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

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. To study the mechanism underlying the anti-pruritic effect of E6005, we examined its effect on the activation of dorsal root ganglion (DRG) neurons associated with the itch sensation. Depolarization of DRG neurons by a transient receptor potential vanilloid 1 (TRPV 1) activator, capsaicin was attenuated by E6005 as well as by a 3 0 ,5 0 -cyclic adenosine monophosphate (cAMP) elevator, forskolin. E6005 elevated intracellular levels of cAMP in DRG cells. Taken together, these results suggest that E6005 suppresses TRPV1-mediated C-fibre depolarization through elevation of cAMP levels, thereby exerting an anti-pruritic effect. Thus, E6005 shows the potential to be a new agent for managing pruritus in various skin disorders, including AD.Abbreviations: AD, atopic dermatitis; PDE, phosphodiesterase; TRPV1, transient receptor potential vanilloid 1; DRG, dorsal root ganglion; cAMP, 3 0 ,5 0 -cyclic adenosine monophosphate.

Effect of topical phosphodiesterase 4 inhibitor E6005 on Japanese children with atopic dermatitis: Results from a randomized, vehicle‐controlled exploratory trial

“…Another important finding is that compared with the vehicle group, the 0.2% E6005 group showed a significant improvement in excoriation, which is consistent with the improvement in the pruritus score. Several antipruritic mechanisms of topical E6005 have been proposed recently: (i) direct inhibition of the PDE4B subtype expressed in dorsal root ganglion neurons; (ii) suppression of the upregulation of skin nerve growth factor levels; and (iii) inhibition of responses to proteinase‐activated receptor 2 stimulation …”

“…Several antipruritic mechanisms of topical E6005 have been proposed recently: (i) direct inhibition of the PDE4B subtype expressed in dorsal root ganglion neurons; (ii) suppression of the upregulation of skin nerve growth factor levels; and (iii) inhibition of responses to proteinase-activated receptor 2 stimulation. 7,8,22,23 The limitations of this exploratory study include its small sample size, which was not calculated from a statistical viewpoint, the concomitant use of antiallergics, the restricted availability of application sites (the skin of the face and head was not an application site), and the short study period (2 weeks), which might not have allowed adequate assessment of the clinical efficacy of treatment with topical E6005 for chronic AD. Therefore, further trials with larger sample sizes and longer study periods are warranted to confirm our findings.…”

“…E6005 is a novel selective inhibitor of phosphodiesterase 4 (PDE4), and use of E6005 may produce topical anti‐inflammatory and antipruritic effects and alleviate systemic adverse reactions . In a previous clinical study evaluating the safety and efficacy of treatment with 0.2% E6005 ointment in adult patients with AD, 0.2% E6005 treatment for up to 12 weeks was found to be adequately safe and well tolerated in the patients, and the systemic distribution of E6005 was very limited .…”

Emerging Treatment Options in Atopic Dermatitis: Topical Therapies

“…E6005 (RVT-501) is a selective PDE4 inhibitor and has shown antipruritic abilities in mouse models mimicking AD [61][62][63]. E6005 is able to suppress C-fibre depolarization and activation of the dorsal root ganglion through elevation of cAMP levels, thereby exerting an antipruritic effect [62].…”

“…E6005 is able to suppress C-fibre depolarization and activation of the dorsal root ganglion through elevation of cAMP levels, thereby exerting an antipruritic effect [62]. An early phase I/II study evaluating safety, tolerability, and pharmacokinetics showed no application site adverse event related to treatment and systemic absorption was below the detection limit [64].…”