The peroxisome proliferator-activated receptor α activator, Wy14,643, is anti-inflammatory in vivo

Abstract

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.

Peripheral leukocyte and endometrium molecular biomarkers of inflammation and oxidative stress are altered in peripartal dairy cows supplemented with Zn, Mn, and Cu from amino acid complexes and Co from Co glucoheptonate

“…Eicosanoids are PPARα activators [36] that can inhibit arachidonic acid-induced inflammation in part by enhancing degradation of leukotriene B4 [37]. It is noteworthy that the expression of ALOX5AP (leukotriene synthesis) and PPARA followed opposite patterns of expression with the AAC treatment indicating that the inflammatory response in those cows likely was of a greater magnitude but of brief duration.…”

Inhibition of fatty acid amide hydrolase produces PPAR‐α‐mediated analgesia in a rat model of inflammatory pain

“…Furthermore, recent studies have revealed impaired production of inflammatory cytokines interferon‐γ, IL‐6 and TNF‐α in vitro ( Cunard et al ., 2002 ; Murakami et al ., 2007 ) following exposure to the PPAR‐α ligand WY14643, with similar inhibitory effects on IL‐6 and TNF secretion observed in lipopolysaccharide‐stimulated macrophages following treatment with the PPAR‐α agonist K‐111 (2,2‐dichloro‐12‐(4‐chlorophenyl)dodecanoic acid) ( Murakami et al ., 2007 ). Similarly, the PPAR‐α agonist WY14643 has anti‐inflammatory effects in arachidonic acid‐evoked oedema in the murine ear‐swelling test ( Colville‐Nash et al ., 2005 ). Mice lacking the PPAR‐α receptor have significantly elevated levels of neutrophils, macrophages and TNF‐α following intranasal administration of lipopolysaccharide compared with wild‐type littermates ( Delayre‐Orthez et al ., 2005 ).…”

Peroxisome Proliferator-Activated Receptor Targets for the Treatment of Metabolic Diseases

“…Moreover, WY14.643, a potent agonist of PPAR- α , can directly increase the expression of adiponectins, antidiabetics, antiatherosclerosis, and anti-inflammatory effects [143]. …”