title: Regulation of Neuronal Stem Cell Proliferation in the Hippocampus by Endothelial Ceramide.
abstract: OBJECTIVE
  Major depressive disorder is one of the most common diseases in western countries. The disease is mainly defined by its psychiatric symptoms. However, the disease has also many symptoms outside the central nervous system, in particular cardiovascular symptoms. Recent studies demonstrated that the acid sphingomyelinase/ceramide system plays an important role in the development of major depressive disorder and functions as a target of antidepressants.
  
  
  METHODS
  Here, we investigated (i) whether ceramide accumulates in endothelial cells in the neurogenetic zone of the hippocampus after glucocorticosterone-mediated stress, (ii) whether ceramide is released into the extracellular space of the hippocampus and (iii) whether extracellular ceramide inhibits neuronal proliferation. Ceramide was determined in endothelial cell culture supernatants or extracellular hippocampus extracts by a kinase assay. Endothelial ceramide in the hippocampus was analyzed by confocal microscopy of brain sections stained with Cy3-labelled anti-ceramide antibodies and FITC-Isolectin B4. Neuronal proliferation was measured by incubation of pheochromocytoma neuronal cells with culture supernatants and extracellular hippocampus extracts.
  
  
  RESULTS
  Treatment of cultured endothelial cells with glucocorticosterone induces a release of ceramide into the supernatant. Likewise, treatment of mice with glucocorticosterone triggers a release of ceramide into the extracellular space of the hippocampus. The release of ceramide is inhibited by concomitant treatment with the antidepressant amitriptyline, which also inhibits the activity of the acid sphingomyelinase. Studies employing confocal microscopy revealed that ceramide is formed and accumulates exclusively in endothelial cells in the hippocampus of stressed mice, a process that was again prevented by co-application of amitriptyline. Ceramide released in the culture supernatant or into the extracellular space of the hippocampus reduced proliferation of neurons in vitro.
  
  
  CONCLUSIONS
  The data suggest a novel model for the pathogenesis of major depressive disorder, i.e. the release of ceramide-enriched microvesicles from endothelial cells that negatively affect neuronal proliferation in the hippocampus, but may also induce cardiovascular disease and other systemic symptoms of patients with major depressive disorder.
authors.affiliation: Gymnasium Essen-Werden, Essen, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Gulbins
authors.forename: Heike
authors.initials: H
authors.lastname: Grassmé
authors.forename: Richard
authors.initials: R
authors.lastname: Hoehn
authors.forename: Barbara
authors.initials: B
authors.lastname: Wilker
authors.forename: Matthias
authors.initials: M
authors.lastname: Soddemann
authors.forename: Marcus
authors.initials: M
authors.lastname: Kohnen
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Edwards
authors.forename: Johannes
authors.initials: J
authors.lastname: Kornhuber
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
mesh_terms: D015062:11-Hydroxycorticosteroids / Q000494:pharmacology; D000639:Amitriptyline / Q000494:pharmacology; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D002518:Ceramides / Q000378:metabolism*; D003865:Major Depressive Disorder / Q000378:metabolism / Q000517:prevention & control; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism*; D016716:PC12 Cells; D051381:Rats; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D015062:11-Hydroxycorticosteroids; D000929:Antidepressive Agents, Tricyclic; D002518:Ceramides; D000639:Amitriptyline; D013108:Sphingomyelin Phosphodiesterase