Prostanoid DP 1 receptor agonist inhibits the pruritic activity in NC/Nga mice with atopic dermatitis

Abstract

NC/Nga mice have similar pathological and behavioral features of human atopic dermatitis and are used as a model of the disease. Under conventional circumstances, spontaneous and persistent scratching is frequent and can lead to the onset of skin inflammation. We examined the effects of several prostanoids and their related compounds on the scratching behavior of NC/Nga mice. Among them, topically applied prostaglandin D 2, prostaglandin E 1, prostaglandin E 2 and prostaglandin I 2 significantly suppressed the scratching, the order of inhibitory activities being prostaglandin D 2≫prostaglandin I 2>prostaglandin E 1=prostaglandin E 2. Prostaglandin D 2 metabolite, prostaglandin J 2 also significantly suppressed the scratching but not so 13,14-dihydro-15-keto-prostaglandin D 2, and 15-deoxy-Δ 12,14-prostaglandin J 2. The order of the inhibitory activities of these prostaglandin D 2 metabolites depended on affinity of the prostanoid DP 1 receptor but not on the DP 2 receptor (chemoattractant receptor-homologous molecule expressed on T helper2 cells, CRTH 2) and PPAR-γ receptors. Likewise, topically applied arachidonic acid significantly suppressed the scratching while indomethacin enhanced it. Pretreatment of arachidonic acid increased the skin prostaglandins (prostaglandin D 2, prostaglandin E 2, prostaglandin F 2α and 6-keto-prostaglandin F 1α) contents, but indomethacin decreased the prostaglandin D 2 and prostaglandin E 2 contents. On the other hand, prostaglandin D 2 and indomethacin had no apparent effects on histamine-induced scratching of ICR mice. These results suggested that prostaglandin D 2 plays a physiological role in inhibiting pruritis of NC/Nga mice via their specific prostanoid DP 1 receptors, and that prostaglandin D 2 and/or a prostanoid DP 1 receptor agonist may have therapeutic effects for cases of consecutive skin inflammation.