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-␣ (TNF-␣) and interferon-␥ (IFN-␥). 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-␣ and IFN-␥ 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 DSSinduced colon shortening and reduced the ex vivo colonic production of IFN-␥. We conclude that the specific type-4 phosphodiesterase inhibitor mesopram ameliorates murine colitis both in a preventive and a therapeutic setting.

Preinoculation With the Probiotic Lactobacillus acidophilus Early in Life Effectively Inhibits Murine Citrobacter rodentium Colitis

“…1E). Furthermore, the inflammation and intestinal damage scores (20,21) were significantly lower in preinoculated mice than those with C. rodentium infection alone (Fig. 1G) versus controls.…”

“…Sections were analyzed without prior knowledge of treatment. Colonic pathology was scored according to a modified histologic scoring system previously published (20,21). The scoring system consists of two parts: Part 1 was the determination of inflammatory cell infiltration in the colon, scored from 0 to 4 (0: normal cells pattern; 1: scattered inflammatory cells in the lamina propria; 2: increased numbers of inflammatory cells in the lamina propria; 3: confluence of inflammatory cells extending into the submucosa; and 4: transmural extension of the infiltrative inflammatory cells).…”

Selective Inhibition of Phosphodiesterase-4 Ameliorates Chronic Colitis and Prevents Intestinal Fibrosis

“…Our findings are in accordance with a previous study in an experimental model of colitis induced by dextran sulfate sodium, where administration of this selective PDE4 inhibitor significantly reduced TNF-␣ synthesis (Hartmann et al, 2000) and MPO activity (DiazGranados et al, 2000) in the colon of colitic mice. In addition, mesopram, another PDE4 inhibitor, has been successfully tested for established dextran sulfate sodium-induced colitis and also prevented colitis induction in a dose-dependent manner (Loher et al, 2003). Furthermore, several studies have revealed a beneficial effect of rolipram in other inflammatory disorders.…”

Concurrent Infection with an Intestinal Helminth Parasite Impairs Host Resistance to EntericCitrobacter rodentiumand EnhancesCitrobacter-Induced Colitis in Mice

“…The sections were analyzed without prior knowledge of the type of treatment. Colonic pathology was scored by using a modified histology scoring system based on previously published methods (7,22). The scoring system consists of two parts.…”