Antagonism of NK-1R using aprepitant suppresses inflammatory response in rheumatoid arthritis fibroblast-like synoviocytes

Abstract

Chronic inflammation in fibroblast-like synoviocytes (FLSs) induced by pro-inflammatory cytokines such as TNF-a plays a key role in the pathogenesis of rheumatoid arthritis (RA). The neurokinin-1 receptor (NK-1R) is one of the G protein-coupled receptors (GPCRs) mediating the intracellular signalling of substance P (SP). However, the possible implications of NK-1R in rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) and the pathogenesis of RA have not yet been reported. In the current study, we report that NK-1R is expressed in FLSs. Importantly, NK-1R expression was found to be significantly increased in RA-FLSs compared to normal FLSs. Interestingly, we found that treatment with tumour necrosis factor (TNF)-a increased the expression of NK-1R at both the gene and protein levels. Treatment with the NK-1R antagonist aprepitant reduced TNF-a-induced expression of NADPH oxidase 4 (NOX-4) and generation of reactive oxygen species (ROS) in FLSs. Our results also display that blockage of NF-1R using aprepitant inhibited TNF-a-induced expression and secretion of proinflammatory cytokines, including interleukin-1b (IL-1b), IL-6, and IL-8. Consistently, aprepitant prevented TNF-a-induced expression of matrix metalloproteinases (MMPs), including matrix metalloproteinase-3 (MMP-3) and matrix metalloproteinase-13 (MMP-13). Mechanistically, our data demonstrate that treatment with aprepitant inhibited TNF-a-induced phosphorylation and degradation of inhibitor of NF-jB (IjBa). Notably, aprepitant attenuated TNF-a-induced nuclear translocation of nuclear factor jB (NF-jB) p65 and reduced luciferase activity of NF-jB in FLSs. The findings implicated a novel function of NK-1R in RA-FLSs. Blockage of NK-1R using its specific antagonist aprepitant might provide a new therapeutic strategy for RA.

Synthesis and Pharmacological Evaluation of Hybrids Targeting Opioid and Neurokinin Receptors

“…The co-administration of NK1 antagonists together with opioids was considered an option in chronic pain management, since NK1 blockade might be able to reduce the development of opioid tolerance, physical dependence, and withdrawal [43,44]. In preclinical animal studies, NK1 antagonists showed a promising profile, attenuating the nociceptive responses caused by inflammation or nerve damage [15][16][17]45]. However, they failed to exhibit efficacy in clinical trials [46].…”

“…Antagonism at the NK1 blocks the signals induced by SP and can inhibit the enhanced secretion of SP and increased expression of NK1 in prolonged pain states. That makes NK1 antagonists potential therapeutic agents for pain relief [15][16][17].…”

The Neurokinin-1 Receptor Antagonist Aprepitant: An Intelligent Bullet against Cancer?

“…This question is an important one, as considerable data exist showing that NK-1R antagonists (e.g., aprepitant and L-733,060) could be used for the treatment of virus infections, pruritus and cancer [ 19 , 20 , 21 , 22 ]. It is also known that aprepitant suppresses both coughing in lung-cancer patients [ 23 , 24 ] and the inflammatory response related to rheumatoid arthritis [ 25 ] and that, by promoting an anti-inflammatory effect, it also protects endothelial cells from the inflammatory response and injury [ 26 ]. To date, it is known that cancer cells (independently of the tumor type) show a common phenomenon: the overexpression of the NK-1R [ 2 , 3 , 19 ].…”

Cell reactions of inflammation focus in carrageenan secondary chronic inflammation on the background of substance P blockade

“…Inflammation is the basis of most human diseases. In local inflammatory reactions, one of the key roles is played by intercellular interactions of the connective tissue continuum, mediated by neurokinin 1 receptors (NK1P), blockade of the function of substance P through which significantly affects the cellular composition of the inflammatory focus [1].…”