The activity of medicinal plants and secondary metabolites on eosinophilic inflammation

Pharmacological Research 62 (2010) 298–307

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Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs

Review

The activity of medicinal plants and secondary metabolites on eosinophilic inflammation Alexandre P. Rogerio a,∗ , Anderson Sá-Nunes b , Lúcia H. Faccioli c a

Universidade Federal do Triângulo Mineiro, Av. Getúlio Guaritá s/n, Uberaba, MG 38025-440, Brazil Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, Av. Prof. Lineu Prestes, 1730, São Paulo, SP 05508-900, Brazil c Departamento de Análises Clínicas, Toxicológicas e Bromatológicas Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café s/n, Ribeirão Preto, SP 14040-903, Brazil b

a r t i c l e

i n f o

Article history: Received 8 December 2009 Received in revised form 16 April 2010 Accepted 27 April 2010 Keywords: Medicinal plants Secondary metabolites Eosinophils Anti-eosinophilic activity

a b s t r a c t Eosinophils are leukocytes that are present in several body compartments and in the blood at relatively low numbers under normal conditions. However, an increase in the number of eosinophils, in the blood or in the tissues, is observed in allergic or parasitic disorders. Although some progress has been made in understanding the development of eosinophil-mediated inflammation in allergic and parasitic diseases, the discovery of new compounds to control eosinophilia has lagged behind other advances. Plant-derived secondary metabolites are the basis for many drugs currently used to treat pathologic conditions, including eosinophilic diseases. Several studies, including our own, have demonstrated that plant extracts and secondary metabolites can reduce eosinophilia and eosinophil recruitment in different experimental animal models. In this review, we summarize these studies and describe the anti-eosinophilic activity of various plant extracts, such as Ginkgo biloba, Allium cepa, and Lafoensia pacari, as well as those of secondary metabolites (compounds isolated from plant extracts), such as quercetin and ellagic acid. In addition, we highlight the medical potential of these plant-derived compounds for treating eosinophil-mediated inflammation, such as asthma and allergy. © 2010 Elsevier Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . TH 2 immune responses and eosinophil trafficking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Treatment of eosinophil-mediated inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Plants with anti-eosinophil activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

298 299 299 300 303 304 304

1. Introduction

Abbreviations: 5-LO, 5-lipoxygenase; BALF, bronchoalveolar lavage fluid; CD, cluster of differentiation; Cys-LTs, cysteinyl leukotrienes; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; EGID, eosinophilic gastrointestinal diseases; EPO, eosinophil peroxidase; GM-CSF, granulocyte-macrophage colony-stimulating factor; hRSV, human respiratory syncytial virus; IFN-␥, interferon-gamma; IgE, immunoglobulin E; IL, interleukin; LTs, leukotrienes; MBP, major basic protein; NF-␬B, nuclear factor-␬B; OVA, ovalbumin; PAF, plateletactivating factor; TGF-␣/␤, transforming growth factor-alpha/beta; TH , T helper; TNF-␣, tumor necrosis factor-alpha; VLMS, visceral larva migrans syndrome. ∗ Corresponding author. Tel.: +55 34 3318 5813; fax: +55 34 3312 1487. E-mail addresses: [email protected], [email protected] (A.P. Rogerio). 1043-6618/$ – see front matter © 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.phrs.2010.04.005

The eosinophil granulocyte was first described by Paul Ehrlich in 1879 [1], although some researchers had identified eosinophillike cells or its products a few years earlier. Eosinophils are derived from CD34+ hematopoietic progenitor cells within the bone marrow, which differentiate into mature eosinophils in the presence of the eosinophilopoietins [interleukin-(IL-)3, IL-5 and granulocytemacrophage colony-stimulating factor (GM-CSF)] [2–5] under the control of specific transcription factors [6–8]. Eosinophils are multifunctional cells and important sources of various inflammatory and regulatory cytokines [IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, IL-13, IL-16, IL-18, transforming growth factor-alpha/beta (TGF-␣/␤), tumor necrosis factor-alpha (TNF-␣), interferon-gamma (IFN-␥)], chemokines (CCL3, CCL5, CCL11, and others), and lipid

