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 PGE2 in activated microglia and OHSCs. Inhibition of PGE2 was partially dependent on the reduced levels of PGE2 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 PGE2 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.
Highlights
Exaggerated inflammatory responses in microglia represent one of the major risk factors for various central nervous system’s (CNS) associated pathologies
Treatment with cap prior to stimulation with LPS resulted in significant decrease of prostaglandin E2 (PGE2) release without substantial effects on other inflammatory mediators when compared with LPS
Measurement of 8-iso-PGF2α release is taken as a sensitive marker to assess free radical formation[43] and we have previously shown that LPS significantly increases the levels of 8-iso-PGF2α in primary microglia[21, 44]
Summary
Exaggerated inflammatory responses in microglia represent one of the major risk factors for various central nervous system’s (CNS) associated pathologies. Sustained inflammation or failure in normal resolution mechanisms in microglia further leads to cellular damage Under such conditions, microglia are known to release a variety of cytotoxic mediators, such as pro-inflammatory cytokines including tumour necrosis factor-alpha (TNF-α), interleukin (IL)-6 and IL-1β, reactive oxygen species, adenosine triphosphate (ATP), nitric oxide (NO), arachidonic acid (AA) derivatives, most importantly prostaglandin E2 (PGE2)[9,10,11,12,13]. COX-2 and mPGES-1 are both regulated at transcriptional levels and both enzymes are important in the synthesis of PGE2 during inflammation[21] These enzymes are regulated by a variety of intracellular signalling molecules including nuclear factor-kappa B (NF-κB) and mitogen activated protein kinases (MAPK). TRPV1 is primarily expressed in somatosensory neurons and is opened by capsaicin, heat reception (≥43 °C), protons and endovanilloids[31,32,33]
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