1. Dose-dependent effects of isoflurane on TrkB and GSK3β signaling: Importance of burst suppression pattern
- Author
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Tomi Rantamäki, Iris Yorke, Wiebke Theilmann, Okko Alitalo, Molecular and Integrative Biosciences Research Programme, Division of Pharmacology and Pharmacotherapy, Laboratory of Neurotherapeutics, and Drug Research Program
- Subjects
Male ,0301 basic medicine ,Antidepressant ,Tropomyosin receptor kinase B ,ACTIVATION ,EEG burst suppression ,0302 clinical medicine ,GSK-3 ,BRAIN ,PHOSPHORYLATION ,Prefrontal cortex ,Electrocerebral silence ,Membrane Glycoproteins ,Isoflurane ,biology ,Chemistry ,General Neuroscience ,Electroencephalography ,Protein-Tyrosine Kinases ,GLYCOGEN-SYNTHASE KINASE-3 ,DEPRESSION ,Antidepressive Agents ,Burst suppression ,317 Pharmacy ,Anesthetics, Inhalation ,MOUSE HIPPOCAMPUS ,Signal transduction ,Signal Transduction ,medicine.drug ,Neurotrophin ,medicine.medical_specialty ,Prefrontal Cortex ,NARCOTHERAPY ,CREB ,03 medical and health sciences ,Protein phosphorylation ,Internal medicine ,medicine ,Animals ,ANESTHESIA ,Glycogen Synthase Kinase 3 beta ,Dose-Response Relationship, Drug ,3112 Neurosciences ,Mice, Inbred C57BL ,NEUROTROPHIN RECEPTOR ,030104 developmental biology ,Endocrinology ,biology.protein ,3111 Biomedicine ,030217 neurology & neurosurgery ,ELECTROCONVULSIVE SHOCK - Abstract
Objectives: Deep burst-suppressing isoflurane anesthesia regulates signaling pathways connected with antidepressant responses in the rodent brain: activation of TrkB neurotrophin receptor and inhibition of GSK3 beta kinase (glycogen synthase kinase 3 beta). The main objective of this study was to investigate whether EEG (electroencephalogram) burst suppression correlates with these intriguing molecular alterations induced by isoflurane. Methods: Adult male mice pre-implanted with EEG recording electrodes were subjected to varying concentrations of isoflurane (1.0-2.0% ad 20 min) after which medial prefrontal cortex samples were collected for molecular analyses, and the data retrospectively correlated to EEG ( + /- burst suppression). Results: Isoflurane dose-dependently increased phosphorylation of TrkB(Y816), CREBS133 (cAMP response element binding protein), GSK3 beta(S9) and p70S6k(T412/S424). The time spent in burst suppression mode varied considerably between individual animals. Notably, a subset of animals subjected to 1.0-1.5% isoflurane showed no burst suppression. While p-GSK3 beta(S9), p-CREBS133 and p-p70S6k(T412/S424) levels were increased in the samples obtained also from these animals, p-TrkB(Y816) levels remained unaltered. Conclusions: Isoflurane dose-dependently regulates TrkB and GSK3 beta signaling and dosing associated with therapeutic outcomes in depressed patients produces most prominent effects.
- Published
- 2019