Inhibitory effect of quercetin on carrageenan-induced inflammation in rats

Abstract

We examined the effect of quercetin on the inflammatory response induced by carrageenan in the rat. Air pouches were induced subcutaneously on the backs of rats and injected with carrageenan. The rats were treated with either vehicle or quercetin at a dose of 10 mg/kg one hour before carrageenan challenge. Fourty-eight hour after carrageenan challenge, the air pourches were removed and analyzed. The volume, protein amounts and cell counts in the exudation obtained from the quercetin-treated animals were significantly reduced compared to those from vehicle-treated animals. The contents of PGE₂, TNF-α, RANTES, MIP-2 and the mRNA for cyclooxygenase-2 were also suppressed in these rats. The histological examination displayed the suppression of the inflammatory response in the pouch tissues from quercetin-treated rats. As the anti-inflammatory effect of the flavonols was more or less at the similar level among the quercetin-, isoquercitrin- or rutin-treated rats, it appeared that the sugar parts did not influence on the anti-inflammatory effect.

Our study indicated that the flavonols modulated the inflammatory response, at least in part, by modulating the prostanoid synthesis as well as cytokine production.

Introduction

Flavonols are the major dietary flavonoid particularly abundant in fruits and vegetables (McCarty, 2001). Quercetin, the main flavonol in the diet, is found not only in these products, but also in drinks such as wine and tea. It is particularly abundant in onions (0.3 mg/g fresh weight) and tea (10–25 mg/L) (Scalbert and Williamson, 2000).

It has been reported that flavonoids possess a number of biological effects such as antiallergic, anti-inflammatory, antiviral, anti-proliferative and anticarcinogenic activities Scalbert and Williamson, 2000, Parr and Bolwell, 2000. However, most of these biological effects of flavonoids have been demonstrated in the in vitro studies, and are still difficult to evaluate their role in the prevention or treatment of diseases. For example, many aglycones that are effective in the in vitro assay on the tumor growth suppression are not effective in the in vivo assay (Kamei et al., 1996). Quercetin can suppress lipopolysaccharide-induced prostaglandin E₂ production in vitro, but not in vivo (Shen et al., 2002).

Anti-inflammatory effect of quercetin has been shown in several cell culture studies Pelzer et al., 1998, Ocete et al., 1998, Sato et al., 1997, Shen et al., 2002, but its mechanism of action has not been clear. In this study, we investigated the effect of quercetin on the acute inflammation using the rat air pouch model.

The rat air pouch is a convenient model to study acute inflammation (Sedwick and Lees, 1986). It is formed by the subcutaneous injection of air over several days and is composed of a lining of cells that consists primarily of macrophages and fibroblasts. Injection of carrageenan into the fully formed air pouch produces an inflammatory granulomatous reaction characterized by a production of chemical mediators in the fluid exudates, including prostaglandin and leukotriene, as well as a significant influx of polymorphonuclear leukocytes (PMNs) and macrophages. The degree of non-immunologically-mediated, carrageenan-induced acute inflammation was characterized by the analysis of the contents of the air pouch. This was manifested by the amounts of fluid exudation, protein amounts, numbers of exudate cells and especially neutrophils, as well as the content of the inflammatory mediators. This model has been utilized to estimate the anti-inflammatory effects of the drugs (Masferrer et al., 1994).

In food, flavonoids naturally occur as glycosides, i.e. linked with various sugars. The chemical structures influence on the bioavailability of flavonoid (Manach et al., 1995). Quercetin linked with glucose, i.e. quercetin glucoside (quercitrin), and quercetin linked with rutinose, i.e. quercetin rutinoside (rutin), both occur widely in foods (McCarty, 2001). The sugar moiety also plays an important role in the biological properties. Linkage with glucose, but not other sugars, in the A-ring is determinant for suppressive activity of tumor growth by flavonoids (Kamei et al., 1996). However, there is very little understanding about a possible relationship between flavonoid structure and their anti-inflammatory activity. The influence of sugar attachment on the anti-inflammatory effect was examined using quercetin, rutin and isoquercitrin in this study. The result has shown that these flavonols have similar suppressive effect on the carrageenan-induced acute inflammation. The anti-inflammatory action of the flavonols is partly explained by their capacity to inhibit the production of cytokines and prostaglandin at the inflammatory sites.