Difamilast topically ameliorates pruritus, dermatitis, and barrier dysfunction in atopic dermatitis model mice by inhibiting phosphodiesterase 4, especially the 4B subtype

Atopic dermatitis (AD) is a common chronic inflammatory skin disorder, characterized by itchy eczema. The complex interplay among pruritus, skin inflammation, and barrier dysfunction contributes to the development, progression, and chronicity of AD. Phosphodiesterase 4 (PDE4), an enzyme that specifically degrades cAMP, is expressed in a variety of cell types, including immune cells, fibroblasts, and keratinocytes. PDE4 is involved in the persistence and exacerbation of chronic inflammatory diseases such as chronic obstructive pulmonary disease, asthma, psoriasis, and AD. One of the topical PDE4 inhibitors, difamilast, has been shown to be effective in the clinical treatment of AD. However, its pharmacological effects and mechanisms of action are not completely understood. Therefore, we evaluated the effects of difamilast on pruritus, dermatitis, and skin barrier dysfunction in MC903-induced AD model mice. The results revealed that a single application of difamilast dramatically reduced the number of scratching events, an indicator of pruritus, and repeated application of difamilast reduced the increase in ear thickness, an indicator of dermatitis, and transepidermal water loss, an indicator of barrier dysfunction. In addition, these symptoms were milder in PDE4B-deficient mice than in wild-type mice, and difamilast treatment had little or no further therapeutic effects on attenuating AD symptoms. In summary, our study demonstrated that difamilast effectively alleviates the primary symptoms of AD through the inhibition of PDE4B, as one of its mechanisms. SIGNIFICANCE STATEMENT: This study characterized the therapeutic effects of difamilast on the major symptoms of atopic dermatitis, including pruritus, dermatitis, and skin barrier dysfunction. The study also revealed a detailed mechanism of action of difamilast, in which its therapeutic effect is mediated mainly by PDE4B inhibition. This study may provide new insights into the use of difamilast for the treatment of atopic dermatitis.