Figure 1.

The kynurenine pathway of tryptophan metabolism produces neuroprotective as well as neurotoxic metabolites that can influence MS pathology. Neurotoxic metabolites are circled in red, and neuroprotective metabolites in green. Tryptophan (blue box) may be metabolized to serotonin and melatonin in multi-step sequential reactions, or alternatively is metabolized via the KP. This reaction is inhibited by 1-methyl tryptophan (1-MT) or berberine. Kynurenine (purple box) is the initial rate-limiting KP product of tryptophan metabolism by the enzymes indoleamine-2,3-dioxygenase (IDO-1) and tryptophan dioxygenase (orange box). Kynurenine is then converted via kynurenine aminotransferases (KATI/II/III) to kynurenic acid, a neuroprotective molecule as it antagonizes glutamate receptor-induced neurotoxicity. 3-hydroxykynurenine is produced by further metabolism of kynurenine, for which evidence is accumulating of its neurotoxic capability. This reaction is inhibited by Ro61-8048 or nicotinylalanine. Leflunomide (Avara^®) is an immunosuppressive and anti-inflammatory drug. Teriflunomide is the active metabolite of leflunomide. These kynurenine analogs are effective in reducing active lesions in both rodent models and in a phase II clinical trial (235). Kynureninase catalyzes the conversion of 3-hydroxykynurenine to 3-hydroxyanthranilic acid. Tranilast is a synthetic anthracillic acid derivative drug with anti-inflammatory action (236). Sequential conversion to 2-amino-3-carboxymuconate-semialdehyde is the penultimate step leading to enzymatic production of (neuroprotective) picolinic acid, and the (non-enzymatic) production of the well-known neurotoxic compound quinolinic acid (QUIN). Further conversion of QUIN to the essential cofactor NAD⁺ is catalyzed by quinolinate phosphoribosyltransferase (QPRT). Dashed boxes indicate synthetic compounds, some of which are in drug development, that are derivatives of the KP metabolite described above.