We examine the relationship between sleep, glymphatics and Alzheimer's disease (AD), and recent work questioning glymphatic clearance during sleep. We highlight a need for understanding glymphatic and/or other mechanism of clearance during sleep, and review glymphatic flow measurement methods. Further, we explore dual orexin receptor antagonists (DORAs) potential to mitigate AD sleep disturbances and enhance clearance. Further research could elucidate a linkage between DORAs, improved sleep and reducing AD pathophysiology.
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http://dx.doi.org/10.1038/s44323-025-00025-5 | DOI Listing |
NPJ Biol Timing Sleep
March 2025
Department of Psychology; Program in Neuroscience; Florida State University, Tallahassee, FL USA.
We examine the relationship between sleep, glymphatics and Alzheimer's disease (AD), and recent work questioning glymphatic clearance during sleep. We highlight a need for understanding glymphatic and/or other mechanism of clearance during sleep, and review glymphatic flow measurement methods. Further, we explore dual orexin receptor antagonists (DORAs) potential to mitigate AD sleep disturbances and enhance clearance.
View Article and Find Full Text PDFBioorg Med Chem
February 2025
Idorsia Pharmaceuticals Ltd, Hegenheimermattweg 91, CH-4123 Allschwil, Switzerland.
We describe the optimization of 2-acyl-1-biarylmethylpyrazolidines, a novel class of dual orexin receptor antagonists (DORAs) designed for the treatment of sleep disorders requiring a rapid onset (<30 min) and a short duration of action (2-4 h). Building on the previously identified lead compound DORA 4, our optimization program yielded several potent pyrazolidine DORAs with carefully tailored in vitro physicochemical and DMPK (drug, metabolism and pharmacokinetics) properties. In vivo studies in animals, combined with pharmacokinetic-pharmacodynamic (PK-PD) simulations, demonstrated that DORA 31 and DORA (R)-38 effectively induced sleep in dogs and met the in silico predicted requirements for rapid onset and short duration in humans.
View Article and Find Full Text PDFNoro Psikiyatr Ars
January 2025
Mersin University Medical Faculty, Department of Neurology, Mersin, Türkiye.
Introduction: Long-reported dual comorbidity between migraine and sleep disorders suggests that some gene variations may play a role in this relationship. Our previous study found an association between poor sleep quality and the G allele of the hypocretin receptor 1 (HCRTR1) rs2271933 gene in patients with chronic migraine (CM). This study aimed to examine the relationship of this gene with some sleep parameters.
View Article and Find Full Text PDFCurr Drug Saf
March 2025
Centre for Translational & Clinical Research, School of Chemical and Life Sciences, Jamia Hamdard, India.
Insomnia is becoming a concern in general practice as it affects around 30% of adults. It is a sleep disorder characterized by trouble getting asleep, staying asleep, waking up early, and difficulty falling back to sleep. The most commonly used hypnotics, such as benzodiazepines, Z drugs, etc, are associated with various issues, including psychomotor and cognitive impairment.
View Article and Find Full Text PDFNat Ment Health
September 2024
Neuropsychiatric Institute and Brain Research Institute, University of California, Los Angeles, Los Angeles, CA, USA.
Heroin use disorder in humans and chronic opioid administration to mice result in an increase in the number and a decrease in the size of detected hypocretin (Hcrt, or orexin) neurons. Chronic morphine administration to mice increases Hcrt axonal projections to the ventral tegmental area (VTA), the level of tyrosine hydroxylase (TH) in VTA and the number of detected TH cells in VTA, and activates VTA and hypothalamic microglia. Co-administration of morphine with the dual Hcrt receptor antagonist suvorexant prevents morphine-induced changes in the number and size of Hcrt neurons, the increase in Hcrt projections to the VTA and microglial activation in the VTA and hypothalamus.
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