Specific type IV phosphodiesterase inhibitor rolipram mitigates experimental colitis in mice.
The specific type IV phosphodiesterase inhibitor rolipram is a potent suppressor of tumor necrosis factor-alpha (TNF) synthesis. We examined the efficacy of rolipram for the prevention and treatment of experimental colitis. To induce colitis, BALB/c mice received 5% dextran sulfate sodium in their drinking water continuously for up to 11 days. Colitis was quantified by a clinical activity score assessing weight loss, stool consistency, and rectal bleeding (range from 0 to 4); by colon length; by a semiquantitative histologic score (range from 0 to 6); and by detecting TNF concentration in colonic tissue by enzyme-linked immunosorbent assay. In a first protocol, rolipram (10 mg/kg b.wt./day i.p.) was started on the same day as dextran sulfate sodium. Rolipram reduced the clinical activity of colitis (score 1.1 +/- 0.3) compared with mice that did not receive rolipram (2.4 +/- 0.4; P =.041). Rolipram also partially reversed the reduction of colon length (without rolipram, 12.4 +/- 0. 3 cm; with rolipram, 15.4 +/- 0.7 cm; P =.004) and improved the histologic score (1.5 +/- 0.6 in rolipram-treated mice versus 4.6 +/- 0.5; P =.020). Rolipram suppressed colonic tissue TNF concentrations. The beneficial effect of rolipram was confirmed in a second protocol in which dextran sulfate sodium exposure was discontinued on day 7 and rolipram was administered from day 8 through day 15. These three series of experiments on a total of 153 mice documented the efficacy of rolipram in both the prevention and treatment of experimental colitis.
Hartmann
G
G
Division of Clinical Pharmacology, Medizinische Klinik, Klinikum Innenstadt, University of Munich, Germany.
Bidlingmaier
C
C
Siegmund
B
B
Albrich
S
S
Schulze
J
J
Tschoep
K
K
Eigler
A
A
Lehr
H A
HA
Endres
S
S
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D016264:Dextran Sulfate; D005243:Feces / Q000737:chemistry; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D020889:Rolipram / Q000494:pharmacology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D010726:Phosphodiesterase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D016264:Dextran Sulfate; D020889:Rolipram