A new phthalimido compound, N-[2-(2-phthalimidoethoxy)acetyl]-L-alanyl-D-glutamic acid (CAS 142489-47-2, LK 423), was examined for its possible activity to modulate levels and species of cytokines in mice carrying a specific inflamed organ. Colonic inflammation was induced in mice by giving 5 % dextran sulfate sodium (DSS) solution as drinking water. The capacity of spleen cells obtained from the DSS-inflamed mice to produce interleukin-10 (IL-10) in response to mitogen was significantly reduced when compared with the capacity of spleen cells from intact mice. Treatment of the mice administered DSS by subcutaneous multiple injections with a low dose of LK423 resulted in delaying the progression to full-blown inflammation in the colon. The mitogen-stimulated spleen cells obtained from the LK423-treated mice yielded significantly greater amounts of IL-10 and IL-6 than the untreated DSS group, and the peritoneal cells from the LK423-treated mice produced significantly lower levels of tumor necrosis factor α Based on this prophylactic effect of LK423 in the murine colitis model, its therapeutic effect was examined in rats in which colitis had been induced by feeding 3 % DSS for 12 days. Intracolonic administration of LK423 to these rats for 7 days resulted in diminishing the ulcerative area in the colon. The immunological characteristics of this new compound are discussed from the point of view of its possible application as a therapeutic agent for inflammatory bowel diseases (IBD) and other inflammatory diseases. ZusammenfassungTherapeutische Wirkungen des Phthalimido-desmuramyldipeptid-Derivats LK423 auf die Dextransulfat-Natrium-induzierte Kolitis bei Nagetieren durch Wiederherstellung ihrer Fähigkeit zur Interleukin-10-Produktion Die neue Phthalimid-Verbindung N-[2-(2-Phthalimidoethoxy)acetyl]-L-alanyl-D-glutaminssäure (CAS 142489-47-2, LK423) wurde auf seinen Einfluß auf die Zytokin-Konzentrationen und -Spezies bei Mäusen mit einem entzündeten Organ untersucht. Durch Verabreichung einer 5%igen Dextransulfat-Natrium-Lösung (dextran sulfate sodium, DSS) als Trinkwasser wurde bei Mäusen eine Kolitis erzeugt. Die Fähigkeit der Milzzellen dieser Mäuse zur Produktion von Interleukin-10 (IL-10) als Reaktion auf Mitogen war signifikant reduziert im Vergleich zu derjenigen der Milzzellen gesunder Mäuse. Die Behandlung der Mäuse, die DSS zu sich nahmen, mit mehrfachen subkutanen Injektionen geringer Dosen von LK423 führte zur Verzögerung der Entwicklung einer hochgradigen Kolitis. Die Mitogen-stimulierten Milzzellen der mit LK423 behandelten Mäuse produzierten deutlich mehr IL-10 und IL-6 als die unbehandelte DSS-Gruppe, und die Peritonealzellen der mit LK423 behandelten Mäuse produzierten signifikant weniger Tumornekrosefaktor α Ausgehend von dieser prophylaktischen Wirkung von LK423 im murinen Kolitis-Modell wurde die therapeutische Wirkung der Substanz an Ratten untersucht, bei denen zuvor durch 12tägige Verabreichung einer 3%igen DSS-Lösung eine Kolitis induziert worden war. Die siebentägige Verabreichung von LK423 in...
A new phthalimido compound, N-[2-(2-phthalimidoethoxy)acetyl]-L-alanyl-D-glutamic acid (CAS 142489-47-2, LK423), was examined along with other N-acyl-desmuramyldipeptide compounds for possible immunomodulating activities in cyclophosphamide (Cy)-treated mice. Reverse transcriptase-polymerase chain reaction (RT-PCR) and Northern blot assays demonstrated that multiple subcutaneous injections of LK423 (1 to 50 micrograms/days, for 4 days) into these mice resulted in upregulating interleukin-10 (IL-10) gene expression in the spleen. In contrast to IL-10, expression of interferon-gamma (IFN-gamma) gene was reduced by treating with this compound. The culture supernatant of spleen cells obtained from the mice that had received LK423 injections was found to contain a larger amount of IL-10 protein than in the culture supernatant of the spleen obtained from the mice that received no LK423 injections when tested by enzyme-linked immunosorbent assay (ELISA). Conversely to IL-10, the concentration of IFN-gamma was lower in the culture supernatant from the LK423-treated group than that in the control group. In contrast to this compound, other N-acyl-desmuramyldipeptide derivatives carrying a L-alanyl-D-isoglutamine moiety, and other immunological stimulants showed an activity to augment production of IFN-gamma and reduce the gene expression of IL-10. The immunological activities of this new phthalimido desmuramyldipeptide compound, LK423, are discussed from the point of view of its therapeutic application.
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