Linking Hypothermia and Altered Metabolism with TrkB Activation.

Autor:	Alitalo O; Laboratory of Neurotherapeutics, Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland.; SleepWell Research Program, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland., González-Hernández G; Laboratory of Neurotherapeutics, Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland.; SleepWell Research Program, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland., Rosenholm M; Laboratory of Neurotherapeutics, Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland.; SleepWell Research Program, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland.; Center for Translational Neuromedicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen DK-2200, Denmark., Kohtala P; Laboratory of Neurotherapeutics, Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland.; SleepWell Research Program, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland.; Department of Psychiatry, Weill Cornell Medicine, New York, New York 10021, United States., Matsui N; Faculty of Pharmacy, Gifu University of Medical Science, 4-3-3 Nijigaoka, Kani, Gifu 509-0293, Japan., Müller HK; Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus N 8200, Denmark., Theilmann W; Laboratory of Neurotherapeutics, Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland., Klein A; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen DK-2200, Denmark.; Department of Drug Design & Pharmacology, University of Copenhagen, Copenhagen DK-2100, Denmark., Kärkkäinen O; School of Pharmacy, University of Eastern Finland, Kuopio 70210, Finland.; Afekta Technologies Ltd., Kuopio 70210, Finland., Rozov S; Laboratory of Neurotherapeutics, Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland.; SleepWell Research Program, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland., Rantamäki T; Laboratory of Neurotherapeutics, Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland.; SleepWell Research Program, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland., Kohtala S; Laboratory of Neurotherapeutics, Drug Research Program, Division of Pharmacology and Pharmacotherapy, Faculty of Pharmacy, University of Helsinki, Helsinki 00014, Finland.; SleepWell Research Program, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland.; Department of Psychiatry, Weill Cornell Medicine, New York, New York 10021, United States.
Jazyk:	angličtina
Zdroj:	ACS chemical neuroscience [ACS Chem Neurosci] 2023 Sep 06; Vol. 14 (17), pp. 3212-3225. Date of Electronic Publication: 2023 Aug 08.
DOI:	10.1021/acschemneuro.3c00350
Abstrakt:	Many mechanisms have been proposed to explain acute antidepressant drug-induced activation of TrkB neurotrophin receptors, but several questions remain. In a series of pharmacological experiments, we observed that TrkB activation induced by antidepressants and several other drugs correlated with sedation, and most importantly, coinciding hypothermia. Untargeted metabolomics of pharmacologically dissimilar TrkB activating treatments revealed effects on shared bioenergetic targets involved in adenosine triphosphate (ATP) breakdown and synthesis, demonstrating a common perturbation in metabolic activity. Both activation of TrkB signaling and hypothermia were recapitulated by administration of inhibitors of glucose and lipid metabolism, supporting a close relationship between metabolic inhibition and neurotrophic signaling. Drug-induced TrkB phosphorylation was independent of electroencephalography slow-wave activity and remained unaltered in knock-in mice with the brain-derived neurotrophic factor (BDNF) Val66Met allele, which have impaired activity-dependent BDNF release, alluding to an activation mechanism independent from BDNF and neuronal activity. Instead, we demonstrated that the active maintenance of body temperature prevents activation of TrkB and other targets associated with antidepressants, including p70S6 kinase downstream of the mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3β (GSK3β). Increased TrkB, GSK3β, and p70S6K phosphorylation was also observed during recovery sleep following sleep deprivation, when a physiological temperature drop is known to occur. Our results suggest that the changes in bioenergetics and thermoregulation are causally connected to TrkB activation and may act as physiological regulators of signaling processes involved in neuronal plasticity.
Databáze:	MEDLINE
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