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

Abstract

Blocking the neurokinin 1 receptor (NK1R) in chronic pruritus has recently been shown to reduce pruritus intensity. Both, central effects involving spinal dorsal horn neurons and peripheral effects involving cutaneous components are discussed as underlying mechanisms. A peripheral effect is assumed as aprepitant shows efficacy in inflammatory skin diseases including prurigo nodularis (PN). Within this study we therefore investigated in vivo and in vitro peripheral effects mediated by NK1R antagonism. For the in vivo study 12 patients suffering from PN received an oral four weeks treatment with aprepitant (80 mg/d). Clinical and immunohistochemical parameter were assessed before and after treatment. Expression of NK1R was analyzed by immunohistochemistry and for downstream pathways ((p)ERK1/2) by western blotting in PN patients and matched healthy volunteers. Studies were continued in vitro using cell cultures of primary keratinocytes. Effects of NK1R blocking were analyzed by western blotting for (p)ERK1/2 and by qPCR for NK1R, interleukin (IL)-1beta, -6, -8, and TNFalpha. Treatment with aprepitant reduced significantly pruritus intensity in PN patients and showed 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 upregulation and reduced expression and activation of ERK1/2 were confirmed. Furthermore, a reduced IL-expression could be shown when blocking NK1R. Our data confirm that NK1R antagonists such as aprepitant exhibit effects in the skin. Epidermal receptor expression, inflammatory interleukins and ERK1/2 signaling were targets of NK1R antagonism. This may explain partly the antipruritic effect of NK1R antagonists next to its role in the central nervous system.