Open AccessAlleviation of Microglial Activation Induced by p38 MAPK/MK2/PGE2 Axis by Capsaicin: Potential Involvement of other than TRPV1 Mechanism/s
Author(s) -
Harsharan S. Bhatia,
Nora Roelofs,
Eduardo Muñóz,
Bernd L. Fiebich
Publication year - 2017
Publication title -
scientific reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.24
H-Index - 213
ISSN - 2045-2322
DOI - 10.1038/s41598-017-00225-5
Subject(s) - capsaicin , trpv1 , mechanism (biology) , p38 mitogen activated protein kinases , mapk/erk pathway , chemistry , microbiology and biotechnology , microglia , pharmacology , medicine , signal transduction , biology , physics , immunology , biochemistry , inflammation , transient receptor potential channel , receptor , quantum mechanics
Exaggerated inflammatory responses in microglia represent one of the major risk factors for various central nervous system’s (CNS) associated pathologies. Release of excessive inflammatory mediators such as prostaglandins and cytokines are the hallmark of hyper-activated microglia. Here we have investigated the hitherto unknown effects of capsaicin (cap) - a transient receptor potential vanilloid 1 (TRPV1) agonist- in murine primary microglia, organotypic hippocampal slice cultures (OHSCs) and human primary monocytes. Results demonstrate that cap (0.1–25 µM) significantly (p < 0.05) inhibited the release of prostaglandin E 2 (PGE 2 ) , 8-iso-PGF 2α, and differentially regulated the levels of cytokines (TNF-α, IL-6 & IL-1β). Pharmacological blockade (via capsazepine & SB366791) and genetic deficiency of TRPV1 (TRPV1 −/− ) did not prevent cap-mediated suppression of PGE 2 in activated microglia and OHSCs. Inhibition of PGE 2 was partially dependent on the reduced levels of PGE 2 synthesising enzymes, COX-2 and mPGES-1. To evaluate potential molecular targets, we discovered that cap significantly suppressed the activation of p38 MAPK and MAPKAPK2 (MK2). Altogether, we demonstrate that cap alleviates excessive inflammatory events by targeting the PGE 2 pathway in in vitro and ex vivo immune cell models. These findings have broad relevance in understanding and paving new avenues for ongoing TRPV1 based drug therapies in neuroinflammatory-associated diseases.