Cytosolic phospholipase A2 alpha inhibitor, pyrroxyphene, displays anti-arthritic and anti-bone destructive action in a murine arthritis model.
OBJECTIVE
The aim of this study is to verify the crucial role of cytosolic phospholipase A2 alpha (cPLA2 alpha) in the pathogenesis of collagen-induced arthritis in mice and to determine the anti-arthritic effects of pyrroxyphene, a cPLA2 alpha inhibitor.


METHODS
Pyrroxyphene was administered (p.o.) twice a day for 18 days at 30 and 100 mg/kg. Its effects on arthritic symptoms, bone destruction, cPLA2 alpha activity, levels of prostaglandin E(2) and leukotriene B(4), and mRNA expression of matrix metalloproteinase (MMP)-3, -8, -9, -13 and cyclooxygenase-2 (COX-2) were tested.


RESULTS
cPLA2 alpha activity gradually increased and showed a correlation with the severity of arthritis. Pyrroxyphene strongly inhibited the incidence of arthritis and bone destruction. Moreover, it significantly inhibited both the increase in levels of cPLA2 alpha and eicosanoids as well as the mRNA expression of MMP-3, -8, -9, -13, and COX-2.


CONCLUSIONS
These results demonstrate that cPLA2 alpha plays an important role in the pathogenesis of collagen-induced arthritis. Oral administration of pyrroxyphene achieved anti-arthritic activity through inhibition of cPLA2 alpha activity, which led to a reduction in eicosanoid levels and suppression of MMP and COX-2 mRNA expression. These results support a potential therapeutic role for cPLA2 alpha inhibitors in the treatment of human rheumatoid arthritis.
Tai
Nobuyuki
N
Shionogi & Co., Ltd., Fukushima-ku, Osaka, Japan. nobuyuki.tai@shionogi.co.jp
Kuwabara
K
K
Kobayashi
M
M
Yamada
K
K
Ono
T
T
Seno
K
K
Gahara
Y
Y
Ishizaki
J
J
Hori
Y
Y
D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000517:prevention & control*; D001847:Bone Diseases / Q000378:metabolism / Q000517:prevention & control*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D004195:Disease Models, Animal; D015777:Eicosanoids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D054513:Group IV Phospholipases A2 / Q000037:antagonists & inhibitors* / Q000502:physiology; D007975:Leukotriene B4 / Q000378:metabolism; D008297:Male; D020782:Matrix Metalloproteinases / Q000378:metabolism; D051379:Mice; D008811:Mice, Inbred DBA; D011759:Pyrrolidines / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000627:therapeutic use
D015777:Eicosanoids; D004791:Enzyme Inhibitors; C548442:N-((4-(biphenyl-2-ylmethoxy)-1-(2-(4-fluorobenzoyl)benzoyl)pyrrolidin-2-yl)methyl)-4-((2,4-dioxothiazolidin-5-ylidene)methyl)benzamide; D011759:Pyrrolidines; D045162:Thiazolidinediones; D007975:Leukotriene B4; D051546:Cyclooxygenase 2; D054513:Group IV Phospholipases A2; D020782:Matrix Metalloproteinases; D015232:Dinoprostone