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

Marilyn J. Duncan; Hannah Farlow; Chairtra Tirumalaraju; Do Hyun Yun; Chanung Wang; James A. Howard; Madison N. Sanden; Bruce F. O'Hara; Kristen J. McQuerry; Adam D. Bachstetter

doi:10.1016/j.trci.2019.01.003

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

Marilyn J. Duncan, Hannah Farlow, Chairtra Tirumalaraju, Do Hyun Yun, Chanung Wang, James A. Howard, Madison N. Sanden, Bruce F. O'Hara, Kristen J. McQuerry, Adam D. Bachstetter

Research output: Contribution to journal › Article › peer-review

19 Scopus citations

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.

Original language	English
Pages (from-to)	70-80
Number of pages	11
Journal	Alzheimer's and Dementia: Translational Research and Clinical Interventions
Volume	5
DOIs	https://doi.org/10.1016/j.trci.2019.01.003
State	Published - Jan 1 2019

Bibliographical note

Publisher Copyright:
© 2019 The Authors

Funding

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.). 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.). Conflicts of interest: The authors declare no competing financial arrangements or connections and no nonfinancial conflicts of interest.

Funders	Funder number
A.D.B.
Merck
NIH R00 AG044445	R00 AG044445
National Institutes of Health (NIH)	NIH - 5P30AG02838
University of Kentucky , Department of Neuroscience
Merck	201607071502
University of Kentucky
Norges Idrettshøgskole	5P30AG02838

Keywords

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

ASJC Scopus subject areas

Clinical Neurology
Psychiatry and Mental health

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.trci.2019.01.003

Cite this

@article{4ecba6b01fdd4110861f7473da1d94b6,

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

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",

author = "Duncan, {Marilyn J.} and Hannah Farlow and Chairtra Tirumalaraju and Yun, {Do Hyun} and Chanung Wang and Howard, {James A.} and Sanden, {Madison N.} and O'Hara, {Bruce F.} and McQuerry, {Kristen J.} and Bachstetter, {Adam D.}",

note = "Publisher Copyright: {\textcopyright} 2019 The Authors",

year = "2019",

month = jan,

day = "1",

doi = "10.1016/j.trci.2019.01.003",

language = "English",

volume = "5",

pages = "70--80",

}

TY - JOUR

T1 - Effects of the dual orexin receptor antagonist DORA-22 on sleep in 5XFAD mice

AU - Duncan, Marilyn J.

AU - Farlow, Hannah

AU - Tirumalaraju, Chairtra

AU - Yun, Do Hyun

AU - Wang, Chanung

AU - Howard, James A.

AU - Sanden, Madison N.

AU - O'Hara, Bruce F.

AU - McQuerry, Kristen J.

AU - Bachstetter, Adam D.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

KW - Alzheimer's disease

KW - Amyloid β

KW - Dual orexin receptor antagonist

KW - Neuroinflammation

KW - Orexin

KW - Sleep fragmentation

KW - Sleep-wake cycles

UR - http://www.scopus.com/inward/record.url?scp=85062092832&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85062092832&partnerID=8YFLogxK

U2 - 10.1016/j.trci.2019.01.003

DO - 10.1016/j.trci.2019.01.003

M3 - Article

AN - SCOPUS:85062092832

VL - 5

SP - 70

EP - 80

JO - Alzheimer's and Dementia: Translational Research and Clinical Interventions

JF - Alzheimer's and Dementia: Translational Research and Clinical Interventions

ER -

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this