Selective Inhibition of COX-2 by a Standardized CO₂Extract ofHumulus lupulus in vitroand its Activity in a Mouse Model of Zymosan-Induced Arthritis

Abstract

A standardized CO(2) extract from Humulus lupulus L. (hop extract) was investigated for its selective COX-1/2 inhibitory properties. An in vitro model of inflammation using lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (PBMC) was used as a model to investigate the effect of hop extract on PGE(2) production. COX-1/2 selective inhibition by the hop extract was investigated in a COX-1 whole blood assay (WBA) and a COX-2 WBA. To evaluate the in vivo activity of hop extract, it was administered orally to C57BL/6 mice in which inflammation of the right joint was induced by injecting zymosan intra-articularly. Ex vivo PGE(2) production of LPS-stimulated blood cells was determined. Also, the effect of hop extract on healthy and arthritic cartilage was investigated as well as effects on inflammatory joint swelling. Hop extract inhibited PGE(2) production by LPS-stimulated PBMC without compromising the metabolic activity of these cells. Furthermore, hop extract showed a decline in PGE(2) production in the COX-2 whole blood assay (WBA) with an IC(50) of 20.4 microg/mL, while in the COX-1 WBA no inhibition of PGE(2) production was observed. This indicates a COX-2 selective inhibition. The COX-1 inhibitor SC-560 inhibited PGE(2) production in the COX-1 WBA but not in the COX-2 WBA. At 2 microM, celecoxib inhibited PGE(2) production in the COX-2 WBA by 92 % and in the COX-1 WBA by 50 %. When hop extract was administered orally to C57BL/6 mice in which joint inflammation was induced with zymosan, PGE(2) production in ex vivo LPS-stimulated whole blood was significantly decreased by 24 %, suggesting that hop extract becomes bioavailable. Furthermore, oral administration of hop extract showed no negative or positive effects on healthy cartilage proteoglycan synthesis, or on zymosan-induced arthritic cartilage proteoglycan synthesis. However, no effect of oral administration of 1.25 mg hop extract daily was observed on joint swelling. In conclusion, this standardized CO(2) extract of Humulus lupulus could be a useful agent for intervention strategies targeting inflammatory disorders and/or inflammatory pain.

Hop bitter acids efficiently block inflammation independent of GRα, PPARα, or PPARγ

“…To the best of our knowledge, this is the first report where systemic administration of AA and IAA proves to be effective in decreasing an acute local inflammation. The discrepancy with the negative results for a hop CO 2 extract, earlier reported by Hougee et al [51], can most probably be explained by different routes of compound administration. Indeed, their orally administered dose of 1.25 mg crude extract, consisting of approximately 18% AA, fairly corresponds to our i.p.…”

“…In contrast, with respect to the anti-inflammatory efficacy of HBA upon oral ingestion, Hougee et al [51] have reported that a whole hop CO 2 extract, consisting of approximately 18% AA, failed to inhibit zymosan-induced joint swelling. In this report, we looked at the potential of HBA to inhibit acute local inflammation in vivo in mice, and administered AA or IAA systemically via intraperitoneal injection.…”

“…The recently increased interest in their effects on human health is justified, since they are -in contrast to the polyphenolspresent in beer in relatively large amounts, even up to 100 mg/L. Consequently, several authors have reported on the possible anticarcinogenic and anti-inflammatory properties of HBA, exemplified by the reports on the inhibition of inflammatory enzyme activity of COX-2 by humulone [33,34,51].…”

Biologically Active Compounds from Hops and Prospects for Their Use

“…Similar results were achieved using a standardized CO 2 hop extract for testing its effectiveness as COX‐1 and COX‐2 inhibitors by using a whole blood assay. Hop extract exhibited a decrease in PGE 2 production in the COX‐2 whole blood assay (IC 50 = 20.4 μg/mL), but for COX‐1 there was no inhibition of PGE 2 production (Hougee and others ).…”

Isohumulones from hops (Humulus lupulus) and their potential role in medical nutrition therapy

“…Hougee et al have described the influence of lipophilic hopsextracts on the reduction of zymosan-induced arthritis in the mouse model [27]. Minich and Bland discuss the role of the hops isohumulones and other phytochemicals on signal transduction associated with regulation of the insulin and inflammation metabolic network [28].…”