The effect of mesalazin and prednisolone on indometacin provoked inflammation and changes of permeability in the intestinal tract

Aim of experiments: The aethiology of Crohn Disease (CD) despite intensive investigations remained unknown, therefore its therapy is unsolved. Chronic administration of non-steroidal anti-inflammatory drugs in humans or single administration of these drugs in experimental animals provoke ulcerative-inflammatory processes which are similar to CD. The change of the intestinal permeability may play a role in the aethiology of CD.

Methods: In our experiments rats (Male Wistar rats weghing 250–300g) were treated by indometacin in a daily dose of 7.5, 10 and 16mg/kg subcutaneously (s.c.) for three days. One day after the last dose of indometacin the changes in the intestinal tract were analysed under urethane (1.2g/kg intraperitoneally) anaesthetized rats. Indometacin induced small intestinal and colonic ulcerations in a dose-dependent fashion. On the base of the number, dimension and the severity of changes (ulcertion, bleeding, hyperemia) found in intestinal tract, the effect of indometacin have been classified in five (0–5) stadiums. For a more precise analysis tissue specimens were taken out from different segments of the intestinal tract to prepare histological sections for histological investigation and evaluation.

To study the possible inhibition of the inestinal inflammatory action of indometacin, mesalazin (5-amino salicylic acid) and steroids (prednisolone, methylprednisolone) were administered in the following doses: prednisolone: 0.5mg/kg orally, methylprednisolone:3.5mg/kg intraperitoneally once or twice per day for three days;mesalazin:1g/kg orally once or twice per day for three days. To investigate the permeability of the intestinal tract, polyethyleneglycol-400(PEG-400) was administered (3.5g/kg orally) and measured in the urine by gaschromatograph.

Results and conclusions: Indometacin pretreatment provoked diarrhoea in all cases. Very severe changes in the middle segment of small intestine were mostly observed. Mucosal ulceration (100%), mucosal adhesion (40%), mesenterial bleeding (70%), intestinal dilatation (100%) and thicker intestinal wall have been detected macroscopically. Indometacin given at a dose of 10mg/kg once a day s.c. for three days produced the most characteristic changes without severe toxic signs, therefore the results of this type of indometacin treatment can be considered in our experiments as a good inestinal inflammatory model, which basically corresponds to CD. Orally given prednisolone was ineffective. Mesalazin and methylprednisolone produced a protective effect: the severity of inflammation became less significant (from stadium 3–4 to 0–2;histological analysis supports these observations, as well), the changes of intestinal permeability also became less significant.