A.P. Rogerio et al. / Pharmacological Research 62 (2010) 298–307

mediators [leukotrienes (LTs) and platelet-activating factor (PAF)] [9–11]. In addition, eosinophils produce and secrete four principal cationic proteins: major basic protein (MBP), eosinophil-derived neurotoxin (EDN), eosinophil cationic protein (ECP), and eosinophil peroxidase (EPO), all of which can cause damage to tissues [11–14]. In recent decades, considerable progress has been made in our understanding of eosinophil functions under physiologic and pathologic conditions by using molecular and biochemical assays, as well as knockout and transgenic animals. However, the true biologic role of eosinophils remains obscure [15,16]. Under physiologic conditions, the average frequency of eosinophils in peripheral blood is low (1–3%), although these cells are part of the resident cell population in tissues such as the gastrointestinal tract, thymus, and others [17–19]. Nevertheless, in the presence of allergic and parasitic diseases, the production and output of eosinophils by the bone marrow increase, leading to their accumulation in the blood (eosinophilia) as well as in different organs and tissues [2]. 2. TH 2 immune responses and eosinophil trafficking Initial exposure of the immune system to allergens or parasitic antigens leads to the activation of a subset of T cells, known as T helper 2 (TH 2) cells, which orchestrate the immune response to these exogenous antigens by secreting cytokines, including IL4, IL-5 and IL-13 [20–23]. IL-4 is the major differentiation factor for the TH 2-type immune response and also blocks differentiation towards a TH 1 axis by downregulating the transcription of IFN-␥ [24,25]. In addition, in conjunction with IL-13, IL-4 also induces immunoglobulin E (IgE) class switching in B cells [26,27]. Most of the IgE produced is bound to mast cells and basophils by their high-affinity Fc receptor (Fc␧RI) [28,29]. Subsequent exposure of immune cells to antigen induces degranulation of IgE-sensitized mast cells and release of both pre-formed and newly generated mediators, a process known as immediate or type I hypersensitivity [28]. These mediators, alone or in conjunction with TH 2 cytokines, increase the contractility of smooth muscle cells, the permeability of epithelial cells and the production of mucus. In addition, these mediators trigger the recruitment of macrophages, eosinophils, and basophils to the inflammatory site [30]. IL-5 is the major cytokine involved in the accumulation of eosinophils in the blood during allergic inflammation and parasitic infections. This cytokine is essential for eosinophil migration from the bone marrow to the blood [21,31] and specifically supports terminal differentiation and proliferation of eosinophil precursors, as well as the activation of mature eosinophils [32–35]. However, residual tissue eosinophils are still found in IL-5-deficient mice [36,37] and asthmatic patients treated with anti-IL-5 monoclonal antibody [38], suggesting the existence of a minor IL-5-independent eosinophil population. The trafficking of eosinophils into physiologic or inflammatory sites involves the interaction of cytokines, chemokines, lipid mediators and adhesion molecules. Under normal conditions, the migration of eosinophils is regulated by the constitutive expression of eotaxin-1 (CCL11; a selective chemokine of eosinophils) in the gastrointestinal tract, thymus and mammary glands [17,39,40]. Notably, trafficking of eosinophils into the uterus is also regulated by estrogen [39]. Under inflammatory conditions, the mediators implicated in leukocyte migration, IL-5 and eotaxins (CCL11, CCL24 and CCL26), have been shown to cooperate in selectively recruiting eosinophils [41–45], and recent studies have demonstrated an important role for the eotaxins receptor, CCR3, in eosinophil recruitment to tissues and body compartments [46]. In addition, IL-5 increases the pool of eotaxin-responsive cells and primes eosinophils to respond to CCR3 ligands [47]. Moreover, IL-4 and IL-13 are potent inducers of eotaxins and when eotaxins are exogenously administered, they collaborate with IL-5 to induce production of IL-13 in the lungs [47], suggesting the existence of a

