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Acid sphingomyelinase-ceramide system mediates effects of antidepressant drugs

  • Major depression is a highly prevalent severe mood disorder that is treated with antidepressants. The molecular targets of antidepressants require definition. We investigated the role of the acid sphingomyelinase (Asm)-ceramide system as a target for antidepressants. Therapeutic concentrations of the antidepressants amitriptyline and fluoxetine reduced Asm activity and ceramide concentrations in the hippocampus, increased neuronal proliferation, maturation and survival and improved behavior in mouse models of stress-induced depression. Genetic Asm deficiency abrogated these effects. Mice overexpressing Asm, heterozygous for acid ceramidase, treated with blockers of ceramide metabolism or directly injected with C16 ceramide in the hippocampus had higher ceramide concentrations and lower rates of neuronal proliferation, maturation and survival compared with controls and showed depression-like behavior even in the absence of stress. The decrease of ceramide abundance achieved by antidepressant-mediated inhibition of Asm normalized theseMajor depression is a highly prevalent severe mood disorder that is treated with antidepressants. The molecular targets of antidepressants require definition. We investigated the role of the acid sphingomyelinase (Asm)-ceramide system as a target for antidepressants. Therapeutic concentrations of the antidepressants amitriptyline and fluoxetine reduced Asm activity and ceramide concentrations in the hippocampus, increased neuronal proliferation, maturation and survival and improved behavior in mouse models of stress-induced depression. Genetic Asm deficiency abrogated these effects. Mice overexpressing Asm, heterozygous for acid ceramidase, treated with blockers of ceramide metabolism or directly injected with C16 ceramide in the hippocampus had higher ceramide concentrations and lower rates of neuronal proliferation, maturation and survival compared with controls and showed depression-like behavior even in the absence of stress. The decrease of ceramide abundance achieved by antidepressant-mediated inhibition of Asm normalized these effects. Lowering ceramide abundance may thus be a central goal for the future development of antidepressants.show moreshow less

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Metadaten
Author:Erich Gulbins, Monica Palmada, Martin Reichel, Anja Lueth, Christoph Boehmer, Davide Amato, Christian P. Mueller, Carsten H. Tischbirek, Teja W. Groemer, Ghazaleh Tabatabai, Katrin A. Becker, Philipp Tripal, Sven Staedtler, Teresa F. Ackermann, Johannes van Brederode, Christian Alzheimer, Michael Weller, Undine E. Lang, Burkhard KleuserORCiDGND, Heike Grassme, Johannes Kornhuber
DOI:https://doi.org/10.1038/nm.3214
ISSN:1078-8956 (print)
Parent Title (English):Nature medicine
Publisher:Nature Publ. Group
Place of publication:New York
Document Type:Article
Language:English
Year of first Publication:2013
Year of Completion:2013
Release Date:2017/03/26
Volume:19
Issue:7
Pagenumber:8
First Page:934
Last Page:+
Funder:Deutsche Forschungsgemeinschaft [GU 335/23-1, KO 947/11-1, GRK 1302]
Organizational units:Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie
Peer Review:Referiert