Chronic stress and brain kynurenine pathway: addressing unresolved issues with a meta-analytic approach of...

The kynurenine pathway (KP) has emerged as a key mediator of inflammation and synaptic plasticity, which play a significant role in the pathophysiology of chronic stress (CS). CS, in turn, is a major environmental factor in the development of psychiatric disorders. Despite growing evidence linking the KP to psychiatric disorders, the mechanisms underlying its alterations under CS remain poorly understood. To address this gap, we conducted the first comprehensive meta-analysis of preclinical rodent studies. Our goal was to systematically evaluate, within controlled experimental paradigms: (1) how, to what extent, and in which brain regions CS affects the KP; (2) which neurochemical pathways are most impacted by CS. We searched PubMed/MEDLINE, EMBASE, Scopus for preclinical studies until 06/27/2025. We performed a systematic review and meta-analysis following a pre-determined protocol (PROSPERO:CRD42023459414), considering KP metabolites and enzymes as outcomes (Standardized Mean Difference=SMD). SYRCLE/CAMARADES tools assessed quality and risk-of-bias. 59 studies entered the meta-analyses. CS proved to increase hippocampal and cortical overall concentrations of kynurenine (SMD=1.71,95 %C.I.[0.99,2.42], p < 0.01,I²=91.3 %,k = 23,n = 508; SMD=1.54,95 %C.I.[1.08,2.01],p < 0.01,I²=57.77 %,k = 16,n = 247), as well as kynurenine/tryptophan ratio and quinolinic acid. KYNA concentrations decreased in the hippocampus and cortex. KP enzyme expression/activity, including Indoleamine-2,3-Dioxygenase, Tryptophan-2,3-Dioxygenase, Kynurenine-3-Monoxygenase, increased. These findings support a shift of tryptophan metabolism towards the KP following CS. Particularly, the increase in neurotoxic quinolinic acid (NMDAR-agonist) and decrease in KYNA (NMDA-antagonist) may disrupt the neuroprotection/excitotoxic neuronal balance, influencing neuroplasticity. The KP may play a key role in the pathophysiology of CS-associated behaviors, and could serve to highlight potential targets for novel therapeutic strategies, specifically for treatment resistance.