Abstract
Atopic dermatitis (AD) is a complex inflammatory skin disorder, characterized by a complicated pathophysiology and a wide range of clinical phenotypes. Roxatidine acetate chloride (RXA) is a precursor of Roxatidine and a histamine H2 receptor antagonist, used for the treatment of gastric ulcers. In this study, we aimed to examine whether RXA had anti-AD effects and determine the underlying molecular mechanism of RXA. The anti-AD effects were examined in Dermatophagoides farinae body (Dfb)-induced AD mouse model, tumor necrosis factor (TNF)-α/interferon (IFN)-γ-stimulated HaCaT keratinocytes, and human skin equivalent model using ELISA, histological analysis, immunohistochemistry, Western blot, and immunofluorescence. Results showed that RXA treatment significantly alleviated Dfb-induced AD skin symptoms and clinical severity in mice by decreasing the levels of immunoglobulin E, histamine, and inflammatory cytokines. RXA effectively inhibited the expression of adhesive molecules and recovered the filaggrin expression in Dfb-induced AD skin lesions and TNF-α/IFN-γ-stimulated HaCaT keratinocytes. Additionally, RXA significantly upregulated the expression of aryl hydrocarbon receptor and sirtuin1. The anti-AD effects of RXA were associated with suppressed nuclear factor kappa cascade. Overall, our results suggest that RXA may be a potential anti-AD candidate owing to its inhibitory effect against skin inflammation and protection of the skin barrier function in AD.
Highlights
Roxatidine acetate hydrochloride (2-acetoxy-N-[3-[m-(1-piperidinylmethyl) phenoxy] propyl] acetamide hydrochloride, Roxatidine acetate chloride (RXA)) is a competitive histamine H2 receptor antagonist, that upon oral absorption, is rapidly converted to its active metabolite, Roxatidine
To investigate the potential activity of RXA on skin, we investigated the molecular mechanisms involved in the antiAD activity of RXA and suggested the targeted potential signal pathway, using house dust mite Dermatophagoides farinae body (Dfb)-induced atopic dermatitis (AD) murine model, human keratinocytes and human skin equivalent (HSE) model
Treatment of mice with Dfb resulted in severe AD skin symptoms, with a significant increase in dermatitis score compared with the control group
Summary
Roxatidine acetate hydrochloride (2-acetoxy-N-[3-[m-(1-piperidinylmethyl) phenoxy] propyl] acetamide hydrochloride, RXA) is a competitive histamine H2 receptor antagonist, that upon oral absorption, is rapidly converted to its active metabolite, Roxatidine. As one of the results among our trials, we have previously reported the anti-inflammatory activities of Roxatidine and inhibition of NF-κB and RXA Alleviates AD Skin Symptom p38 MAPK activation in LPS-induced RAW 264.7 macrophages (Cho et al, 2011), and the inhibitory effect of Roxatidine on mast cell-mediated allergic response via suppression of NF-κB and p38 MAPK In continuation with our previous study that reported the anti-inflammatory and anti-allergic effect of RXA, we postulated that RXA could play a role in skin inflammatory disease. Since our previous results demonstrated that RXA could remarkably suppress the level of histamine in PMACI-stimulated human mast cell, we hypothesized that it may play a key role in the pathogenesis of atopic dermatitis (AD)
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