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

Abstract

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.

FABP7 inhibits proliferation and invasion abilities of cutaneous squamous cell carcinoma cells via the Notch signaling pathway

“…PPARβ/δ KO mice displayed increased inflammation in response to 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment ( 26 ). Notably, Slipicevic et al ( 11 ) demonstrated that FABP7 enhances the invasion and proliferation of melanoma cells via the ERK and MAPK pathways, and this pathway is crucial for the pathogenesis of cutaneous disease ( 27 ). For instance, microRNA-148a inhibits the MAPK pathway and suppresses the development of CSCC ( 28 ).…”

Chronic Nodular Prurigo: An Update on the Pathogenesis and Treatment

“…Aprepitant, an NK1R antagonist, showed a significant decrease in visual analog scale (VAS) for pruritus from 6.33 ± 1.3 to 4.46 ± 2.88 after 4-week oral administration of 80 mg/day in a study with 12 patients. Downregulation of ERK1/2 MAPK signaling with decreased expression of inflammatory B and T cell markers, CD5 and CD25 were found after aprepitant treatment, suggesting the peripheral cutaneous role of NK1R in the pathogenesis of CNPG [ 101 ]. A trend of reduction in the intensity of pruritus and clinical scores with topical aprepitant without significance was reported [ 70 ].…”

Aprepitant Inhibits JNK and p38/MAPK to Attenuate Inflammation and Suppresses Inflammatory Pain

“…Aprepitant is safe and well tolerated for currently used in clinical practice. Furthermore, it has been reported that aprepitant plays specific anti-inflammatory roles in HIV infection ( Wang et al, 2008 ; Tebas et al, 2015 ), osteoarthritis pain ( Ogawa et al, 2016 ), rheumatoid arthritis ( Liu X. et al, 2019 ), prurigo nodularis ( Agelopoulos et al, 2019 ). This drug exerts anti-inflammatory, analgesic, antiviral, and antiemetic effects ( Liu BK.…”