Reducing brain kynurenic acid synthesis precludes kynurenine-induced sleep disturbances

Patients with neurocognitive disorders often battle sleep disturbances. Kynurenic acid (KYNA) is a tryptophan metabolite of the kynurenine pathway 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. 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 sleep (REMS) and non-REM sleep (NREMS) following each treatment. Kynurenine challenge increased brain KYNA and resulted in reduced REMS duration, NREMS delta power and sleep spindles. PF-04859989 reduced brain KYNA formation when given prior to kynurenine, prevented disturbances in REM sleep and sleep spindles, and enhanced NREM sleep. Our findings suggest that reducing KYNA in conditions where the kynurenine pathway is activated may serve as a potential strategy for improving sleep dynamics.