Cytosolic phospholipase A2 alpha inhibitor, pyrroxyphene, displays anti-arthritic and anti-bone destructive action in a murine arthritis model

Abstract

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.

Pharmacological inhibition of lipid droplet formation enhances the effectiveness of curcumin in glioblastoma

“…Because of the importance of cPLA2a in lipid metabolism and the production of pro-inflammatory mediators, its inhibition has also been studied in the context of inflammatory conditions such as arthritis [86,87]. The microenvironment of glioblastoma tumors is characterized by the infiltration of hyperactivated immune cells, which aggravate disease progression.…”

Molecular Mechanisms Regulating the Vascular Prostacyclin Pathways and Their Adaptation during Pregnancy and in the Newborn

“…Studies in knockout and transgenic mice support a role of PLA 2 in physiological processes, such as host defense and pathological processes such as inflammation and atherosclerosis (Murakami et al, 2010). Mice lacking cPLA 2␣ are deficient in PG and/or LT-mediated pathways and therefore demonstrate resistance to airway and joint inflammation and smaller brain infarct volume (Tai et al, 2010). Mice lacking group V and X sPLA 2 show reduced atherosclerosis and ischemia/reperfusion injury, respectively; although mice overexpressing group II-A sPLA 2 show increased atherosclerosis compared with nontransgenic littermates (Murakami et al, 2010).…”

“…Pyrrolidine-based inhibitors such as pyrrophenone and indole derivatives such as ecopladib, efipladib, and 4-(3-(5-chloro-2-(2-(((2,6-dimethylbenzyl)sulfonyl)amino)ethyl)-1-(diphenylmethyl)-1H-indol-3-yl)propyl)benzoic acid (WAY-196025) are among the most potent and selective cPLA 2␣ inhibitors (Ramarao et al, 2008). Pyrroxyphene, a pyrrolidine-based cPLA 2␣ inhibitor that decreases PGE 2 and LTB 4 levels (and reduces COX2 mRNA expression, probably by inhibiting NF-B), decreases arthritis, and bone damage in a rat model of collagen-induced arthritis (Tai et al, 2010). Target inhibition of cPLA 2␣ may also be beneficial in ischemia-reperfusion injury.…”

The molecular basis of ceramide-1-phosphate recognition by C2 domains

“…The higher affi nity of the C2 domain for C1P in an acidic environment could have important physiological implications, because cellular pH can vary during infl ammation ( 60 ) or cancer ( 61 ) with a more-profound acidic pH. Because cPLA 2 ␣ has been implicated in infl ammatory diseases and cancers ( 15,16 ), the pH dependence of cPLA 2 ␣ translocation and activation at acidic pH warrants further investigation. and supplementary Fig.…”