The peroxisome proliferator-activated receptor alpha activator, Wy14,643, is anti-inflammatory in vivo.
The peroxisome proliferator-activated receptor system is exciting much interest as a novel point of therapeutic intervention in inflammation. Here, the effect of a peroxisome proliferator-activated receptor alpha agonist, [4-chloro-6-(2,3-xylidine)-pyrimidinylthio]acetic acid (Wy14,643), was examined in arachidonic acid-induced murine ear inflammation. 3-[1-(4-Chlorobenzyl)-3-t-butyl-thio-5-isopropylindol-2-yl]-2,2-dimethylpropanoic acid (MK886, a 5-lipoxygenase inhibitor) and indomethacin (a cyclo-oxygenase inhibitor) were used as reference compounds. Wy14,643 dose dependently inhibited ear swelling and polymorphonuclear leukocyte influx, as did MK886, associated with reduced tissue leukotriene B4 but not prostaglandin E2 levels. Unlike MK886, Wy14,643 did not inhibit ex vivo leukotriene B4 production. However, Wy14,643, but not MK886, induced peroxisomal enzyme activity. Indomethacin was less effective, though tissue prostaglandin E2 but not leukotriene B4 levels were reduced. Again, unlike indomethacin, Wy14,643 did not reduce ex vivo prostaglandin E2 production. However, indomethacin did increase peroxisomal enzyme activity but to a lesser extent than Wy14,643. This study demonstrates that peroxisome proliferator-activated receptor alpha activation can inhibit arachidonic acid-induced inflammation in part by enhancing degradation of leukotriene B4.
Colville-Nash
Paul
P
Department of Experimental Pathology, St. Bartholomew's and The Royal London School of Medicine and Dentistry, Charterhouse Square, London, EC1M 6BQ, UK.
Willis
Dean
D
Papworth
Jonathan
J
Freemantle
Claire
C
Lam
Connie
C
Andrews
Gemma
G
Willoughby
Derek
D
D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004431:Ear, External / Q000187:drug effects / Q000473:pathology; D004487:Edema / Q000517:prevention & control; D005260:Female; D007211:Indoles / Q000008:administration & dosage / Q000627:therapeutic use; D007213:Indomethacin / Q000008:administration & dosage / Q000627:therapeutic use; D007249:Inflammation / Q000517:prevention & control*; D007975:Leukotriene B4 / Q000378:metabolism; D016859:Lipoxygenase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism; D047493:PPAR alpha / Q000819:agonists*; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D020675:Peroxisomes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use*; D002722:Chlorobenzenes
D000893:Anti-Inflammatory Agents; D001094:Arachidonate 5-Lipoxygenase; D015232:Dinoprostone; D007211:Indoles; D007213:Indomethacin; D007975:Leukotriene B4; D016859:Lipoxygenase Inhibitors; D047493:PPAR alpha; D010171:Palmitoyl Coenzyme A; D011451:Prostaglandin-Endoperoxide Synthases; D011743:Pyrimidines; C060893:MK-886; D002722:Chlorobenzenes; C006253:pirinixic acid