299

positive feedback loop between specific cytokines and chemokines in eosinophil recruitment. In allergic or parasitic diseases, the local chemokine network appears to regulate eosinophil accumulation independently of IL-5, a mechanism that could also play an important role in eosinophil-mediated inflammatory processes [40]. In addition, lipid mediators seem to have important roles in allergic and parasitic diseases. These mediators include leukotriene B4 (LTB4 ) and the cysteinyl leukotrienes (Cys-LTs): LTC4 , LTD4 and LTE4 . LTB4 induces the activation and chemotaxis of neutrophils and eosinophils [48–50], while Cys-LTs induce constriction of airway smooth muscle, subepithelial fibrosis, plasma leakage and mucus hypersecretion [51]. These lipid mediators are produced by a variety of cells, including eosinophils, mast cells, and macrophages [52], from the metabolism of membrane-derived arachidonic acid via the activity of the enzyme 5-lipoxygenase (5-LO) and its helper protein 5-LO-activating protein [53–55]. Although eosinophil recruitment and eosinophilia are hallmarks of asthma and parasitic diseases, their presence is also associated with the pathogenesis of other conditions. For example, in inflammatory bowel disease, eosinophils usually represent only a small percentage of the infiltrating leukocytes [56,57]. However, their presence has been proposed as a negative prognostic indicator [56,58]. High accumulation of eosinophils without a known cause is also observed in eosinophilic gastrointestinal diseases (EGID) and is believed to be caused by TH 2-derived cytokines and chemokines [59]. Eosinophils have also been detected in the bronchoalveolar lavage fluid (BALF) of patients infected with respiratory syncytial virus (hRSV; a RNA virus of the family Paramyxoviridae) [60–62]; however, the role of eosinophils in the pathogenesis of this viral infection is still unclear. 3. Treatment of eosinophil-mediated inflammation Pharmacologic compounds capable of inhibiting eosinophil function or migration are desirable for the treatment of patients with atopy/allergy, parasitic disorders and other eosinophil-related diseases. The majority of clinically important medicines used for the treatment of inflammation of different origins, including those mediated by eosinophils, belong to the steroid (e.g., corticosteroids) or non-steroid (e.g., LT inhibitors or antagonists) anti-inflammatory drug families. Corticosteroids are the most established therapeutics for controlling virtually all types of inflammatory reactions, and they exert a strong effect on leukocyte recruitment when administered locally or systemically [63–65]. The effects of steroids on eosinophil distribution and function seem to result from a combination of direct and indirect mechanisms. The potential targets of glucocorticoid-mediated action include eosinophil generation, priming and recruitment of eosinophils and the production/release of eosinophil chemoattractants by distinct cellular sources, including mast cells, endothelial cells, epithelial cells, fibroblasts and other cell types [66–68]. The most striking effect of corticosteroids is their ability to inhibit the expression of multiple inflammatory mediators whose genes are regulated by transcription factors, such as nuclear factor-␬B (NF-␬B) [65]. Thus, inhibition of the NF-␬B pathway is associated with suppressed expression of genes encoding cytokines (e.g., IL-5), chemokines (e.g., eotaxins) and adhesion molecules (e.g., integrins), all of which play critical roles in controlling eosinophil recruitment [11,69,70]. Inhibitors of LT synthesis (such as zileuton, which directly inhibits 5-LO) or CysLT1 antagonists (such as montelukast, zafirlukast, and pranlukast) may also have complementary effects for the therapeutic treatment of asthma by reducing the requirement for corticosteroid use [51,55,71]. Although the drugs described above have potent antiinflammatory activity (individually or combined), they also have adverse side effects that severely limit their long-term use.

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Fig. 1. Potential target of medicinal plants or secondary metabolites in eosinophilic inflammation.

