title: The specific type-4 phosphodiesterase inhibitor mesopram alleviates experimental colitis in mice.
abstract: Mesopram, a specific inhibitor of type-4 phosphodiesterase, decreases the synthesis of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). In the present study, we investigated the effect of mesopram in dextran sulfate sodium (DSS)-induced murine colitis. In the preventive model, colitis was induced by DSS simultaneously with the application of mesopram in BALB/c mice. In the therapeutic model, colitis was induced in BALB/c mice by DSS over 7 days. At day 8, DSS was discontinued, and treatment was started. Mesopram was applied intraperitoneally or orally. The clinical score was calculated daily during the course of each study. Post mortem, colon length, histologic score, and expression of TNF-alpha and IFN-gamma in colons were determined. In the preventive model, mesopram significantly reduced the maximal clinical score, decreased colon shortening, and the histologic score. A dose finding study, using the preventive model, showed that most clinical and post mortem benefit was achieved with 50 mg/kg mesopram compared with 2 and 10 mg/kg. In the therapeutic model, i.p. mesopram treatment led to a significant reduction of clinical score. Both, i.p. and p.o. mesopram significantly reversed DSS-induced colon shortening and reduced the ex vivo colonic production of IFN-gamma. We conclude that the specific type-4 phosphodiesterase inhibitor mesopram ameliorates murine colitis both in a preventive and a therapeutic setting.
authors.affiliation: Division of Clinical Pharmacology and Section of Gastroenterology, Medizinische Klinik Innenstadt, University of Munich, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Loher
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schmall
authors.forename: Philipp
authors.initials: P
authors.lastname: Freytag
authors.forename: Nikola
authors.initials: N
authors.lastname: Landauer
authors.forename: Roland
authors.initials: R
authors.lastname: Hallwachs
authors.forename: Christian
authors.initials: C
authors.lastname: Bauer
authors.forename: Britta
authors.initials: B
authors.lastname: Siegmund
authors.forename: Florian
authors.initials: F
authors.lastname: Rieder
authors.forename: Hans-Anton
authors.initials: HA
authors.lastname: Lehr
authors.forename: Marc
authors.initials: M
authors.lastname: Dauer
authors.forename: Joachim Friedrich
authors.initials: JF
authors.lastname: Kapp
authors.forename: Stefan
authors.initials: S
authors.lastname: Endres
authors.forename: Andreas
authors.initials: A
authors.lastname: Eigler
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000636:Aminosalicylic Acids / Q000627:therapeutic use; D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D003106:Colon / Q000473:pathology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D016207:Cytokines / Q000096:biosynthesis; D016264:Dextran Sulfate; D004305:Dose-Response Relationship, Drug; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D010080:Oxazoles / Q000627:therapeutic use*; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000636:Aminosalicylic Acids; D016207:Cytokines; D010080:Oxazoles; D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; C412083:mesopram; D007371:Interferon-gamma; D016264:Dextran Sulfate; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C032587:olsalazine