Journal Article Review Ppublish 2 citations
PubMed: 39365407 DOI: 10.1007/s40265-024-02096-3
Orexin Receptor Antagonists for the Prevention and Treatment of Alzheimer's Disease and Associated Sleep Disorders.
Drugs 84(11):1365-1378
Authors: Matteo Carpi, Nicola Biagio Mercuri, Claudio Liguori
Affiliations
- Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy.
- Sleep Medicine Centre, Neurology Unit, University Hospital of Rome "Tor Vergata", Viale Oxford 81, 00133, Rome, Italy.
- Department of Systems Medicine, University of Rome "Tor Vergata", Viale Oxford 81, 00133, Rome, Italy.
- Sleep Medicine Centre, Neurology Unit, University Hospital of Rome "Tor Vergata", Viale Oxford 81, 00133, Rome, Italy.
- Department of Systems Medicine, University of Rome "Tor Vergata", Viale Oxford 81, 00133, Rome, Italy.
Abstract
Orexins/hypocretins are neuropeptides produced by the hypothalamic neurons, binding two G-protein coupled receptors (orexin 1 and orexin 2 receptors) and playing a critical role in regulating arousal, wakefulness, and various physiological functions. Given the high prevalence of sleep disturbances in Alzheimer's disease (AD) and their reported involvement in AD pathophysiology, the orexin system is hypothesized to contribute to the disease pathogenesis. Specifically, recent evidence suggests that orexin's influence may extend beyond sleep regulation, potentially affecting amyloid-β and tau pathologies. Dual orexin receptor antagonists (DORAs), namely suvorexant, lemborexant, and daridorexant, demonstrated efficacy in treating chronic insomnia disorder across diverse clinical populations. Considering their stabilizing effects on sleep parameters and emerging evidence of a possible neuroprotective role, these agents represent a promising strategy for AD management. This leading article reviews the potential use of orexin receptor antagonists in AD, particularly focusing on their effect in modulating disease-associated sleep disturbances and clinical outcomes. Overall, clinical studies support the use of DORAs to enhance sleep quality in patients with AD with comorbid sleep and circadian sleep-wake rhythm disorders. Preliminary results also suggest that these compounds might influence AD pathology, potentially affecting disease progression. Conversely, research on selective orexin receptor antagonists in AD is currently limited. Further investigation is needed to explore orexin antagonism not only as a symptomatic treatment for sleep disturbances, but also for its broader implications in modifying AD neurodegeneration, emphasizing mechanisms of action and long-term outcomes.
MeSH
Alzheimer Disease, Pharmaceutical Preparations, Sleep, Pathology, Drug Therapy, Orexin Receptors, Therapeutics, Orexin Receptor Antagonists, Orexins