The specific type-4 phosphodiesterase inhibitor mesopram alleviates experimental colitis in mice.
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.
Loher
Florian
F
Division of Clinical Pharmacology and Section of Gastroenterology, Medizinische Klinik Innenstadt, University of Munich, Germany.
Schmall
Kathrin
K
Freytag
Philipp
P
Landauer
Nikola
N
Hallwachs
Roland
R
Bauer
Christian
C
Siegmund
Britta
B
Rieder
Florian
F
Lehr
Hans-Anton
HA
Dauer
Marc
M
Kapp
Joachim Friedrich
JF
Endres
Stefan
S
Eigler
Andreas
A
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
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