A promising approach for the treatment of allergy and other related diseases is the development of therapies to control the TH 2 immune response. For example, monoclonal antibodies against IgE [72], IL-4 [73], IL-5 [74] and IL-13 [75] have been tested in animal models, as well as in human preclinical trials. Although some of these antibodies have failed to demonstrate therapeutic efficacy, additional studies are still in progress [30]. Several other mediators, such as endothelins [76,77], PAF [78], tachykinins [79], bradykinin [80], adenosine [81] and others, are involved in the induction of eosinophilia and eosinophil recruitment. Consequently, antagonists to these mediators may also have therapeutic potential for the control of eosinophil-mediated inflammation. 4. Plants with anti-eosinophil activity A number of experimental models are able to reproduce one or more features of allergic responses and have been studied for a few decades, such as the classical ovalbumin-(OVA-)induced allergic asthma model [82,83] and the Toxocara canis helminth infection, also known as visceral larva migrans syndrome (VLMS) or toxocariasis [21,84–86]. Some other models induce recruitment of different cell types, predominantly eosinophils; these models include acute peritonitis induced by the polysaccharide-rich F1 fraction from Histoplasma capsulatum yeast [87,88] or the inoculation of a variety of molecules, such as cytokines [89], chemokines [90,91], lipid mediators [48,92,93] and several other substances. These experimental models differ from each other in the kinetics (acute or chronic) and localization (local or systemic) of the eosinophilic response. A more detailed description of the most commonly used models of eosinophilia, including the ones described above, and their characteristics can be found in Table 1. In the course of a continued search for bioactive natural products derived from plants, several groups, including our own,

have successfully employed experimental models to screen the pharmacologic activities of plant extracts, as well as isolated compounds (secondary metabolites). Thus, many plant extracts and secondary metabolites have been shown to reduce eosinophilia and/or eosinophil recruitment (Fig. 1). We have generated a catalog that describes many plant-derived products reported in the literature and includes information on administration routes, doses and species employed for the study of each type of preparation or isolated compound. Tables 2 and 3 display lists of published studies on different plant extracts and secondary metabolites, respectively. In this section, the major findings in the field will be discussed, with special attention to those agents already tested in preclinical and clinical human studies. Ginkgo biloba L. (Ginkgoaceae) is one of the most well-known plants in Chinese culture and has been used for therapeutic purposes for about 1,000 years. Its extracts are marketed worldwide to prevent or delay cognitive impairment associated with aging or neurodegenerative disorders. In addition, G. biloba leaves have been used for the treatment of airway diseases, such as asthma and bronchitis [94]. In fact, treatment of asthmatic patients with fluticasone propionate (by aerosol; 1,000 mg) plus a daily oral dose of G. biloba extract (240 mg) significantly reduced eosinophil and lymphocyte numbers in BALF compared to the asthmatic subgroups treated with fluticasone propionate alone [95], confirming the potential anti-asthmatic activity of the extract. Additionally, a concentrated liquor of G. biloba leaves also provided improvement of clinical symptoms and pulmonary functions of asthmatic patients when orally administrated [96]. Two major anti-eosinophilic mechanisms of G. biloba seem to explain the observed effects. First, the total flavonoid content in G. biloba leaves presents a pro-apoptotic effect on eosinophils [97]. Second, the ginkgolide BN52021, isolated from G. biloba, has been described as a specific PAF antagonist, inhibiting human eosinophil chemotaxis in vitro [98] and eosinophil infiltration into the lungs of OVA-sensitized guinea pigs

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301

Table 1 Experimental models of eosinophil-mediated inflammationa . Model

Eosinophil localization

Kinetics of eosinophil increase

References

Experimental allergic asthma model induced by OVA sensitization and challenge

Lungs (intranasal or aerosol challenge), pleural cavity (intrathoracic inoculation), skin (intradermal challenge)

[118,45–150]

Infection with T. canis eggs

Blood, peritoneal cavity, lungs

Infection with Strongyloides venezuelensis Inoculation of F1 fraction (␤-glucan) from yeast wall of H. capsulatum LTB4 administration

Blood, peritoneal cavity, lungs

From 1 to 24 days after challenge (model-dependent) Peak at 1–3 days after challenge (model-dependent) From 3 to 48 days Peak at 18–24 days Peak at 14 day

[21,20,31,151,117,152] [205]

Peritoneal cavity (intraperitoneal inoculation)

