The intestinal anti‐inflammatory activity of UR‐12746S on reactivated experimental colitis is mediated through downregulation of cytokine production

• Published in: Inflammatory bowel diseases Vol. 9; no. 6; pp. 363 - 371
• Main Authors: Gálvez, Julio, Garrido, Margarita, Rodríguez‐Cabezas, Maria Elena, Ramis, Isabel, de Medina, Fermín Sánchez, Merlos, Manuel, Zarzuelo, Antonio
• Format: Journal Article
• Language: English
• Published: Philadelphia Lippincott Williams & Wilkins, Inc 01.11.2003
• Subjects: Aminosalicylic Acids - therapeutic use; Animals; Anti-Inflammatory Agents, Non-Steroidal - therapeutic use; Aza Compounds - therapeutic use; Azo Compounds - therapeutic use; Cell Line; Colitis - chemically induced; Colitis - drug therapy; Colitis - metabolism; Colitis - pathology; Colon - pathology; Cytokines - biosynthesis; Down-Regulation; Female; IL‐1β‐TNFα; IL‐8; Inflammation Mediators - metabolism; Interleukin-1 - biosynthesis; Interleukin-8 - biosynthesis; Mesalamine - therapeutic use; Neutrophil Infiltration; Peroxidase - metabolism; Platelet Activating Factor - antagonists & inhibitors; Rat experimental colitis; Rats; Rats, Wistar; Secondary Prevention; Trinitrobenzenesulfonic Acid; Tumor Necrosis Factor-alpha - biosynthesis; UR‐12746S (dersalazine sodium)
• ISSN: 1078-0998; 1536-4844
• DOI: 10.1097/00054725-200311000-00004

Background UR‐12746S (dersalazine sodium) is cleaved by colonic bacteria delivering the PAF antagonist UR‐12715 and 5‐ASA. This study describes the anti‐inflammatory activity of UR‐12746S in an experimental model of reactivated colitis and its effects on cytokine production. Methods Rats were initially rendered colitic by a colonic instillation of 10 mg of trinitrobenzenesulphonic acid (TNBS) dissolved in 0.25 ml of 50 % ethanol, and colitis was reactivated two weeks after by a second administration of the same dose of TNBS. Two groups of colitic rats received UR‐12746S (25 and 50 mg/kg daily, p.o.) and colonic damage was evaluated every week for 4 weeks. Different biochemical markers of colonic inflammation were assayed: MPO activity and cytokine (IL‐1β and TNFα) levels. Also, the in vitro effects of UR‐12715 and 5‐ASA on cytokine production were assayed. Results UR‐12746S showed anti‐inflammatory effect in reactivated colitis in rats, as evidenced by a significant reduction in MPO activity. Both doses of UR‐12746S decreased IL‐1β production, while only the highest dose assayed inhibited TNFα production. In vitro studies revealed that UR‐12715 or 5‐ASA (from 10−6 to 10−4 M) inhibited IL‐8 production (30–40 %) in HT‐29 cells when incubated with LPS. This inhibitory effect was enhanced when both compounds were administered simultaneously at 10−4 M. In addition, UR‐12715 inhibited IL‐1β or TNFα production in THP‐1 or U937 cells, respectively, when these cells were stimulated by PMA and LPS; whereas 5‐ASA only showed a weak effect in inhibiting IL‐1β production. Conclusion UR‐12746S was able to prevent relapse in experimental colitis and inhibition of proinflammatory cytokine production participates in the intestinal anti‐inflammatory activity exerted by this compound.