Reducing brain kynurenic acid synthesis precludes kynurenine-induced sleep disturbances

Abstract

Study Objectives Patients with neurocognitive disorders often battle sleep disturbances. Kynurenic acid (KYNA) is a tryptophan metabolite implicated in the pathology of these illnesses. Modest increases in KYNA, an antagonist at glutamatergic and cholinergic receptors, result in cognitive impairments and sleep dysfunction. We explored the hypothesis that inhibition of the KYNA synthesizing enzyme, kynurenine aminotransferase II (KAT II), may alleviate sleep disturbances. Methods At the start of the light phase, adult male and female Wistar rats received systemic injections of either i) vehicle, ii) kynurenine (100mg/kg; i.p.), iii) the KAT II inhibitor, PF-04859989 (30 mg/kg; s.c), or iv) PF-04859989 and kynurenine in combination. Kynurenine and KYNA levels were evaluated in the plasma and brain. Separate animals were implanted with electroencephalogram (EEG) and electromyogram (EMG) telemetry devices to record polysomnography and evaluate vigilance states wake, rapid eye movement (REM) sleep and non-REM (NREM) sleep following each treatment. Results Kynurenine challenge increased brain KYNA and resulted in reduced REM duration, NREM delta power and sleep spindles. PF-04859989 reduced brain KYNA formation when given prior to kynurenine, prevented sleep disturbances, and enhanced NREM sleep. Conclusion REM sleep was restored when PF-04859989 was administered prior to kynurenine challenge, suggesting that reducing KYNA attenuated the kynurenine-induced decrease in REM. Further, KAT II inhibition may cause mild somnolence. Our findings suggest for the first time that reducing KYNA may serve as a potential strategy for improving sleep dynamics.