Biochemical Regulation of Brain Kynurenic Acid Synthesis and Inhibition in Rats is Sensitive to the Time of Day

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.