Neurokinin 1 receptor antagonists exhibit peripheral effects in prurigo nodularis including reduced ERK1/2 activation

• Published in: Journal of the European Academy of Dermatology and Venereology Vol. 33; no. 12; pp. 2371 - 2379
• Main Authors: Agelopoulos, K., Rülander, F., Dangelmaier, J., Lotts, T., Osada, N., Metze, D., Luger, T. A., Loser, K., Ständer, S.
• Format: Journal Article
• Language: English
• Published: England 01.12.2019
• Subjects: Adult; Aged; Female; Humans; Male; MAP Kinase Signaling System - drug effects; Middle Aged; Neurokinin-1 Receptor Antagonists - pharmacology; Neurokinin-1 Receptor Antagonists - therapeutic use; Prurigo - drug therapy
• ISSN: 0926-9959; 1468-3083; 1468-3083
• DOI: 10.1111/jdv.15905

Background Aprepitant is a neurokinin 1 receptor (NK1R) antagonist used for its antipruritic properties in dermatoses and systemic diseases. The mode of action is still unclear. A peripheral effect is assumed as aprepitant shows efficacy in inflammatory skin diseases including prurigo nodularis (PN). Objectives To investigate the peripheral effects of NK1R antagonism in PN and cell culture models. Methods Subjects with PN received an aprepitant treatment. Clinical, morphological and immunohistochemical changes were investigated in skin biopsies before and after treatment. Expression of NK1R was analysed by immunohistochemistry and for downstream pathways ((p)ERK1/2) by Western blotting in PN patients and matched healthy volunteers. Effects of NK1R blocking were analysed in cell cultures of primary keratinocytes by Western blotting for (p)ERK1/2 and by qPCR for NK1R, interleukin (IL)‐1beta, IL‐6, IL‐8 and TNFalpha. Results Aprepitant treatment showed significant reduction in pruritus intensity (P < 0.05) in PN and relevant immunohistochemical changes (down: CD5, CD25, up: CD79a, IL4). NK1R expression was higher in keratinocytes of PN patients compared to healthy controls. After treatment, epidermal NK1R expression increased while expression and activation of ERK1/2 decreased. In vitro, receptor up‐regulation and reduced expression and activation of ERK1/2 were confirmed and reduced IL‐expression shown when blocking NK1R. Conclusion Our data confirm that NK1R antagonists such as aprepitant exhibit effects in the skin. Epidermal receptor expression, epidermal inflammatory ILs, ERK1/2 MAPK signalling and cutaneous inflammatory infiltrate were targets of NK1R antagonism. This may explain partly the antipruritic effect of NK1R antagonists next to its role in the central nervous system. Linked Commentary: J.Wallengren. J Eur Acad Dermatol Venereol 2019; 33: 2221–2222. https://doi.org/10.1111/jdv.16031.