Fig. 1

Kynurenine pathway of tryptophan metabolism. Tryptophan is metabolized to kynurenine by indoleamine 2,3-dioxygenase (IDO), IDO-like enzyme, IDO2, and tryptophan 2,3-dioxygenase (TDO). Tryptophan can also be metabolized by tryptophan hydroxylase (TrpH) and l-aromatic amino acid decarboxylase ( _L -AADC) to serotonin (5-HT) which is further broken down by monoamine oxidase (MAO) to 5-hydroxyindoleacetic acid (5-HIAA). Kynurenine can be metabolized to kynurenic acid (KA) by one of four isoforms of kynurenine aminotransferase (KAT), of which KATI and KATII are most relevant to mammals. The production of KA by KATs mainly occurs in astrocytes, cells which predominantly express glial fibrillary acidic protein (GFAP). Alternately, kynurenine can be metabolized to 3-hydroxykynurenine (3-HK) by kynurenine 3-monooxygenase (KMO). 3-HK is metabolized to 3-hydroxyanthranilic acid (3-HAA) by kynureninase (KYNU) and 3-HAA to quinolinic acid (QA) by 3-hydroxyanthranilic acid dioxygenase (HAAO). This branch of the kynurenine pathway is compartmentalized in microglia, indicated by ionized calcium-binding adapter molecule 1 (Iba1) and CD11b expression. The elevation in expression of pro-inflammatory cytokines, such as interleukin-1β (IL-1β), tumor necrosis factor α (TNFα), and interleukin-6 (IL-6), during inflammatory conditions activates glial cells. Further, IDO expression is up-regulated and flux through the neurotoxic kynurenine metabolic branch increases. Underlined targets were assessed by real-time RT-PCR to determine changes in mRNA