From 24 to 168 h Peak at 48 h

[87,88,153]

Measured at 2 and 24 hb

[48,92,152]

Eotaxin administration

Peritoneal cavity (intraperitoneal inoculation), bronchoalveolar lavage fluid (aerosol), skin (intradermal inoculation) Lungs (aerosol or intratracheal inoculation)

[91,155]

LPS administration

Pleural cavity (intrathoracic inoculation)

IL-5 administration

Bronchoalveolar lavage fluid (intratracheal inoculation), skin (intradermal inoculation), peritoneal cavity (intraperitoneal inoculation) Blood (intravenous inoculation) Skin (intradermal inoculation), bronchoalveolar lavage fluid (intratracheal inoculation)

From 6 h to 7 daysb Peak at 24 h From 24 to 96 h Peak at 48 h From 5 to 24 h Peak at 24 h From 30 min to 3 h Peak at 1 h From 2 to 4 hb (skin); 6–24 h (peritoneal cavity) Peak at 2 hb (skin); 24 h (peritoneal cavity) Measured at 48 h (bronchoalveolar lavage fluid) Measured at 4, 24 and 48 hb No apparent peak 48 h Peak at 48 hb From 4 to 48 h Peak at 24 h From 2 to 14 days (blood) From 2 to ∼80 days (lung) Peak at 7 days From 12 to 48 hb Peak at 24 h (mouse) and 48 h (ratb ) From 30 min to 6 hb Peak at 6 hb Measured at 2 and 4 h

IL-8 administration

Polybia paulista venom inoculation

Peritoneal cavity (intraperitoneal inoculation)

Large volume of saline

Peritoneal cavity (intraperitoneal inoculation)

Stem cell factor inoculation

Pleural cavity (intrathoracic inoculation)

Inoculation of sephadex particles

Blood and lungs (intravenous inoculation) Peritoneal cavity (intraperitoneal inoculation)

Zymosan-activated plasma inoculation C5a inoculation

Skin (intradermal inoculation)

Carrageenan

Pleural cavity (intrathoracic inoculation)

Bradykinin

Pleural cavity (intrathoracic inoculation)

PAF inoculation

Pleural cavity (intrathoracic inoculation), skin (intradermal inoculation) Pleural cavity (intrathoracic inoculation), skin (intradermal inoculation) Peritoneal cavity (intraperitoneal inoculation)

Compound 48/80 DMTI-II inoculation a b

Skin (intradermal inoculation)

From 6 to 48 hb Peak at 24 h From 24 to 48 hb Peak at 24 h From 6 to 120 h (pleural cavity) Peak at 24 h (pleural cavity) From 24 to 96 h (pleural cavity) Peak at 24 h (pleural cavity) From 4 to 24 h Peak at 16 h

[156] [89,157–159]

[90,157,159]

[160] [154,159] [149] [161–165]

[48] [48,90] [166] [166] [93,167] [48,93] [168]

Parasitic model, except T. canis model and infection with Strongyloides venezuelensis, not included. No further time points were analysed.

[99]. Unfortunately, despite its ability to suppress PAF- and antigeninduced bronchoconstriction in normal subjects, this compound was not able to inhibit the neutrophilia and eosinophilia in asthmatic patients under the same conditions [100]. Allium cepa L. (Alliaceae), commonly known as onion, is among the oldest of all cultivated plants, and its extracts have been used as therapeutic agents for thousands of years. Their effects include antimicrobial, antithrombotic and antitumor properties, among others [101]. In the therapy, a cream, which includes onion in its composition, has been used in human to treat burn scars, keloids and contractures [102]. Interestingly, in the murine model of OVA-induced allergic airway inflammation, A. cepa extract (50–200 mg/kg, p.o.) significantly decreased eosinophil numbers in BALF, as well as other hallmarks of asthma [103]. The flavonoid quercetin is found in high amounts in A. cepa. This secondary metabolite is also found in other vegetables and several fruits consumed in a regular diet, as well as in a wide variety of plants [104,105]. Usually quercetin is linked to sugars, such as glu-

