The intestinal anti-inflammatory activity of UR-12746S on reactivated experimental colitis is mediated through downregulation of cytokine production.
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-1beta and TNFalpha) 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-1beta production, while only the highest dose assayed inhibited TNFalpha 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-1beta or TNFalpha 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-1beta production.


CONCLUSIONS
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.
Gálvez
Julio
J
Department of Pharmacology, University of Granada, Granada, Spain. jgalvez@ugr.es
Garrido
Margarita
M
Rodríguez-Cabezas
Maria Elena
ME
Ramis
Isabel
I
de Medina
Fermín Sánchez
FS
Merlos
Manuel
M
Zarzuelo
Antonio
A
D000636:Aminosalicylic Acids / Q000627:therapeutic use*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001372:Aza Compounds / Q000627:therapeutic use*; D001391:Azo Compounds / Q000627:therapeutic use*; D002460:Cell Line; D003092:Colitis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003106:Colon / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis*; D015536:Down-Regulation; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism*; D007375:Interleukin-1 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D019804:Mesalamine / Q000627:therapeutic use; D020556:Neutrophil Infiltration; D009195:Peroxidase / Q000378:metabolism; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D051381:Rats; D017208:Rats, Wistar; D055502:Secondary Prevention; D014302:Trinitrobenzenesulfonic Acid; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000636:Aminosalicylic Acids; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001372:Aza Compounds; D001391:Azo Compounds; D016207:Cytokines; D018836:Inflammation Mediators; D007375:Interleukin-1; D016209:Interleukin-8; D010972:Platelet Activating Factor; D014409:Tumor Necrosis Factor-alpha; C571878:dersalazine; D019804:Mesalamine; D014302:Trinitrobenzenesulfonic Acid; D009195:Peroxidase; C419382:UR 12746