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Neurokinin 1 receptor antagonists exhibit peripheral effects in prurigo nodularis including reduced ERK 1/2 activation
Author(s) -
Agelopoulos K.,
Rülander F.,
Dangelmaier J.,
Lotts T.,
Osada N.,
Metze D.,
Luger T. A.,
Loser K.,
Ständer S.
Publication year - 2019
Publication title -
journal of the european academy of dermatology and venereology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.655
H-Index - 107
eISSN - 1468-3083
pISSN - 0926-9959
DOI - 10.1111/jdv.15905
Subject(s) - tachykinin receptor 1 , mapk/erk pathway , aprepitant , medicine , prurigo nodularis , substance p , receptor , immunohistochemistry , keratinocyte , pharmacology , immunology , kinase , cell culture , biology , neuropeptide , chemotherapy , antiemetic , genetics , microbiology and biotechnology
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 NK 1R 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 NK 1R was analysed by immunohistochemistry and for downstream pathways ((p) ERK 1/2) by Western blotting in PN patients and matched healthy volunteers. Effects of NK 1R blocking were analysed in cell cultures of primary keratinocytes by Western blotting for (p) ERK 1/2 and by qPCR for NK 1R, interleukin ( IL )‐1beta, IL‐6, IL‐8 and TNF alpha. Results Aprepitant treatment showed significant reduction in pruritus intensity ( P < 0.05) in PN and relevant immunohistochemical changes (down: CD 5, CD 25, up: CD 79a, IL 4). NK 1R expression was higher in keratinocytes of PN patients compared to healthy controls. After treatment, epidermal NK 1R expression increased while expression and activation of ERK 1/2 decreased. In vitro , receptor up‐regulation and reduced expression and activation of ERK 1/2 were confirmed and reduced IL ‐expression shown when blocking NK 1R. Conclusion Our data confirm that NK 1R antagonists such as aprepitant exhibit effects in the skin. Epidermal receptor expression, epidermal inflammatory ILs, ERK 1/2 MAPK signalling and cutaneous inflammatory infiltrate were targets of NK 1R antagonism. This may explain partly the antipruritic effect of NK 1R antagonists next to its role in the central nervous system.