Kynurenine pathway at the crossroads of neurological and psychiatric disorders: Bridging metabolic dysregulation, therapeutic challenges, and emerging strategies.
Level 5 - mechanism / opinion, no new human data
Narrative review evaluating preclinical and clinical mechanistic evidence without systematic review methodology.
PubMed 42315009 · doi:10.1016/j.pnpbp.2026.111796
What was done
This narrative review synthesized preclinical and clinical evidence examining the kynurenine pathway of tryptophan metabolism in neurological and psychiatric pathophysiology. The authors evaluated the neuromodulatory roles of metabolites including kynurenine, kynurenic acid, and quinolinic acid, along with pharmacological strategies targeting enzymes such as IDO, TDO, KMO, and KAT.
What was found
The abstract reports no numerical data or effect sizes. It qualitatively identifies core translational challenges, including concentration-dependent paradoxical neuroprotective versus neurotoxic effects, incompletely mapped spatiotemporal metabolite dynamics across central nervous system compartments, poor blood-brain barrier penetration of candidate drugs, off-target disruptions of the kynurenic acid to quinolinic acid ratio, and interspecies differences in enzyme expression profiles.
Why it matters
The kynurenine pathway links immune-metabolic dysregulation to glutamatergic and nicotinic signaling, making it an important target in neuropsychiatry. This review frames why single-target enzyme inhibition often struggles clinically and underscores the need for region-selective modulation that preserves metabolite equilibrium.
Limits
The paper is a narrative review presenting no primary experimental or clinical human data and no quantitative meta-analysis. The number of reviewed studies is not specified in the abstract, and translational relevance remains constrained by marked interspecies differences in enzyme dynamics.
Cited by
- context Kynurenic acid and quinolinic acid are neurotoxic serotonin/tryptophan pathway metabolites associated with brain inflammation.