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.
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This research was supported by a contract from Merck (MIS #201607071502 [M.J.D. and B.F.O.]), pilot funds from National Institutes of Health (NIH) grant NIH-5P30AG02838 (L. Van Eldik, PI of grant; M.J.D. and A.D.B., MPIs of pilot study), NIH R00 AG044445 (A.D.B.), and pilot funds from the University of Kentucky, Department of Neuroscience (M.J.D. and A.D.B.).
Supplementary data related to this article can be found at https://doi.org/10.1016/j.trci.2019.01.003.
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.; and Bachstetter, Adam D., "Effects of the Dual Orexin Receptor Antagonist DORA-22 on Sleep in 5XFAD Mice" (2019). Neuroscience Faculty Publications. 64.