Inhibition of benzalkonium chloride-induced skin inflammation in mice by an indol-1-ylpropan-2-one inhibitor of cytosolic phospholipase A2α

Abstract

Irritant contact dermatitis (ICD) is a frequent and often underrated problem for which the major efficacious therapy is still local glucocorticoids, although they have known adverse effects due to their wide spectrum of action. A more focused therapeutic strategy would be the inhibition of a key enzyme for biosynthesis of the lipid mediators, cytosolic phospholipase A(2) α (cPLA(2) α), in ICD. We are analysing the pharmacological and biological effects of a selective cPLA(2) α inhibitor. To examine the usefulness of the potent and selective cPLA(2) α inhibitor 3-(5-carboxypentanoyl)-1-[3-(4-octylphenoxy)-2-oxopropyl]indole-5-carboxylic acid (compound 1) for therapy of inflammatory skin disorders. We examined clinical and cellular effects of a selective cPLA(2) α inhibitor (compound 1) on ICD in mice. Topical application of the compound significantly reduced ear swelling after induction by the irritant benzalkonium chloride. Concomitantly, compound 1 inhibited the accumulation of granulocytes as well as the expression of inflammatory proteins such as tumour necrosis factor-α, interleukin-1β and macrophage inflammatory proteins 1α and 1β in the ear tissue. In primary murine keratinocytes, the benzalkonium chloride-induced expression of these proteins was also downregulated after treatment with compound 1 in vitro. Compound 1 is a well-aimed agent for the treatment of nonspecific skin inflammation as it selectively inhibits cPLA(2) α and as it acts on an early stage of skin inflammation after its elicitation.