title: Alterations of the Ceramide Metabolism in the Peri-Infarct Cortex Are Independent of the Sphingomyelinase Pathway and Not Influenced by the Acid Sphingomyelinase Inhibitor Fluoxetine.
abstract: Ceramides induce important intracellular signaling pathways, modulating proliferation, migration, apoptosis, and inflammation. However, the relevance of the ceramide metabolism in the reconvalescence phase after stroke is unclear. Besides its well-known property as a selective serotonin reuptake inhibitor, fluoxetine has been reported to inhibit the acid sphingomyelinase (ASM), a key regulator of ceramide levels which derives ceramide from sphingomyelin. Furthermore, fluoxetine has shown therapeutic potential in a randomized controlled rehabilitation trial in stroke patients. Our aim was to investigate and modulate ceramide concentrations in the peri-infarct cortex, whose morphological and functional properties correlate with long-term functional outcome in stroke. We show that certain ceramide species are modulated after experimental stroke and that these changes do not result from alterations of ASM activity, but rather from nontranscriptional induction of the ceramide de novo pathway. Unexpectedly, although reducing lesion size, fluoxetine did not improve functional outcome in our model and had no significant influence on ASM activity or the concentration of ceramides. The ceramide metabolism could emerge as a potential therapeutic target in the reconvalescence phase after stroke, as its accumulation in the peri-infarct cortex potentially influences membrane functions as well as signaling events in the tissue essential for neurological recovery.
authors.affiliation: Department of Neurology, Goethe University, 60590 Frankfurt am Main, Germany ; Institute of General Pharmacology and Toxicology, Goethe University, 60590 Frankfurt am Main, Germany.
authors.forename: R
authors.initials: R
authors.lastname: Brunkhorst
authors.affiliation: Department of Neurology, Goethe University, 60590 Frankfurt am Main, Germany ; Institute of General Pharmacology and Toxicology, Goethe University, 60590 Frankfurt am Main, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Friedlaender
authors.affiliation: Institute of Clinical Pharmacology, Goethe University, 60590 Frankfurt am Main, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Ferreirós
authors.affiliation: Institute of General Pharmacology and Toxicology, Goethe University, 60590 Frankfurt am Main, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Schwalm
authors.affiliation: Institute of General Pharmacology and Toxicology, Goethe University, 60590 Frankfurt am Main, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Koch
authors.affiliation: Institute of General Pharmacology and Toxicology, Goethe University, 60590 Frankfurt am Main, Germany ; Department of Internal Medicine I, Goethe University, 60590 Frankfurt am Main, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Grammatikos
authors.affiliation: Institute of Forensic Medicine, Goethe University, 60590 Frankfurt am Main, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Toennes
authors.affiliation: Department of Neurology, Goethe University, 60590 Frankfurt am Main, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Foerch
authors.affiliation: Institute of General Pharmacology and Toxicology, Goethe University, 60590 Frankfurt am Main, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Pfeilschifter
authors.affiliation: Department of Neurology, Goethe University, 60590 Frankfurt am Main, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Pfeilschifter
mesh_terms: D000818:Animals; D002518:Ceramides / Q000378:metabolism*; D002540:Cerebral Cortex / Q000378:metabolism*; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005473:Fluoxetine / Q000627:therapeutic use*; D020767:Intracranial Thrombosis / Q000150:complications; D053858:Metabolic Networks and Pathways; D051379:Mice; D008810:Mice, Inbred C57BL; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use*; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D020521:Stroke / Q000188:drug therapy / Q000209:etiology; D016896:Treatment Outcome
chemical_list: D002518:Ceramides; D004791:Enzyme Inhibitors; D005473:Fluoxetine; D017367:Selective Serotonin Reuptake Inhibitors; D013108:Sphingomyelin Phosphodiesterase