002 Daridorexant, a dual orexin receptor antagonist, improves age-related insomnia in rats. (3rd May 2021)

• Record Type: Journal Article
• Authors: Roch, Catherine; Fischer, Cédric; Jenck, Francois; Steiner, Michel
• Is Part Of: Sleep. Volume 44(2021)Supplement 2
• Page Start: A1
• Page End: A1
• Publication Date: 2021-05-03
• Subjects: Sleep -- Physiological aspects -- Periodicals; Sleep disorders -- Periodicals; Sommeil -- Aspect physiologique -- Périodiques; Sommeil, Troubles du -- Périodiques; Sleep disorders; Sleep -- Physiological aspects; Sleep -- physiological aspects; Sleep Wake Disorders; Psychophysiology; Electronic journals; Periodicals; 616.8498
• DOI: 10.1093/sleep/zsab072.001
• Languages: English
• ISSNs: 0161-8105

Abstract

Abstract: Introduction: Sleep disturbances develop with age, and prevalence of insomnia is higher in the elderly. Daridorexant is a new medication in development for the treatment of insomnia. Our aim was to investigate whether an insomnia-like phenotype develops in old rats, and then to assess the effect of repeated administration of daridorexant in these animals. Methods: We recorded the electroencephalogram and electromyogram of freely moving male Wistar rats implanted with telemetry transmitters. Time spent sleeping during the inactive phase was measured at the ages of 4 (n=50), 6 (n=55), 8 (n=37), 12 (n=44), 18 (n=22) and 24 (n=9) months. The age at which the rats' time spent sleeping started to be significantly reduced compared to that of 4-month-old rats was when the insomnia-like phenotype would start to occur. The impact of 100 mg/kg daridorexant, given orally at the beginning of the inactive phase, was evaluated in 16-month-old rats (n=8). Rats were consecutively treated daily for 6 days with vehicle (baseline period), for 3 weeks with daridorexant, and again for 1 week with vehicle (wash-out period). Results: The total time spent sleeping during the 12-h inactive period decreased from 51.3±1.1% (mean ± SEM) at 4-months old to 39.3±4.4% at 24-months, with a significant decrease starting from 8-months (p<0.05). Whereas the time spent in rapid-eye-movement (REM) sleep (~10%) was not affected by age (p=0.64), the time spent in non-REM sleep decreased from 41.7±0.8% at 4 months to 28.7±3.2% at 24 months (p<0.001). In 16-month-old rats daridorexant increased the time spent in non-REM sleep over the first 6-h following administration (p<0.001). The time spent in REM sleep was unaffected (p=0.47). The average time spent in non-REM sleep over those 6h was 37.2±2.5% at baseline, and 43.8±2.4%, 44.6±2.7% and 44.5±3.0% in the 1st (p<0.05 vs baseline), 2nd (p<0.001) and 3rd (p<0.01) week of treatment, respectively. During the wash-out period, the non-REM sleep time returned to baseline levels (35.6±2.7%; p=0.06). Conclusion: In rats, an insomnia-like phenotype, characterized by reduced non-REM sleep time, develops with age. Daridorexant improves this phenotype and its effect is maintained upon repeated administration over three weeks. Support (if any): Funded by Idorsia Pharmaceuticals Ltd