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Effects of indomethacin and dexamethasone on recovery of cutaneous barrier disruption induced by mechanical scratching were examined. Cutaneous barrier was disrupted by scratching using a stainless-steel wire brush (mechanical scratching) and compared to cutaneous application of acetone/ether (1:1) mixture (AE) and tape-stripping. Increase of transepidermal water loss (TEWL), as an indicator of a broken skin barrier, and recovery period for mechanical scratching were higher and longer than those for AE treatment and tape-stripping and we also confirmed the severity of skin damage in a histological study. Topical application of moisturizers showed a temporal effect, rapidly decreased TEWL on mechanical scratching- or AE treatment-induced cutaneous barrier disruption, and gradually increased base levels from 4 to 12 h after treatment. Topical application of indomethacin or dexamethasone prolonged the recovery period for the cutaneous barrier, and concomitant use further worsened the status of the barrier. Additionally, we examined the effects of prostaglandins (PGs) and inflammatory cytokine on mechanical scratching-induced cutaneous barrier disruption pretreated with indomethacin and dexamethasone. As a results, PGD2 and interleukin (IL)-1beta significantly accelerated the recovery of cutaneous barrier disruption by mechanical scratching but such was not the case with PGE2, IL-1alpha, and tumor necrosis factor-alpha treatment. These results suggest that indomethacin and dexamethasone prolonged the recovery period caused by inhibition of PGD2 and IL-1beta. Mechanical scratching-induced cutaneous barrier disruption may be a useful method for evaluating means of recovery from skin damage.

The aim of this study was to evaluate the efficacy of multiple applications of S(1)-flurbiprofen plaster (SFPP), a novel Nonsteroidal anti-inflammatory drug (NSAID) patch, for the alleviation of inflammatory pain and edema in rat adjuvant-induced arthritis (AIA) model as compared to other NSAID patches. The AIA model was induced by the injection of Mycobacterium butyricum and rats were treated with a patch (1.0 cm 3 0.88 cm) containing each NSAID (SFP, ketoprofen, loxoprofen, diclofenac, felbinac, flurbiprofen, or indomethacin) applied to the paw for 6 h per day for 5 days. The pain threshold was evaluated using a flexion test of the ankle joint, and the inflamed paw edema was evaluated using a plethysmometer. cyclooxygenase (COX)21 and COX-2 inhibition was evaluated using human recombinant proteins. Multiple applications of SFPP exerted a significant analgesic effect from the first day of application as compared to the other NSAID patches. In terms of paw edema, SFPP decreased edema from the second day after application, Multiple applications of SFPP were superior to those of other NSAID patches, in terms of the analgesic effect with multiple applications. These results suggest that SFPP may be a beneficial patch for providing analgesic and anti-inflammatory effects clinically. [ABSTRACT FROM AUTHOR]

Abstract: TS-022 is a prostanoid DP1 receptor agonist, originally developed as a novel anti-pruritic drug for atopic dermatitis. The drug has been shown to suppress scratching and improve the skin inflammation in the NC/Nga (NC) mouse, a model of atopic dermatitis. Corticosteroids are commonly used as effective agents for the treatment of atopic dermatitis. We examined the anti-pruritic efficacy of TS-022 in NC mice cohabited with skin-lesioned NC mice, which showed spontaneous scratching without skin lesions in the early phase and chronic itching with severe dermatitis in the late phase, in comparison with that of dexamethasone. We have previously reported that prostaglandin D2 might have a physiological role in the inhibition of pruritus. While after 2 weeks of cohabitation with skin-lesioned NC mice (early phase of dermatitis, characterized by the appearance of spontaneous scratching), topically applied TS-022 exhibited a weak anti-pruritic effect in the NC mice, after 6 weeks of cohabitation (late phase, characterized by both chronic scratching and dermatitis), the drug exerted potent anti-pruritic activity. In contrast, dexamethasone exerted potent anti-pruritic effect in both the early and late phases. Indomethacin aggravated the scratching in the early phase, but had no effect in the late phase. The skin prostaglandin D2 level was significantly increased in the early phase, to subsequently declined and return to the basal level in the late phase. The cutaneous ability for prostaglandin D2 production following topical application of arachidonic acid or mechanical scratching was decreased in the late phase. Moreover, the expression level of the prostanoid DP1 receptor in the skin was increased in the late phase. These findings suggest that the potent anti-pruritic activity of TS-022 in the late phase might be attributable to the decrease of endogenous prostaglandin D2 production and increase of prostanoid DP1 receptor expression. [Copyright &y& Elsevier]

NC/Nga (NC) mice, spontaneously develop an eczematous atopic dermatitis (AD)-like skin lesion when kept under conventional condition (Conv), but not under specific pathogen-free (SPF) conditions, have been thought to be an animal model of AD. We have previously shown that PGD2 and arachidonic acid inhibited the scratching behaviour of NC mice, while indomethacin enhanced it. This study was designed to assess the role of cyclooxygenase (COX)-1 and COX-2 in the itch-related scratching behaviour of NC mice. We examined the expression of COX in the skin using real-time PCR and Western blotting and the effects of SC-560 (a COX-1 selective inhibitor) or NS-398 (a COX-2 selective inhibitor) on scratching behaviour in relation to skin prostaglandin (PG) levels in NC mice. COX-1 mRNA expression was unchanged and protein expression decreased in Conv NC mice compared with that of SPF mice. By contrast, COX-2 mRNA and protein expression increased in Conv NC mice. SC-560 increased scratching behaviour and significantly reduced skin PGD2, PGE2 and PGF2 α levels, but NS-398 did not have effects on scratching and skin PG level. Moreover, the topical application of PGD2, which might be the endogenous inhibitor of itching, suppressed the SC-560-induced enhancement of scratching behaviour by NC mice. These results suggest COX-1-coupled skin PGD2 biosynthesis plays a physiological role in inhibiting regulation of pruritus in NC mice with AD. [ABSTRACT FROM AUTHOR]

Abstract: The role of prostaglandins in mechanical scratching-induced cutaneous barrier disruption in mice was investigated. Skin prostaglandins contents were measured after cutaneous barrier function was disrupted by scratching using a stainless-steal wire brush (mechanical scratching), then effects of prostanoids on recovery of cutaneous barrier functions were examined. This mechanical scratching increased transepidermal water loss and skin prostaglandins (prostaglandin D2, prostaglandin E2, 6-keto-prostaglandin F1α and prostaglandin F2α) contents, count-dependently. Topical application of indomethacin immediately after cutaneous barrier disruption delayed the recovery period of cutaneous barrier disruption. We examined effects of several prostanoids (prostaglandin D2, prostaglandin E2, prostaglandin F2α, prostaglandin I2 and U46619) on delay of the recovery process of mechanical scratching-induced cutaneous barrier disruption with treatment of indomethacin. Topically applied prostaglandin D2 and prostaglandin E2 accelerated the recovery of cutaneous barrier disruption and topical application of prostaglandin J2, limaprost, sulprostone and ONO-4819, but not 13,14-dihydro-15-keto-prostaglandin D2, 15-deoxy-Δ12,14-prostaglandin J2, 17-phenyl-trinor-prostaglandin E2 or butaprost had effects on recovery of the cutaneous barrier. These results suggest that prostaglandin D2 and prostaglandin E2 accelerate the recovery process of cutaneous barrier disruption caused by mechanical scratching, via specific prostanoid DP1, EP3 and EP4 receptors. [Copyright &y& Elsevier]