Orexin 2 receptor antagonism sex-dependently improves sleep/wakefulness and cognitive performance in tau transgenic mice.

Autor: Keenan RJ; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.; Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia., Daykin H; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.; Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia., Metha J; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.; Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia.; Department of Finance, Faculty of Business and Economics, The University of Melbourne, Parkville, Victoria, Australia., Cornthwaite-Duncan L; Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia., Wright DK; Department of Neuroscience, Central Clinical School, Monash University, Melbourne, Victoria, Australia., Clarke K; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia., Oberrauch S; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.; Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia., Brian M; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.; Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia., Stephenson S; Bruce Lefroy Centre, Murdoch Children's Research Institute, Parkville, Victoria, Australia.; Department of Paediatrics, The University of Melbourne, Parkville, Victoria, Australia., Nowell CJ; Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, Victoria, Australia., Allocca G; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.; Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia.; Somnivore Inc. Ltd Pty, Bacchus Marsh, Victoria, Australia., Barnham KJ; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia., Hoyer D; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.; Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia.; Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA., Jacobson LH; Florey Institute of Neuroscience and Mental Health, Parkville, Victoria, Australia.; Department of Biochemistry and Pharmacology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, Victoria, Australia.; Melbourne Dementia Research Centre, Florey Institute of Neuroscience and Mental Health and The University of Melbourne, Parkville, Victoria, Australia.
Jazyk: angličtina
Zdroj: British journal of pharmacology [Br J Pharmacol] 2024 Jan; Vol. 181 (1), pp. 87-106. Date of Electronic Publication: 2023 Sep 08.
DOI: 10.1111/bph.16212
Abstrakt: Background and Purpose: Tau pathology contributes to a bidirectional relationship between sleep disruption and neurodegenerative disease. Tau transgenic rTg4510 mice model tauopathy symptoms, including sleep/wake disturbances, which manifest as marked hyperarousal. This phenotype can be prevented by early transgene suppression; however, whether hyperarousal can be rescued after onset is unknown.
Experimental Approach: Three 8-week experiments were conducted with wild-type and rTg4510 mice after age of onset of hyperarousal (4.5 months): (1) Tau transgene suppression with doxycycline (200 ppm); (2) inactive phase rapid eye movement (REM) sleep enhancement with the dual orexin receptor antagonist suvorexant (50 mg·kg -1 ·day -1 ); or (3) Active phase non-NREM (NREM) and REM sleep enhancement using the selective orexin 2 (OX 2 ) receptor antagonist MK-1064 (40 mg·kg -1 ·day -1 ). Sleep was assessed using polysomnography, cognition using the Barnes maze, and tau pathology using immunoblotting and/or immunohistochemistry.
Key Results: Tau transgene suppression improved tauopathy and hippocampal-dependent spatial memory, but did not modify hyperarousal. Pharmacological rescue of REM sleep deficits did not improve spatial memory or tau pathology. In contrast, normalising hyperarousal by increasing both NREM and REM sleep via OX 2 receptor antagonism restored spatial memory, independently of tauopathy, but only in male rTg4510 mice. OX 2 receptor antagonism induced only short-lived hypnotic responses in female rTg4510 mice and did not improve spatial memory, indicating a tau- and sex-dependent disruption of OX 2 receptor signalling.
Conclusions and Implications: Pharmacologically reducing hyperarousal corrects tau-induced sleep/wake and cognitive deficits. Tauopathy causes sex-dependent disruptions of OX 2 receptor signalling/function, which may have implications for choice of hypnotic therapeutics in tauopathies.
(© 2023 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)
Databáze: MEDLINE
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