cose (quercetin-3-glucoside; isoquercitrin) or rutinose (rutin), and exhibits many activities in humans, such as in overweight-obese carriers [106,107], and in animals, such as anti-inflammatory and anti-allergic properties [108], among other activities. By further exploring the medicinal properties of plant-derived molecules, we have demonstrated, for the first time, that treatment with quercetin (10 mg/kg) reduces eosinophils in blood, BALF and pulmonary parenchyma in the murine OVA-induced allergic model [109]. Similar results have been found by many others employing the same experimental model in mice and guinea pigs under different treatment routes with quercetin [110–112]. Thus, the potential effects of A. cepa extract and, perhaps, other plants in inhibiting eosinophilic inflammation [101,113] may be due to the quercetin content or to the association (additive or synergistic) of this compound with other secondary metabolites. Another plant with anti-eosinophilic potential is Lafoensia pacari, Jaumes St. Hilaire (Lythraceae). Its extract is traditionally used by the population of Mato Grosso State, Brazil to treat inflam-

302

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Table 2 Plant extracts with anti-eosinophil activitya . Plant species

Formulation

Model/disease

Species tested

Effective dose/route

References

Actinidia arguta (Siebold & Zucc.) Planch. ex Miq. (Actinidiaceae)

Dried fruits boiled in distilled water for 3 h. Extract filtered and concentrated, followed by a freeze-drying process. Powder dissolved in distilled water Ethanol extract from dried leaves and branches Aged garlic bulbs peeled, homogenized with distilled water, filtered and centrifuged. NH4 SO4 added to the supernatant (5%) and the solution centrifuged at 3600 × g for 30 min. Pellet resuspended in saline, dialyzed against buffered saline and sterilized Bulbs dried, finely ground, and percolated in 50% ethyl alcohol for 16 h at room temperature. This procedure was repeated four times, and the pooled extract was dried under reduced pressure (50 ± 1 ◦ C) in a rotary evaporator. The extract, was further partitioned into butanol Ethanol extract prepared (DA-9601) and dissolved in 3% hydroxypropyl methylcellulose Herbal preparation of the gum resin, called “S compound” (trade name). Sold by Rahul Pharma, Jammu Extract produced by Beaufour Ipsen, France (no details published) Plant materials were extracted three times with distilled water at 100 ◦ C for 2 h separately, filtered and evaporated on a rotator evaporator and finally dried using a freeze drier Stem bark ethanol extract dried to obtain a powder. Aqueous suspension of powder prepared for treatment Stem bark aqueous extract prepared by decoction and dried to obtain a powder. Aqueous suspension of powder prepared for treatment Aqueous extract prepared by infusion of dried leaves, filtered and lyophilized. Powder dissolved in saline for treatment Rice bran extracted with 70% ethanol for 24 h. Extract was filtered, concentrated and lyophilized. The dried extract (DA-9201) was suspended in a 1% hydroxypropyl methylcellulose solution for treatment Fresh leaves extracted with 1% (w/v) citric acid at 90 ◦ C for 30 min. Extract concentrated and mixed with n-butanol. Resulting n-butanol layer dried and the residue dissolved in distilled water for treatment Extract manufactured using liquid carbon dioxide with leaves of the cultivated Petasites variety PETZELL –

OVA-induced asthma

Mouse

300 mg/kg, p.o.

[169]

OVA-induced asthma

Mouse

200 and 400 mg/kg, p.o.

[170]

OVA-induced asthma

Mouse

200 mg/kg, i.p.

[113]

OVA-induced asthma

Mouse

50–200 mg/kg, p.o.

[103]

OVA-induced asthma

Mouse

30 and 100 mg/kg, p.o.

[171]

Bronchial asthma

Human

300 mg, p.o.

[172]

Asthma

Human

240 mg, p.o.

[95]

OVA-induced asthma

Mouse

200 and 400 mg/kg, p.o.

[173]

Toxocariasis F1-induced peritonitis OVA-induced asthma Toxocariasis

Mouse

200 mg/kg, p.o.

