title: Alleviation of Microglial Activation Induced by p38 MAPK/MK2/PGE2Axis by Capsaicin: Potential Involvement of other than TRPV1 Mechanism/s.
abstract: 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 E2(PGE2),8-iso-PGF2α,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 PGE2in activated microglia and OHSCs. Inhibition of PGE2was partially dependent on the reduced levels of PGE2synthesising 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 PGE2pathway 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.
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, Hauptstrasse 5, D-79104, Freiburg, Germany. harsharan.singh.bhatia@uniklinik-freiburg.de.|VivaCell Biotechnology GmbH, Ferdinand-Porsche-Strasse 5, D-79211, Denzlingen, Germany. harsharan.singh.bhatia@uniklinik-freiburg.de.
authors.forename: Harsharan S
authors.identifier: 0000-0001-9912-8263
authors.initials: HS
authors.lastname: Bhatia
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, Hauptstrasse 5, D-79104, Freiburg, Germany.
authors.forename: Nora
authors.initials: N
authors.lastname: Roelofs
authors.affiliation: Maimonides Biomedical Research Institute of Córdoba, Reina Sofía University Hospital, Department of Cell Biology, Physiology and Immunology, University of Córdoba, Avda Menéndez Pidal s/n., 14004, Córdoba, Spain.|VivaCell Biotechnology España, Parque Científico Tecnológico Rabanales 21, 14014, Córdoba, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Muñoz
authors.affiliation: Department of Psychiatry and Psychotherapy, University of Freiburg Medical School, Hauptstrasse 5, D-79104, Freiburg, Germany.|VivaCell Biotechnology GmbH, Ferdinand-Porsche-Strasse 5, D-79211, Denzlingen, Germany.
authors.forename: Bernd L
authors.initials: BL
authors.lastname: Fiebich
mesh_terms: D000818:Animals; D002211:Capsaicin / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D017628:Microglia / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D050916:TRPV Cation Channels / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D002211:Capsaicin; D016207:Cytokines; D015232:Dinoprostone; D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; D050916:TRPV Cation Channels; D000099190:MAP-Kinase-Activated Kinase 2; C494484:TRPV1 receptor