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Alzheimers Dement (N Y). 2019 Feb 28;5:70-80. doi: 10.1016/j.trci.2019.01.003. eCollection 2019.

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

Author information

1
Department of Neuroscience, University of Kentucky College of Medicine, Lexington, KY, USA.
2
Department of Biology, University of Kentucky, Lexington, KY, USA.
3
Department of Statistics, University of Kentucky, Lexington, KY, USA.
4
Spinal Cord and Brain Injury Research Center, University of Kentucky College of Medicine, Lexington, KY, USA.

Abstract

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.

KEYWORDS:

Alzheimer's disease; Amyloid β; Dual orexin receptor antagonist; Neuroinflammation; Orexin; Sleep fragmentation; Sleep-wake cycles

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