Inhibitory Effect of a Potent and Selective Cytosolic Phospholipase A2α Inhibitor RSC-3388 on Skin Inflammation in Mice

Abstract

Cytosolic phospholipase A₂α (cPLA₂α) preferentially hydrolyzes membrane phospholipids containing arachidonic acid, resulting in the biosynthesis of eicosanoids such as prostaglandins and leukotrienes. To examine the contribution of cPLA₂α to skin inflammation, we evaluated the effect of (E)-N-[(2S,4R)-4-[N-(biphenyl-2-ylmethyl)-N-2-methylpropylamino]-1-[2-(2,4-difluorobenzoyl)benzoyl]pyrrolidin- 2-yl]methyl-3-[4-(2,4-dioxothiazolidin-5-ylidenemethyl) phenyl]acrylamide (RSC-3388), a potent and selective cPLA₂α inhibitor, on 2,4,6-trinitro-1-chlorobenzene (TNCB)-induced ear inflammation and mite antigen-induced dermatitis in mice. Topical application of RSC-3388 showed a significant inhibitory activity against TNCB-induced ear swelling and eicosanoid production in mice. Comprehensive expression analysis using Gene-Chip technology and subsequent experiments concerning mRNA and protein expression demonstrated that RSC-3388 clearly reduced the levels of interleukin-1β, macrophage inflammatory protein-1α (MIP-1α) and MIP-1β in a TNCB-induced mouse model. In addition, RSC-3388 ointment significantly alleviated atopic dermatitis-like skin lesions induced by repeated application of mite antigen. Furthermore, increased expression of cPLA₂α, assessed by anti-phospho-cPLA₂α antibody, was observed in the skin lesions of mite-antigen-induced dermatitis. These results indicate that cPLA₂α is involved in the development of skin inflammation in mice, and RSC-3388 is expected to be useful for the treatment of inflammatory skin disorders such as atopic dermatitis.