Fig. 1: Simplified kynurenine pathway.

Rectangles highlight the metabolites measured in the present study, with fill indicating neuroprotective (blue) or neurotoxic (red) properties. The KP begins with the catabolism of over 90% of the essential amino acid tryptophan (TRP) into L-kynurenine (KYN), with a relatively small amount converted to serotonin (5HT). KYN is then further catabolized along several branches into multiple neuroactive metabolites, known as kynurenines. The central branch is the 3-hydroxykynurenine-quinolinic acid (3HK-QUIN) branch, which leads to synthesis of NAD⁺, a coenzyme essential for cellular energy production and redox homeostasis that declines with age. Buildups of 3HK and QUIN can both contribute to oxidative stress, and QUIN is neurotoxic by multiple other mechanisms, including glutamate excitotoxicity primarily due to selective agonist effects on NMDA receptors. Along other branches and off-branches, neuroprotective kynurenines are produced that balance the effects of 3HK and QUIN. These include kynurenic acid (KYNA), a glutamate receptor antagonist, and anthranilic acid (AA) and picolinic acid (PIC), both metal chelators. Enzymes (in italics) along the pathway drive the relative production of kynurenines and are influenced by pro-inflammatory cytokines, such as IFN-γ. The ratios of 3HK and QUIN to neuroprotective kynurenines are altered in inflammation and many neurological and neuropsychiatric diseases, including Parkinson’s disease.