Evaluation of SAMP8 Mice as a Model for Sleep-Wake and Rhythm Disturbances Associated with Alzheimer’s Disease: Impact of Treatment with the Dual Orexin (Hypocretin) Receptor Antagonist Lemborexant
| Autor: | Margaret Moline, Carsten T. Beuckmann, Masahiro Bando, Erik S. Musiek, Toshitaka Sato, Takashi Ueno, Hiroyuki Suzuki, Yoshihide Osada |
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| Rok vydání: | 2021 |
| Předmět: |
Male
Sleep Wake Disorders medicine.medical_specialty Pyridines medicine.drug_class Lemborexant Motor Activity Mice Rhythm Alzheimer Disease Internal medicine medicine Animals Circadian rhythm sleep mouse dual orexin receptor antagonist irregular sleep-wake rhythm disorder business.industry General Neuroscience Antagonist General Medicine Receptor antagonist animal models Orexin receptor Circadian Rhythm Orexin Disease Models Animal E2006 in vivo Psychiatry and Mental health Clinical Psychology Pyrimidines Endocrinology orexin Orexin Receptor Antagonists running wheel Wakefulness Geriatrics and Gerontology business Alzheimer’s disease psychological phenomena and processes Research Article lemborexant |
| Zdroj: | Journal of Alzheimer's Disease |
| ISSN: | 1875-8908 1387-2877 |
| Popis: | Background: Many patients with Alzheimer’s disease (AD) display circadian rhythm and sleep-wake disturbances. However, few mouse AD models exhibit these disturbances. Lemborexant, a dual orexin receptor antagonist, is under development for treating circadian rhythm disorders in dementia. Objective: Evaluation of senescence-accelerated mouse prone-8 (SAMP8) mice as a model for sleep-wake and rhythm disturbances in AD and the effect of lemborexant by assessing sleep-wake/diurnal rhythm behavior. Methods: SAMP8 and control senescence-accelerated mouse resistant-1 (SAMR1) mice received vehicle or lemborexant at light onset; plasma lemborexant and diurnal cerebrospinal fluid (CSF) orexin concentrations were assessed. Sleep-wake behavior and running wheel activity were evaluated. Results: Plasma lemborexant concentrations were similar between strains. The peak/nadir timing of CSF orexin concentrations were approximately opposite between strains. During lights-on, SAMP8 mice showed less non-rapid eye movement (non-REM) and REM sleep than SAMR1 mice. Lemborexant treatment normalized wakefulness/non-REM sleep in SAMP8 mice. During lights-off, lemborexant-treated SAMR1 mice showed increased non-REM sleep; lemborexant-treated SAMP8 mice displayed increased wakefulness. SAMP8 mice showed differences in electroencephalogram architecture versus SAMR1 mice. SAMP8 mice exhibited more running wheel activity during lights-on. Lemborexant treatment reduced activity during lights-on and increased activity in the latter half of lights-off, demonstrating a corrective effect on overall diurnal rhythm. Lemborexant delayed the acrophase of activity in both strains by approximately 1 hour. Conclusion: SAMP8 mice display several aspects of sleep-wake and rhythm disturbances in AD, notably mistimed activity. These findings provide some preclinical rationale for evaluating lemborexant in patients with AD who experience sleep-wake and rhythm disturbances. |
| Databáze: | OpenAIRE |
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