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

Bibliographic

Year of Publication:

2019

Contact PI Name:

Marilyn J. Duncan

Contact PI Affiliation:

Department of Neuroscience, University of Kentucky College of Medicine, Lexington, Kentucky, USA

Co-Authors:

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

Primary Reference (PubMED ID):

30859123

Funding Source:

National Institute on Aging (NIA)

University of Kentucky

Merck Research Laboratories

Study Goal and Principal Findings:

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.

Therapeutic Agent

Therapeutic Information:

Therapy Type:

Small Molecule

Therapeutic Agent:

DORA-22

PubMed

PubChem

Patents

Therapeutic Target:

Orexin Receptor

Open Targets

Pharos

Animal Model

Model Information:

Species:

Mouse

Model Type:

APPxPS1

Model Name:

5xFAD

ALZFORUM

Strain/Genetic Background:

C57BL/6 x SJL

Experimental Design

Is the following information reported in the study?:

Power/Sample Size Calculation

Randomized into Groups

Blinded for Treatment

Blinded for Outcome Measures

Pharmacokinetic Measures

Pharmacodynamic Measures

Toxicology Measures

ADME Measures

Biomarkers

Dose

Formulation

Route of Delivery

Duration of Treatment

Frequency of Administration

Age of Animal at the Beginning of Treatment

Age of Animal at the End of Treatment

Sex as a Biological Variable

Study Balanced for Sex as a Biological Variable

Number of Premature Deaths

Number of Excluded Animals

Statistical Plan

Genetic Background

Inclusion/Exclusion Criteria Included

Conflict of Interest

Outcomes

Outcome Measured

Outcome Parameters

Behavioral

Y Maze

Histopathology

beta Amyloid Deposits

beta Amyloid Load

Biochemical

Complement C1qa mRNA

Complement C1qb mRNA

Complement C1qc mRNA

Complement C3 mRNA

CD68 mRNA

C-Type Lectin Domain Containing 7A (CLEC7A) mRNA

Cystatin-F (CST7) mRNA

Integrin Subunit alpha X (ITGAX) mRNA

Interleukin 1 beta (IL-1 beta) mRNA

Interleukin 6 (IL-6) mRNA

Insulin-Like Growth Factor 1 (IGF1) mRNA

Tumor Growth Factor beta (TGF beta) mRNA

Glial Fibrillary Acidic Protein (GFAP) mRNA

Lipocalin 2 (LCN2) mRNA

Pentraxin-Related Protein (PTX3) mRNA

S100 Calcium-Binding Protein B (S100B) mRNA

Chemokine C-C Motif Ligand 3/Macrophage Inflammatory Protein 1 (CCL3/MIP1) mRNA

Chemokine C-C Motif Ligand 4 (CCL4) mRNA

Chemokine C-C Motif Ligand 6 (CCL6) mRNA

Chemokine C-X-C Motif Ligand 10/Interferon gamma-Induced Protein 10 (CXCL10/IP-10) mRNA

Electrophysiology

Electroencephalogram (EEG)

Toxicology

Body Weight

Outcomes Notes:

A sleep recording system using piezoelectric films that detect pressure changes induced by movements, including small respiratory movements, was used as described for 5XFAD mice.