A novel hybrid aspirin-NO-releasing compound inhibits TNFalpha release from LPS-activated human monocytes and macrophages

Abstract

Background: The cytoprotective nature of nitric oxide (NO) led to development of NO-aspirins in the hope of overcoming the gastric side-effects of aspirin. However, the NO moiety gives these hybrids potential for actions further to their aspirin-mediated anti-platelet and anti-inflammatory effects. Having previously shown that novel NO-aspirin hybrids containing a furoxan NO-releasing group have potent anti-platelet effects, here we investigate their anti-inflammatory properties. Here we examine their effects upon TNFα release from lipopolysaccharide (LPS)-stimulated human monocytes and monocyte-derived macrophages and investigate a potential mechanism of action through effects on LPS-stimulated nuclear factor-kappa B (NF-κB) activation.

Aspirin and immune system

“…NCX-4040 caused a concentration-dependent indirect inhibition of I-kB degradation and accumulation. A similar result was reported in a prior investigational study [71] that involved novel NO-aspirin hybrid compounds, the existing nitroaspirin (NCX-4016), aspirin, and dexamethasone. The novel NO-aspirin hybrid containing a furoxan NO-releasing group (B8; 10 μM) significantly reduced TNF-α release from LPS-activated human monocytes and macrophages through NF-kB inhibition [71].…”

Inhibitory Effects of Acetylsalicylic Acid and Ibuprofen on Interleukin-17 Production

“…When considering the data from the aforementioned studies along with our own results, it is conceivable that the inhibition of IL-17 could be secondary to the inhibition of IL-23 because PGE2 is a known inducer of IL-23 production. [9,10,13] Furthermore, these drugs had no significant effect on IL-4 or IFN-γ production. The well-known inhibitory effects of these drugs on PGE2 synthesis may be the essential cause of this effect, but we have no evidence to support this conclusion.…”

“…Recently, Alvarez-Soria et al [12] showed an inhibition in the TNF-α gene expression level in osteoarthritic patients who were being treated by NSAIDs in vivo, but they did not observe a similar effect in vitro. In addition, Turnbull et al [13] showed that aspirin can significantly inhibit the release of monocyte TNF-α. Our findings agree with these studies.…”

Nitric Oxide-Releasing Molecules for Cancer Therapy and Chemoprevention

“…At least three of these five hybrid NORMs have reported anti-inflammatory activity in the ability to inhibit cytokine release independent of the bioactive NSAID carrier: B8 (Turnbull et al 2008); GT-094 ; NCX-4016 (Fiorucci et al 2000), although this is queried by Turnbull et al (2008). Two of these five are apoptotic cytotoxins, viz., NCX-4040 (Fabbri et al 2005) and GIT-27NO (Mijatovic et al 2008), as is the sixth hybrid NORM, JS-K (Kitagaki et al 2008;Kiziltepe et al 2007).…”