Abstract

In a disease-state-dependent manner, the histamine-resistant itch in dry skin-based skin diseases such as atopic dermatitis (AD) and xerosis is mainly due to hyperinnervation in the epidermis. Semaphorin 3A (Sema3A) is a nerve repulsion factor expressed in keratinocytes and it suppresses nerve fiber elongation in the epidermis. Our previous studies have shown that Sema3A ointment inhibits epidermal hyperinnervation and scratching behavior and improves dermatitis scores in AD model mice. Therefore, we consider Sema3A as a key therapeutic target for improving histamine-resistant itch in AD and xerosis. This study was designed to screen a library of herbal plant extracts to discover compounds with potential to induce Sema3A in normal human epidermal keratinocytes (NHEKs) using a reporter gene assay, so that positive samples were found. Among the positive samples, only the extract of S. baicalensis was found to consistently increase Sema3A levels in cultured NHEKs in assays using quantitative real-time PCR and ELISA. In evaluation of reconstituted human epidermis models, the level of Sema3A protein in culture supernatants significantly increased by application of the extract of S. baicalensis. In addition, we investigated which components in the extract of S. baicalensis contributed to Sema3A induction and found that baicalin and baicalein markedly increased the relative luciferase activity, and that baicalein had higher induction activity than baicalin. Thus, these findings suggest that S. baicalensis extract and its compounds, baicalin and baicalein, may be promising candidates for improving histamine-resistant itch via the induction of Sema3A expression in epidermal keratinocytes.

Highlights

  • Itching is a sensation of discomfort that leads to scratching

  • We found five positive samples from 91 herbal plant extracts as potent inducers for human Semaphorin 3A (Sema3A) gene in normal human epidermal keratinocytes (NHEKs) using our Sema3A reporter gene assay

  • The extract of S. baicalensis significantly increased the level of Sema3A protein in the supernatants of NHEKs cultured for 24 hours (Fig 3A) and in cell lysates from NHEKs cultured for 6 and 24 hours (Fig 3B)

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Summary

Introduction

Itching is a sensation of discomfort that leads to scratching. Induction of endogenous Sema3A in NHEKs by S. baicalensis. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Three of the authors (YY, IY, NM), who are employees of Kobayashi Pharmaceutical Co., Ltd, had a partial role in data collection and analysis, and preparation of the manuscript

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