Fig. 1

Tryptophan Metabolism along the kynurenine pathway. a The kynurenine pathway within the periphery and brain under healthy conditions. Proper enzyme regulation results in a healthy balance of TRP and TRP metabolites. As a result, adequate levels of TRP are available for 5-HT synthesis and properly regulated SERT proteins ensure that extra-cellular concentrations of 5-HT are not depleted. Healthy levels of TRP metabolites within the brain (e.g., QUIN) ensure normal activation of NMDA receptors thereby maintaining healthy hippocampal function and proper regulation of the HPA axis. b The kynurenine pathway within the periphery and brain in a state of chronic inflammation. Elevated levels of pro-inflammatory cytokines cause upregulation of enzymes such as IDO thereby resulting in an increased breakdown of TRP and production of TRP metabolites. As a result, reduced levels of TRP are available for the synthesis of 5-HT. Pro-inflammatory cytokines also upregulate SERT proteins causing further depletion of extra-cellular 5-HT. Elevated levels of TRP metabolites within the brain such as QUIN (potent NMDA agonist) result in over-activation of NMDA receptors, neuronal damage, and potential atrophy. This may also lead to a loss of inhibition of the HPA axis and excessive production of stress hormones