Elsevier

Il Farmaco

Volume 56, Issue 9, 1 August 2001, Pages 683-687
Il Farmaco

Anti-inflammatory properties of plant flavonoids. Effects of rutin, quercetin and hesperidin on adjuvant arthritis in rat

https://doi.org/10.1016/S0014-827X(01)01111-9Get rights and content

Abstract

The anti-inflammatory activities of three flavonoids were investigated in rats using the Mizushima et al. model of acute and chronic inflammation. Intraperitoneal administration of rutin, quercetin (flavonols) and hesperidin (flavanone), given at daily doses equivalent to 80 mg/kg, inhibited both acute and chronic phases of this experimental model of inflammation. Rutin was the most active in the chronic phase.

Introduction

Flavonoids are polyphenolic compounds that occur ubiquitously in foods of plant origin. Over 4000 different flavonoids have been described [1], and they are categorized into flavonols, flavones, catechins, flavanones, anthocyanidins and isoflavonoids. Flavonoids have a variety of biological effects in numerous mammalian cell systems, in vitro as well as in vivo. They have been shown to exert antimicrobial, antiviral, antiulcerogenic, cytotoxic, antineoplastic, mutagenic, anti-inflammatory, antioxidant, antihepatotoxic, antihipertensive, hypolipidemic and antiplatelet activities [2]. Flavonoids were investigated in models of inflammation in rats and were found to possess significant activity in both proliferative and exudative phases of inflammation [3]. Studies on the in vivo anti-inflammatory activity of flavonoids showed that inhibition of both paw edema and edema was caused by croton oil [4]. We have previously reported that flavonoids showed anti-inflammatory activity and inhibited the development of the induced granuloma, mostly when a catechol or guaiacol-like B ring is contained in the compound structure [5].

Some flavonoids, such as quercetin, blocked both the cyclooxygenase and lipooxygenase pathways at relatively high concentrations, while at lower concentrations, the lipooxygenase pathway was the primary target of inhibitory anti-inflammatory activity [6]. A micronized flavonoid complex, consisting of 90% diosmin+10% hesperidin (Daflon 500 mg), protected against the formation of perivascular edema and its therapeutic values were determined by its inhibitory activity on the inflammatory process [7]. On the other hand, when administered subcutaneously, hesperidin (hesperetin-7-rutinoside), although inactive per os, exhibited significant anti-inflammatory activity on rat paw edema induced by both carrageenan and dextran and on carrageenan pleurisy, without producing the side effects that are caused by other classes of anti-inflammatory drugs [8].

Some authors have reported that flavonoids such as rutin (quercetin-3-rutinoside) and quercetin show antioxidant activity [9], [10]. In rheumatoid arthritis, acute and chronic inflammation occur together in synovial pannus. Features of chronic inflammation, inducing altered expression of matrix metalloproteinases and formation of new blood vessels, are stimulated by prostaglandins [11]. In the regulation of prostaglandin production, cyclooxygenase is an enzyme that represents the critical control point [12]. This enzyme is a target of pharmacologic action of the non-steroidal anti-inflammatory drugs.

The pharmacological treatment continues to be inadequate in preventing the progression of this disease to the stage of irreversible joint erosion and deformity.

The development of new anti-inflammatory drugs continues to be essential not only because of the need for compounds that will prevent joint destruction but also because compounds with unique mechanism of action can be used as tools to further clarify the pathogenesis of rheumatoid arthritis [13].

There is growing interest in the pharmacological potential of natural products and the purpose of our study, therefore, was to investigate the ability of quercetin, rutin and hesperidin to inhibit acute and chronic inflammation on experimental arthritis. Scheme 1, Scheme 2

Section snippets

Animals

Experimental animals: female Wistar rats, weighing 150–180 g, were used in these experiments. They were randomly assigned to different groups and a period of 4 days was allowed for adaptation. Animals were provided with food (standard chow diet manufacturer) and water ad libitum and were maintained at a constant temperature of 22±1°C and humidity of 55±5%.

Anti-inflammatory evaluation

Experimental arthritis was induced in rats according to the method of adjuvant-carrageenan-induced inflammation (ACII) [14]. A total of 35

Results

The effect of flavonols (rutin and quercetin) and flavanone (hesperidin) are shown in Table 1.

There was no significant difference in paw edema between basal measure (day 0) prior to adjuvant and that just prior to the carrageenan injection (day 6, 0 h).

Rutin and quercetin decreased the edema produced in the acute phase, induced 3–5 h after carrageenan injection (day 6) but hesperidin was active only at 3 h.

In the chronic phase (days 7–30) only rutin was significantly active on all the days.

Discussion

The experimental model of inflammation has acute and chronic phases and has been proposed as a suitable and simple model system for evaluating potential anti-arthritic agents. In summary, the data reported herein suggest the anti-inflammatory activity of flavonoids in adjuvant arthritis.

In the inflammatory process there are fenestration of the microvasculature, leakage of the elements of blood into the interstitial spaces and migration of leukocytes into the inflamed tissue. During this complex

Acknowledgements

The authors are grateful to the Department of Organic Chemistry, University of San Luis, for providing the plant flavonoids.

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