ArticleInternational journal of immunopathology and pharmacology
Attenuation of senile pruritus by PAC-14028-mediated downregulation of the NF-κB and MAPK pathways.
Article in International journal of immunopathology and pharmacology. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
objectiveSenile pruritus is a specific type of itching that occurs in elderly persons. Previously, we assessed antagonism of the nonselective ligand-gated cation channel transient receptor potential vanilloid 1 (TRPV1; capsaicin receptor or vanilloid receptor 1) and attenuation of atopic dermatitis by the non-steroidal TRPV1 antagonist PAC-14028 in clinical studies. The findings led us to postulate that PAC-14028 may also reduce itching in elderly people by antagonizing the TRPV1 pathway. In this study, we evaluated whether PAC-14028 modulates inflammatory markers present in senile pruritus. MATERIALS AND
methodsHaCaT, RAW264.7, and differentiated THP-1 cells under itching-inducing conditions were treated with zymosan or IL-17A and variety of experimental approaches such as molecular modeling simulations, site-directed mutagenesis, overexpression strategies, confocal microscopy, mRNA analyses, and immunoprecipitation/Western blotting analyses were assessed to check changes in inflammatory markers and explore the underlying mechanisms of PAC-14028 activity.
resultsIn the bioinformatic analyses, skin inflammation markers were found to be closely related to TRPV1, and the MAPK and NF-κB pathways were upregulated when TRPV1 was activated. In HaCaT cells, PAC-14028 was found to directly bind to TRPV1, inhibiting inflammatory cytokine gene expression and downstream MAPK and NF-κB signaling under various skin inflammatory conditions.
conclusionsBy combining the results of multiple assays, we were able to elucidate the molecular mechanism of PAC-14028 to TRPV1. Taken together, the findings indicate that PAC-14028 as a potential therapeutic agent for elderly people with pruritus.
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