A metabolite produced when tryptophan is shunted away from serotonin synthesis into the kynurenine pathway via indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3-dioxygenase (TDO). Kynurenine crosses the blood-brain barrier and is converted to downstream metabolites with neuroactive properties.
Inflammatory cytokines (IFN-Ξ³, TNF, IL-6) activate IDO in peripheral tissues and microglia, shunting tryptophan into kynurenine instead of serotonin. Kynurenine crosses BBB and is metabolized by astrocytes to neuroprotective kynurenic acid (KYNA, NMDA antagonist) or by activated microglia to neurotoxic quinolinic acid (QUIN, NMDA agonist). QUIN produces oxidative stress, excitotoxicity, and neuroinflammation. KYN/TRP ratio serves as marker of IDO activity and inflammation.
The kynurenine pathway links inflammation to depression, cognitive dysfunction, and neurodegeneration. In inflammation-driven depression (hot depression), IDO activation depletes tryptophan for serotonin synthesis while producing neurotoxic quinolinic acid. This explains why some depressed patients don't respond to SSRIs (low serotonin is consequence, not cause). Treatment requires addressing underlying inflammation rather than serotonin manipulation.
- Inflammation activates IDO, shunting tryptophan from serotonin to kynurenine
- KYN/TRP ratio is biomarker of IDO activation and inflammation
- Kynurenine crosses blood-brain barrier efficiently
- In brain: astrocytes β kynurenic acid (neuroprotective), microglia β quinolinic acid (neurotoxic)
- Quinolinic acid activates NMDA receptors causing excitotoxicity
- Elevated in depression, especially inflammation-associated depression
- High kynurenine/KYNA ratio predicts cognitive decline
- Exercise shifts metabolism toward kynurenic acid (neuroprotective)
- IDO activation is immune tolerance mechanism (T cell suppression)
- tryptophan β Precursor; kynurenine pathway competes with serotonin synthesis for tryptophan
- serotonin β Inflammation reduces serotonin synthesis by shunting tryptophan to kynurenine
- IDO β Indoleamine 2,3-dioxygenase catalyzes first step of kynurenine pathway
- inflammation β Inflammatory cytokines activate IDO, driving kynurenine production
- IFN-Ξ³ β Potent inducer of IDO and kynurenine pathway
- IL-6 β Pro-inflammatory cytokine activating IDO
- quinolinic acid β Neurotoxic metabolite produced from kynurenine by activated microglia
- kynurenic acid β Neuroprotective metabolite produced from kynurenine by astrocytes
- microglia β Activated microglia produce neurotoxic quinolinic acid from kynurenine
- depression β Elevated kynurenine and quinolinic acid implicated in inflammation-driven depression
- NMDA receptor β Quinolinic acid activates (excitotoxic), kynurenic acid inhibits (neuroprotective)
- blood-brain barrier β Kynurenine crosses BBB; determines CNS effects
- cognitive decline β High kynurenine pathway activity associated with cognitive impairment
- neurodegeneration β Quinolinic acid-mediated excitotoxicity contributes to neuronal death
- T cells β IDO activation suppresses T cell proliferation (immune tolerance mechanism)
- exercise β Shifts kynurenine metabolism toward protective kynurenic acid
- SSRIs β Ineffective in inflammation-driven depression with active kynurenine pathway