title: Fluoxetine and amitriptyline inhibit nitric oxide, prostaglandin E2, and hyaluronic acid production in human synovial cells and synovial tissue cultures.
abstract: OBJECTIVE
  To evaluate the effects of fluoxetine and amitriptyline on nitric oxide (NO), prostaglandin E2 (PGE2), and hyaluronic acid (HA) production in human synovial cells and synovial tissue cultures.
  
  
  METHODS
  Human synovial cells, synovial tissue, and cartilage were cultured in the presence or absence of cytokines, lipopolysaccharides (LPS), fluoxetine, or amitriptyline. Production of NO, PGE2, and HA was determined in culture media. Sulfated glycosaminoglycan (S-GAG) synthesis was evaluated in cartilage by 35S incorporation.
  
  
  RESULTS
  Fluoxetine (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) inhibited NO release by 56%, 62%, and 71%, respectively, in the media of synovial cells stimulated by interleukin-1alpha (IL-1alpha; 1 ng/ml) plus tumor necrosis factor alpha (TNFalpha; 30 ng/ml). Amitriptyline (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) caused a 16%, 27.3%, and 51.4% inhibition of NO release. Fluoxetine and amitriptyline (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) significantly (P<0.05) inhibited PGE2 release in the media of human synovial cells in the presence of IL-1alpha plus TNFalpha, in a dose-dependent manner (up to 88% inhibition). Fluoxetine (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) and amitriptyline (1 microg/ml and 3 microg/ml) significantly (P<0.05) inhibited PGE2 release in the media of human synovial tissue in the presence of LPS. Fluoxetine and amitriptyline (0.3 microg/ml, 1 microg/ml, and 3 microg/ml) also significantly (P<0.05) inhibited HA production by human synovial cells in the presence of IL-1beta plus TNFalpha. Fluoxetine and amitriptyline (1 microg/ml) partially reversed IL-1beta-induced inhibition of 35S-GAG synthesis by human cartilage cultures (P<0.05). Neither fluoxetine nor amitriptyline had a toxic effect on cells in the concentrations used.
  
  
  CONCLUSIONS
  Inhibition of NO and PGE2 production by connective tissue cells is a mechanism by which some antidepressant medications may affect pain, articular inflammation, and joint damage.
authors.affiliation: Ichilov Hospital, Tel Aviv University, Israel.
authors.forename: I
authors.initials: I
authors.lastname: Yaron
authors.forename: I
authors.initials: I
authors.lastname: Shirazi
authors.forename: R
authors.initials: R
authors.lastname: Judovich
authors.forename: D
authors.initials: D
authors.lastname: Levartovsky
authors.forename: D
authors.initials: D
authors.lastname: Caspi
authors.forename: M
authors.initials: M
authors.lastname: Yaron
mesh_terms: D000368:Aged; D000639:Amitriptyline / Q000494:pharmacology*; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000494:pharmacology; D046508:Culture Techniques; D015232:Dinoprostone / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D005260:Female; D005473:Fluoxetine / Q000494:pharmacology*; D006025:Glycosaminoglycans / Q000096:biosynthesis; D006801:Humans; D006820:Hyaluronic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013462:Sulfur Radioisotopes; D013583:Synovial Membrane / Q000166:cytology* / Q000378:metabolism*
chemical_list: D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D006025:Glycosaminoglycans; D013462:Sulfur Radioisotopes; D005473:Fluoxetine; D000639:Amitriptyline; D009569:Nitric Oxide; D006820:Hyaluronic Acid; D015232:Dinoprostone