune response. Two theories have been proposed: 1) that TRP degradation suppresses T cell proliferation by dramatically depleting the supply of this critical amino acid; 2) that some downstream KP metabolites act to suppress certain immune cells. Induction of the KP regulatory enzyme indoleamine 2,3 dioxygenase (IDO) in dendritic cells completely blocks clonal expansion of T cells. TRP depletion and IDO/KP activation have been implicated in the development of immuno-tolerance associated with pregnancy and persistence of tumors. The cellular location of the KP is only partly understood. It is complete in monocytic lineage cells, including macrophages, and microglia and we showed that it is partly present in astrocytes. The products of the KP have numerous neurotoxic and neuroprotective effects. Among them, QUIN is perhaps the most important. It leads acutely to human neuronal death and chronically to dysfunction by at least four mechanisms. Another product of the KP, kynurenic acid (KYNA), is an antagonist of all ionotropic glutamate receptors and thus can antagonize some of the effects of QUIN and other excitotoxins. It is noteworthy that in disease states where excess QUIN is produced there is insufficient KYNA to block QUIN. Several drugs that can block the KP are under investigation by our laboratory and others. For example, 4-chlorokynurenine crosses the BBB and blocks QUIN toxicity at the glycine site on NMDA receptors. KYNA analogues are in or about to enter clinical trials for treatment of epilepsy, stroke and possibly Parkinson’s disease.
Current Collaborations
