title: Inhibition of Acid Sphingomyelinase by Antidepressants Counteracts Stress-Induced Activation of P38-Kinase in Major Depression.
abstract: OBJECTIVE
  Major depressive disorder is a common disease with serious morbidity, including increased risk of death from suicide. Major depressive disorder is treated with antidepressants. However, the molecular targets of antidepressants remained ill-defined and require further elucidation.
  
  
  METHODS
  Mice were treated with corticosterone to induce stress, amitriptyline and the p38-kinase (p38K) inhibitor SB239063 or a combination of these drugs. Phosphorylation of p38K in hippocampal neurons was determined by immunostaining with a phospho-specific antibody, neuronal proliferation using BrdU-labelling and behaviour employing a set of behavioural tests.
  
  
  RESULTS
  Corticosterone induced phosphorylation/activation of p38K in the hippocampus in vivo. Antidepressants reversed the effect of corticosterone on p38K activation in wildtype mice, but had no effect in acid sphingomyelinase-deficient animals. Corticosterone also reduced neurogenesis and triggered depression-like behavioural changes, effects that were prevented by pharmacological inhibition of p38K.
  
  
  CONCLUSIONS
  Stress induces p38K phosphorylation/activation in the hippocampus and thereby reduces neurogenesis and induces depression-like symptoms, events that are prevented by antidepressants via inhibition of the acid sphingomyelinase/ceramide system.
authors.affiliation: Department of Molecular Biology, University of Duisburg-Essen, Essen, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Grassmé
authors.forename: Peter L
authors.initials: PL
authors.lastname: Jernigan
authors.forename: Richard S
authors.initials: RS
authors.lastname: Hoehn
authors.forename: Barbara
authors.initials: B
authors.lastname: Wilker
authors.forename: Matthias
authors.initials: M
authors.lastname: Soddemann
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Edwards
authors.forename: Christian P
authors.initials: CP
authors.lastname: Müller
authors.forename: Johannes
authors.initials: J
authors.lastname: Kornhuber
authors.forename: Erich
authors.initials: E
authors.lastname: Gulbins
mesh_terms: D000221:Adaptation, Ocular / Q000187:drug effects / Q000235:genetics; D000639:Amitriptyline / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D003345:Corticosterone / Q000633:toxicity; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005106:Exploratory Behavior / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics / Q000378:metabolism*; D013109:Sphingomyelins / Q000493:pharmacokinetics; D013315:Stress, Psychological / Q000139:chemically induced / Q000188:drug therapy* / Q000201:enzymology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000928:Antidepressive Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011743:Pyrimidines; D013109:Sphingomyelins; D000639:Amitriptyline; D048051:p38 Mitogen-Activated Protein Kinases; C577975:ASMase, mouse; D013108:Sphingomyelin Phosphodiesterase; C406525:SB 239063; D003345:Corticosterone