title: Anti-inflammatory properties of desipramine and fluoxetine.
abstract: BACKGROUND
  Antidepressants are heavily prescribed drugs and have been shown to affect inflammatory signals. We examined whether these have anti-inflammatory properties in animal models of septic shock and allergic asthma. We also analysed whether antidepressants act directly on peripheral cell types that participate in the inflammatory response in these diseases.
  
  
  METHODS
  The antidepressants desipramine and fluoxetine were compared in vivo to the glucocorticoid prednisolone, an anti-inflammatory drug of reference. In a murine model of lipopolysaccharides (LPS)-induced septic shock, animals received the drugs either before or after injection of LPS. Circulating levels of tumour necrosis factor (TNF)-alpha and mortality rate were measured. In ovalbumin-sensitized rats, the effect of drug treatment on lung inflammation was assessed by counting leukocytes in bronchoalveolar lavages. Bronchial hyperreactivity was measured using barometric plethysmography. In vitro production of TNF-alpha and Regulated upon Activation, Normal T cell Expressed and presumably Secreted (RANTES) from activated monocytes and lung epithelial cells, respectively, was analysed by immunoassays. Reporter gene assays were used to measure the effect of antidepressants on the activity of nuclear factor-kappaB and activator protein-1 which are involved in the control of TNF-alpha and RANTES expression.
  
  
  RESULTS
  In the septic shock model, all three drugs given preventively markedly decreased circulating levels of TNF-alpha and mortality (50% mortality in fluoxetine treated group, 30% in desipramine and prednisolone treated groups versus 90% in controls). In the curative trial, antidepressants had no statistically significant effect, while prednisolone still decreased mortality (60% mortality versus 95% in controls). In ovalbumin-sensitized rats, the three drugs decreased lung inflammation, albeit to different degrees. Prednisolone and fluoxetine reduced the number of macrophages, lymphocytes, neutrophils and eosinophils, while desipramine diminished only the number of macrophages and lymphocytes. However, antidepressants as opposed to prednisolone did not attenuate bronchial hyperreactivity. In vitro, desipramine and fluoxetine dose-dependently inhibited the release of TNF-alpha from LPS-treated monocytes. In lung epithelial cells, these compounds decreased TNF-alpha-induced RANTES expression as well as the activity of nuclear factor-kappaB and activator protein-1.
  
  
  CONCLUSIONS
  Desipramine and fluoxetine reduce the inflammatory reaction in two animal models of human diseases. These antidepressants act directly on relevant peripheral cell types to decrease expression of inflammatory mediators probably by affecting their gene transcription. Clinical implications of these observations are discussed.
authors.affiliation: Inserm, U454, Montpellier, France. caroline.roumestan@macors.com
authors.forename: Caroline
authors.initials: C
authors.lastname: Roumestan
authors.forename: Alain
authors.initials: A
authors.lastname: Michel
authors.forename: Florence
authors.initials: F
authors.lastname: Bichon
authors.forename: Karine
authors.initials: K
authors.lastname: Portet
authors.forename: Maëlle
authors.initials: M
authors.lastname: Detoc
authors.forename: Corinne
authors.initials: C
authors.lastname: Henriquet
authors.forename: Dany
authors.initials: D
authors.lastname: Jaffuel
authors.forename: Marc
authors.initials: M
authors.lastname: Mathieu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001249:Asthma / Q000150:complications / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D003891:Desipramine / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005473:Fluoxetine / Q000627:therapeutic use*; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects; D011239:Prednisolone / Q000627:therapeutic use; D051381:Rats; D020545:Respiratory Mucosa / Q000187:drug effects; D012772:Shock, Septic / Q000150:complications / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D000928:Antidepressive Agents; D016207:Cytokines; D005473:Fluoxetine; D011239:Prednisolone; D003891:Desipramine