The tryptophan field has long been associated with melatonin and the regulation of sleep–wake cycles, positioning tryptophan primarily within the serotonergic axis of sleep biology. However, this represents only one facet of its metabolic relevance. Increasing attention has shifted toward the kynurenine pathway, which accounts for the majority of tryptophan metabolism and plays a central role in neuroimmune regulation and neurodegenerative processes. Among its metabolites, kynurenic acid (KYNA) has emerged as a key neuromodulator, influencing glutamatergic and cholinergic signalling, and implicated in cognitive function and neurodegeneration. This raises an important question as to whether sleep and circadian processes may also regulate kynurenine pathway dynamics.
A new study by Wright et al (2026) provides compelling evidence that brain KYNA synthesis is tightly regulated by circadian timing. Using in vivo microdialysis in the rat hippocampus, the authors show that kynurenine-driven KYNA production is significantly greater during the active (dark) phase, reaching approximately twofold higher levels compared to the resting (light) phase. This time-of-day effect is further amplified under metabolic challenge, with kynurenine administration increasing KYNA levels by up to 8–11-fold, particularly during the dark phase. Pharmacological inhibition of kynurenine aminotransferase II (KAT II) reduced KYNA levels by approximately 36–48%, with a more pronounced effect when administered during the dark phase, indicating that both enzyme activity and drug efficacy are circadian-dependent. Notably, acute sleep deprivation during the light phase led to a sustained increase in extracellular KYNA, an effect that was fully reversed by KAT II inhibition. Together, these findings demonstrate that kynurenine pathway metabolism is dynamically regulated across the sleep–wake cycle, with both endogenous synthesis and pharmacological modulation varying as a function of time of day.
Taken together, this study highlights the kynurenine pathway as a dynamic system shaped by circadian timing and biological sex. By showing that both KYNA synthesis and its inhibition vary across the day, it underscores the importance of considering time-of-day in experimental design and therapeutic strategies targeting kynurenine metabolism.