The Kynurenic Acid Synthesis Inhibitor PF-04859989 Prevents Acute Kynurenine-Induced Sleep Disturbances in Rats

Kynurenic acid (KYNA) is a tryptophan metabolite implicated in the pathophysiology of several neurocognitive disorders including schizophrenia, bipolar disorder, and age-related dementias. KYNA, an endogenous astrocyte-derived antagonist of α7nACh and NMDA receptors, is synthesized from kynurenine by kynurenine aminotransferase II (KAT II). Sleep disturbances and comorbid parasomnias remain a common complaint among patients suffering from neurocognitive disorders. Elevated KYNA levels have been detected in the cerebrospinal fluid and postmortem brain tissue from affected patients, and elevated KYNA is thought to causally contribute to impaired sleep-wake behavior and associated cognitive deficits. To investigate the acute effects of KYNA on sleep in vivo, telemetry devices were surgically implanted to record electroencephalography (EEG) and electromyography (EMG) polysomnography from freely moving Wistar rats. The recordings allowed us to assess cortical oscillations and muscle activity associated with rapid-eye movement (REM) sleep, non-rapid eye movement (NREM) sleep, and wake parameters. Presently, acute administration of the precursor to KYNA, kynurenine (100 mg/kg), at zeitgeber time (ZT) 0 elicited a 15% decrease in REM duration. To combat these deficits, we designed a within animal study (n=9), and treated rats with the KAT II inhibitor PF-04859989 (30 mg/kg) 30 minutes prior to acute kynurenine administration (100 mg/kg) at ZT 0. PF-04859989 attenuated kynurenine-induced deficits in REM sleep, and all sleep-wake parameters were comparable to vehicle treatments. Interestingly, PF-04859989 increased NREM duration and decreased wake duration across 24 hours in both vehicle and kynurenine-treated trials, which suggests that the KAT II inhibitor may have slight sedative properties. Furthermore, PF-04859989 enhanced NREM delta power in kynurenine-treated animals during the dark phase. Taken together, KAT II inhibition may serve as a potential therapeutic avenue for improving sleep disturbances associated with neurocognitive disorders.