Topical E6005, a novel phosphodiesterase 4 inhibitor, attenuates spontaneous itch‐related responses in mice with chronic atopy‐like dermatitis

Abstract

proliferation and an enhancement of stimuli responses. Metabolic process genes are highly enriched in both hyper-and hypomethylated groups indicates that the shifting of metabolic processes might be important in skin ageing and may represent a fruitful area for further inquiry.We also observed a locus of a keratin gene cluster is hypermethylated in ageing skin, and this has been partially cross-validated by a human counterpart study that both Krt1 and Krt16 are hypermethylated in skin ageing (20). However, omics-level study including MeDIP-chip is easily biased, the careful confirmation work is essential if any findings are interested to pursue further.Skin fibroblasts can be induced towards pluripotent stem cells by a combination of transcription factors, and it is essentially an epigenetic reprogramming process (30). Therefore, there is a likelihood that modulation of epigenetics could be an innovative anti-skin-ageing strategy in the future. AcknowledgementsXX conceived this project, HQ performed the research, and XX wrote the paper. This work was supported by Yale University. We appreciate LEN for reviewing/editing the manuscript. Conflict of interestsThe authors have declared no conflicting interests. Supporting InformationAdditional Supporting Information may be found in the online version of this article: Figure S1. Genome-wide distribution of skin ageinduced DNA methylation patterns. Figure S2. Gene clusters change their methylation status with skin ageing. Table S1. Age-induced hypermethylated promoters. Abstract: Atopic dermatitis is a chronic inflammatory cutaneous disease with difficult-to-treat pruritus. Although phosphodiesterase (PDE) 4 inhibitors have an anti-inflammatory effect on inflammatory skin diseases, such as atopic dermatitis, their acute antipruritic activities remain unclear. Therefore, in this study, we examined whether E6005, a novel PDE4 inhibitor, has antipruritic activity in dermatitis, using a mouse model of atopic dermatitis (NC/Nga mice). A single topical application of E6005 inhibited spontaneous hind-paw scratching, an itch-associated response and spontaneous activity of the cutaneous nerve in mice with chronic dermatitis. The cutaneous concentration of cAMP was significantly decreased in mice with chronic dermatitis, and this decrease was reversed by topical E6005 application. These results suggest that E6005 increases the cutaneous concentration of cAMP to relieve dermatitis-associated itching. Thus, E6005 may be a useful therapy for pruritic dermatitis such as atopic dermatitis. 359Letter to the Editor BackgroundAtopic dermatitis is a chronic inflammatory skin disease characterized by severe difficult-to-treat pruritus (1). Itching in atopic dermatitis may be mediated by manifold mediators, including interleukin-31 (2), thymic stromal lymphopoietin (3), tryptase (4), leukotriene B 4 (5) and sphingosylphosphorylcholine (6) and may not be fully relieved by selective receptor antagonists. Therefore, effective antipruritic medicines with novel mechanisms of action are requi...

A putative antipruritic mechanism of the phosphodiesterase‐4 inhibitor E6005 by attenuating capsaicin‐induced depolarization of C‐fibre nerves

“…E6005 is a PDE4 inhibitor developed as a topical agent for AD. We and other group have demonstrated that topical application of E6005 immediately inhibits itching behaviour as well as itch-related cutaneous nerve firing in a mouse model (4,5). This effect was not due to a local anaesthetic effect ( Figure S1).…”

“…Abstract: E6005, a potent, selective phosphodiesterase (PDE) 4 inhibitor, has been developed as a novel topical agent of atopic dermatitis (AD). It has been shown to inhibit itching in patients with AD as well in mouse models.…”

Methods for Preclinical Assessment of Antipruritic Agents and Itch Mechanisms Independent of Mast-Cell Histamine

“…31) On the other hand, a single topical application of E6005, a phosphodiesterase 4 inhibitor, decreases both spontaneous scratching and the activity of the cutaneous nerves, suggesting that E6005 inhibits itching by acting primarily in the periphery. 52,53) In ICR mice, acute cutaneous allergy increased hind-paw scratching and cutaneous nerve activity, the time courses of which were similar. 54) Terfenadine, a non-sedative H 1 histamine receptor antagonist, 55) inhibited neither the increased scratching nor nerve activity.…”

Cyclic Adenosine Monophosphate Signalling in Inflammatory Skin Disease

“…The molecule has demonstrated selective and effective inhibition of PDE4 and prevents the elaboration of proinflammatory cytokines and adhesion molecules in both lymphocytes and monocytes [138]. E6005 has also demonstrated inhibition of hapten-induced scratching in sensitized mice and spontaneous scratching in mice with chronic dermatitis [138][139][140]. Preliminary studies of 76 subjects in Japan have established safety and tolerability in healthy volunteers as well as patients with AD [140].…”