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Effects of the dual orexin receptor antagonist DORA-22 on sleep in 5XFAD mice

INTRODUCTION: Sleep disruption is a characteristic of Alzheimer's disease (AD) that may exacerbate disease progression. This study tested whether a dual orexin receptor antagonist (DORA) would enhance sleep and attenuate neuropathology, neuroinflammation, and cognitive deficits in an AD-relevan...

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Detalles Bibliográficos
Autores principales: Duncan, Marilyn J., Farlow, Hannah, Tirumalaraju, Chairtra, Yun, Do-Hyun, Wang, Chanung, Howard, James A., Sanden, Madison N., O'Hara, Bruce F., McQuerry, Kristen J., Bachstetter, Adam D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396100/
https://www.ncbi.nlm.nih.gov/pubmed/30859123
http://dx.doi.org/10.1016/j.trci.2019.01.003
Descripción
Sumario:INTRODUCTION: Sleep disruption is a characteristic of Alzheimer's disease (AD) that may exacerbate disease progression. This study tested whether a dual orexin receptor antagonist (DORA) would enhance sleep and attenuate neuropathology, neuroinflammation, and cognitive deficits in an AD-relevant mouse model, 5XFAD. METHODS: Wild-type (C57Bl6/SJL) and 5XFAD mice received chronic treatment with vehicle or DORA-22. Piezoelectric recordings monitored sleep and spatial memory was assessed via spontaneous Y-maze alternations. Aβ plaques, Aβ levels, and neuroinflammatory markers were measured by immunohistochemistry, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction, respectively. RESULTS: In 5XFAD mice, DORA-22 significantly increased light-phase sleep without reducing Aβ levels, plaque density, or neuroinflammation. Effects of DORA-22 on cognitive deficits could not be determined because the 5XFAD mice did not exhibit deficits. DISCUSSION: These findings suggest that DORAs may improve sleep in AD patients. Further investigations should optimize the dose and duration of DORA-22 treatment and explore additional AD-relevant animal models and cognitive tests.