Therapeutic administration of 3,4,5-trimethoxy-4'-fluorochalcone, a selective inhibitor of iNOS expression, attenuates the development of adjuvant-induced arthritis in rats.
We have previously investigated the effects of a series of dimethoxy- and trimethoxychalcone derivatives, with various patterns of fluorination, on nitric oxide production in LPS-stimulated murine RAW 264.7. The present study was designed to determine if 3,4,5-trimethoxy-4'-fluorochalcone (CH 17) could modulate the production of NO and/or prostaglandins in vivo. On the mouse macrophage cell line RAW 264.7 CH 17 inhibited dose-dependently NO production, with an IC(50) value in the nanomolar range, and reduced PGE(2) levels by a 58% at 10 microM. This compound had no direct inhibitory effect on iNOS and COX-2 activities. NO reduction was the consequence of inhibition of the expression of iNOS. In vitro experiments indicated that CH 17 is an inhibitor of the nuclear factor-kappaB (NF-kappaB) pathway of cellular activation in macrophages. This compound exhibited in vivo an inhibitory behaviour correlated with its in vitro results on nitrite and PGE(2) accumulation. In the rat adjuvant-induced arthritis, oral administration of CH 17 (25 mg/kg) on days 17-24 after adjuvant injection, significantly inhibited paw oedema, protected from weight loss and reduced the levels of inflammatory mediators (nitrites and PGE(2)) in paw homogenates, without affecting PGE(2) levels in stomach homogenates. The profile and potency of this compound, a selective inhibitor of iNOS expression that interferes with NF-kappaB activation, may have relevance for the inhibition of the inflammatory response, representing a new approach to the modulation of different inflammatory pathologies.
Rojas
Javier
J
Departamento de Farmacología, Facultad de Farmacia, Universidad de Valencia, Avda Vicent Andrés Estellés s/n, 46100, Burjasot, Valencia, Spain.
Payá
Miguel
M
Devesa
Isabel
I
Dominguez
José N
JN
Ferrándiz
M Luisa
ML
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy*; D015153:Blotting, Western; D002478:Cells, Cultured; D002599:Chalcone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D047188:Chalcones; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D004586:Electrophoresis; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D009000:Monocytes / Q000187:drug effects / Q000201:enzymology; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew
C488299:3,4,5-trimethoxy-4'-fluorochalcone; D047188:Chalcones; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D016328:NF-kappa B; D009569:Nitric Oxide; D002599:Chalcone; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; C496318:Nos2 protein, rat; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; C496513:Ptgs1 protein, rat