A new ditriazine inhibitor of NF-kappaB modulates chronic inflammation and angiogenesis.
We have previously shown that a ditriazine derivative 4,10-dichloropyrido[5,6:4,5]thieno[3,2- d':3,2- d]-1, 2, 3-ditriazine (DTD) modulates acute inflammation in murine models by inhibition of leukocyte functions and expression of inducible enzymes including nitric oxide synthase and cyclooxygenase-2 (COX-2). In the present work, we have demonstrated the anti-inflammatory effect of DTD after oral administration in the rat adjuvant-induced arthritis, by reduction of interleukin-1beta and tumour necrosis factor-alpha levels and COX-2 expression in the inflamed tissues. These mediators were also significantly decreased by DTD treatment in the angiogenesis-dependent murine air pouch granuloma model, where this agent exerted anti-inflammatory and antiangiogenic effects. In vitro experiments indicated that DTD is an inhibitor of the nuclear factor-kappaB (NF-kappaB) pathway of cellular activation in macrophages, in parallel with the regulation of cytokine release. Our results suggest that the anti-inflammatory and antiangiogenic properties of DTD can be related to the inhibition of cytokine and PGE(2) production by interfering with NF-kappaB activation. This compound thus offers a therapeutic potential for the treatment of chronic inflammatory diseases with an angiogenic component, such as rheumatoid arthritis.
Rioja
Inmaculada
I
Departamento de Farmacología, Facultad de Farmacia. Av. Vicent Andrés Estellés s/n, 46100 Burjasot, Valencia, Spain.
Terencio
M Carmen
MC
Ubeda
Amalia
A
Riguera
Ricardo
R
Quintela
José M
JM
Alcaraz
M José
MJ
D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002908:Chronic Disease; D051546:Cyclooxygenase 2; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis; D005260:Female; D006099:Granuloma / Q000188:drug therapy / Q000473:pathology; D020672:I-kappa B Proteins; D007375:Interleukin-1 / Q000378:metabolism; D007527:Isoenzymes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology; D051379:Mice; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D014227:Triazines / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C412523:4,10-dichloropyrido(5,6:4,5)thieno(3,2-d')-1,2,3-ditriazine; D020533:Angiogenesis Inhibitors; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004268:DNA-Binding Proteins; D020672:I-kappa B Proteins; D007375:Interleukin-1; D007527:Isoenzymes; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606205:Nfkbia protein, mouse; C000606206:Nfkbia protein, rat; D014227:Triazines; D014409:Tumor Necrosis Factor-alpha; D000072000:NF-KappaB Inhibitor alpha; D004247:DNA; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone