ArticlebioRxiv : the preprint server for biology2026
Biochemical Regulation of Brain Kynurenic Acid Synthesis and Inhibition in Rats is Sensitive to the Time of Day.
Article in bioRxiv : the preprint server for biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Neurochemical imbalances, including elevations of the tryptophan metabolite kynurenic acid (KYNA), an endogenous antagonist of glutamatergic and cholinergic receptors, are linked to cognitive and sleep disturbances in psychiatric and neurocognitive disorders. Therapeutic strategies to reduce brain KYNA by inhibiting kynurenine aminotransferase II (KAT II) are under investigation. However, few studies consider time as a biological variable, despite recent evidence that the time of day can affect brain metabolism and drug effectiveness. Therefore, we explore the hypothesis that KYNA formation and synthesis inhibition change throughout the day. Using rats of both sexes, we measured basal KYNA levels and the effects of kynurenine (100 mg/kg, i.p.), to stimulate Lay Summary: Changes in brain neurochemistry, including elevations in the tryptophan metabolite kynurenic acid (KYNA), are common in brain disorders that present with sleep disturbances and cognitive deficits as symptoms. KYNA interferes with neurotransmission critical for cognition and sleep, so therapeutic strategies to reduce brain KYNA are being pursued. As recent literature has highlighted the impact of time on brain metabolism and drug efficacy, we, for the first time, explored the hypothesis that KYNA formation and synthesis inhibition change throughout the day. We measured extracellular KYNA levels in the brains of male and female rats and stimulated KYNA synthesis with physiological challenges (exogenous kynurenine, the KYNA bioprecursor, or acute sleep deprivation) and/or inhibited KYNA synthesis pharmacologically (PF-04859989, an inhibitor of the KYNA-synthesizing enzyme kynurenine aminotransferase II (KAT II)). KYNA formation, KAT II enzyme activity, and the effectiveness of PF-04859989 varied throughout the day, highlighting time as a key factor modulating KYNA brain metabolism. PF-04859989 reduced KYNA levels under most conditions. Our findings suggest that the timing of KYNA-targeted treatments should be carefully considered in therapeutic strategies to improve cognition and sleep in brain disorders.
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