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...
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| Format: | Article |
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Wiley
2019-01-01
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| Series: | Alzheimer’s & Dementia: Translational Research & Clinical Interventions |
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| Online Access: | https://doi.org/10.1016/j.trci.2019.01.003 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Marilyn J. Duncan |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a1a5298591bb468fbf618d6a72644db5 |
| institution | OA Journals |
| issn | 2352-8737 |
| language | English |
| publishDate | 2019-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Alzheimer’s & Dementia: Translational Research & Clinical Interventions |
| spelling | doaj-art-a1a5298591bb468fbf618d6a72644db52025-08-20T02:09:55ZengWileyAlzheimer’s & Dementia: Translational Research & Clinical Interventions2352-87372019-01-0151708010.1016/j.trci.2019.01.003Effects of the dual orexin receptor antagonist DORA‐22 on sleep in 5XFAD miceMarilyn J. Duncan0Hannah Farlow1Chairtra Tirumalaraju2Do‐Hyun Yun3Chanung Wang4James A. Howard5Madison N. Sanden6Bruce F. O'Hara7Kristen J. McQuerry8Adam D. Bachstetter9Department of NeuroscienceUniversity of Kentucky College of MedicineLexingtonKYUSADepartment of NeuroscienceUniversity of Kentucky College of MedicineLexingtonKYUSADepartment of NeuroscienceUniversity of Kentucky College of MedicineLexingtonKYUSADepartment of NeuroscienceUniversity of Kentucky College of MedicineLexingtonKYUSADepartment of BiologyUniversity of KentuckyLexingtonKYUSADepartment of NeuroscienceUniversity of Kentucky College of MedicineLexingtonKYUSADepartment of StatisticsUniversity of KentuckyLexingtonKYUSADepartment of BiologyUniversity of KentuckyLexingtonKYUSADepartment of StatisticsUniversity of KentuckyLexingtonKYUSADepartment of NeuroscienceUniversity of Kentucky College of MedicineLexingtonKYUSAAbstract 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.https://doi.org/10.1016/j.trci.2019.01.003Sleep‐wake cyclesSleep fragmentationOrexinDual orexin receptor antagonistAmyloid βNeuroinflammation |
| spellingShingle | 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 Effects of the dual orexin receptor antagonist DORA‐22 on sleep in 5XFAD mice Alzheimer’s & Dementia: Translational Research & Clinical Interventions Sleep‐wake cycles Sleep fragmentation Orexin Dual orexin receptor antagonist Amyloid β Neuroinflammation |
| title | Effects of the dual orexin receptor antagonist DORA‐22 on sleep in 5XFAD mice |
| title_full | Effects of the dual orexin receptor antagonist DORA‐22 on sleep in 5XFAD mice |
| title_fullStr | Effects of the dual orexin receptor antagonist DORA‐22 on sleep in 5XFAD mice |
| title_full_unstemmed | Effects of the dual orexin receptor antagonist DORA‐22 on sleep in 5XFAD mice |
| title_short | Effects of the dual orexin receptor antagonist DORA‐22 on sleep in 5XFAD mice |
| title_sort | effects of the dual orexin receptor antagonist dora 22 on sleep in 5xfad mice |
| topic | Sleep‐wake cycles Sleep fragmentation Orexin Dual orexin receptor antagonist Amyloid β Neuroinflammation |
| url | https://doi.org/10.1016/j.trci.2019.01.003 |
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