Previously we demonstrated an ameliorating effect of the interleukin-1beta converting enzyme (ICE) inhibitor pralnacasan on dextran sulfate sodium (DSS)-induced colitis. This study investigates the effects of pralnacasan on cytokine expression in DSS-induced colitis. Colitis was induced by oral administration of DSS. Mice were treated intraperitoneally with the ICE inhibitor pralnacasan (50 mg/kg body weight twice daily). Body weight as well as the presence of occult blood or diarrhea was monitored daily. Subgroups were sacrificed at days 4, 8, and 11 after the beginning of DSS application. Cytokine profiles in colonic tissue were analyzed on the protein level by ELISA and on the mRNA level by real time RT-PCR. Administration of DSS led to an increase in IL-18, IL-12, TNF-alpha, and IFN-gamma protein as well as IP-10 and TNF-alpha mRNA. The increase in IL-18 and IFN-gamma was reduced by ICE inhibition. Pralnacasan prevented DSS-induced colitis in C57BL/6 mice. In C57BL/6 mice, the DSS-induced increase in IP-10 mRNA, but not TNF-alpha mRNA, was completely prevented by ICE inhibition. In conclusion, prevention of colitis in C57BL/6 mice was associated with a suppresion of IP-10 mRNA, but not TNF-alpha mRNA expression, indicating that IL-18-mediated cytokine production is a key element in the pathogenesis of DSS-induced colitis.
In recent years, several strategies that selectively inhibit pro-inflammatory cytokines, have yielded effective protein-based therapies for inflammatory disorders, validating the therapeutic hypothesis that intervention in cytokine signalling can provide clinical benefit. However, these protein-based products must be administered by injection, a constraint associated with inconvenience, adverse effects and expense for patients, caregivers and insurers. Besides interfering with the effects of cytokines such as TNF-alpha or IL-1beta that have already been produced, inhibition of pro-inflammatory cytokine production or signalling with low-molecular weight orally-active drugs would combine the convenience of conventional pharmaceuticals with the focused efficacy of the protein therapies. Reducing IL-1beta and IL-18 production by inhibition of IL-1beta converting enzyme (ICE, caspase-1) is one promising strategy because of the key roles of these cytokines in many inflammatory diseases. Pralnacasan, the first orally available, potent and selective ICE inhibitor to enter clinical trials, is currently under investigation in rheumatoid arthritis.
Colchicine undergoes oxidative demethylation by liver microsomes in the presence of NADPH and atmospheric oxygen. O 2 -Demethylcolchicine and 0 3 -demethylcolchicine are always produced, although their rates of formation and their relative proportions vary according to the species. O 10 -demethylcolchicine ( = colchiceine) is, however, normally found only with colchicinesensitive species, such as rat and mouse. 0 3 -demethylcolchicine undergoes glucuronidation by hamster microsomes in vitro, whereas the rat produces only the glucuronide of O 2 -demethylcolchicine. The metabolism of colchicine is about fourfold higher in the highly colchicine-resistant hamster than in the rat and mouse. Monodemethylated derivates of colchicine are not metabolized further. The microsomal metabolism of colchicine is enhanced after induction by phenobarbital, 20-methy 1-cholanthrene, and colchicine itself. The possible participation of such metabolites in the biological effects following colchicine administration is discussed. The pattern of metabolites depends to some extent on the method which is used for the preparation of microsomes; this constitutes further evidence for the mechanism of formation of these metabolites, which was postulated earlier.
Zum Stoffwechsel vonColchicin, II. m. Die Metabolisierung von Colchicin durch Lebermikrosomen verschiedener Säugetiere Zusammenfassung: Colchicin wird durch Lebermikrosomen in Gegenwart von NADPH und Luftsauerstoff oxidativ demethyliert. 0 2 -Demethylcolchicin und O 3 -Demethylcolchicin sind -allerdings in unterschiedlichem Umfang und Verhältnis -stets als Metaboliten anzutreffen. Dagegen wird 0 10 -Demethylcolchicin (= Colchicein) in der Regel nur bei Colchicin-empfmdlichen Tierarten (Ratte, Maus) gebildet. O 3 -Demethylcolchitin wird in vitro vom Hamster glucuronidiert, während bei der Ratte nur das Glucuronid von O 2 -Demethylcolchicin entsteht. Das Ausmaß der Metabolisierung von Colchicin beträgt beim hochgradig Colchicin-resistenten Hamster
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