[31,119,117]

Mouse

50 mg/kg, p.o.

[174]

Allergic pleurisy, OVA-induced asthma

Mouse

2 mg/kg, i.p.

[175]

OVA-induced asthma

Mouse

100 and 300 mg/kg, p.o.

[176]

Asthma induced by house dust mite allergen

Mouse

1.5 mg/day, p.o.

[177]

Allergic rhinitis OVA-induced asthma

Human Mouse

8 mg/three times a day, p.o. 100 ␮g/mouse, i.n.

[178,179]

Allergic asthma

Rat

–

[180]

Allergic pleurisy

Mouse

100 mg/kg, p.o.

[181]

Asthma

Human

40 or 60 mg

[182]

OVA-induced asthma

Mouse

45–720 mg/kg, i.p.

[183]

Ailanthus altissima Swingle (Simaroubaceae) Allium sativum L. (Liliaceae)

Allium cepa L. (Liliaceae)

Artemisia asiatica Nakai (Asteraceae) Boswellia serrata Roxb. (Burseraceae) Ginkgo biloba L. (Ginkgoaceae) Citrus reticulata, Blanco (Rutaceae), Pinellia ternata (Thunb.) Breit (Araceae) and their combination Lafoensia pacari Jaumes St. Hilaire (Lythraceae) Mangifera indica L. (Anacardiaceae)

Nidularium procerum Lindiman (Bromeliaceae) Oryza sativa L. (Poaceae)

Perilla frutescens Britton (Laminaceae)

Petasites hybridus L. (Asteraceae) Salvia miltiorrhiza Bunge. (Labiatae)b Syzygium cumini (L.) Skeels (Myrtaceae)

Tripterygium wilfordii Hook.f. (Celastraceae)b Zingiber officinale Rosoce (Zingiberaceae)

a b

Aqueous extract from fresh leaves prepared by decoction, filtered and lyophilized. Powder dissolved in distilled water for treatment – ◦

Rhizoma dried at 70 C, ground to a fine powder and soaked in distilled water for 24 h. Extract was filtered, evaporated, concentrated and freeze dried. Aqueous solutions were prepared for treatment

Organized in alphabetic order. No access to the entire manuscript, no answer from the corresponding authors.

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303

Table 3 Secondary metabolites with anti-eosinophil activitya . Secondary metabolite

Chemical class

Model or disease

Dose and route

References

Andrographolide Apigenin Astragaloside IV Caffeic acid phenethyl ester Curcumin Ellagic acid

Diterpenoid Flavonoid Triterpene Polyphenol Polyphenol Polyphenol

0.5 and 1 mg/kg, i.p. 5 and 10 mg/kg, i.p. 50 mg/kg, p.o. 10 mg/kg, i.p. 20 mg/kg, i.p. 1 and 10 mg/kg, p.o.

[184] [185] [186] [187] [188] [119,118]

Epigallocatechin-3-gallate Genistein Gingerol Ginkgolide Glycyrrhizin ␣-Humulene Isoquecetrin Lupeol Luteolin Luteolin-7-O-glucoside Narirutin Kaempferol Nicotine

Flavonoid Flavonoid Polyphenol Terpenoid Triterpene Sesquiterpenes Flavonoid Triterpene Flavonoid Flavonoid Flavonoid Flavonoid Alkaloid

Allergic asthma in mice Allergic asthma in mice Allergic asthma in mice Allergic asthma in mice Allergic asthma in mice Peritonitis induced by H. capsulatum in mice Allergic asthma in mice Allergic asthma in guinea pigs Allergic asthma in guinea pigs Allergic asthma in mice Allergic asthma in guinea pigs Allergic asthma in mice Allergic asthma in mice Allergic asthma in mice Allergic asthma in mice Allergic asthma in mice Allergic asthma in mice Allergic asthma in mice Allergic asthma in mice Allergic asthma in rat

[129] [189] [183] [99] [190] [191] [109] [192] [193] [194] [195] [196] [197]

Nobiletin Piperineb 1H,8H-Pyrano [3,4-c]pyran-1,8-dioneb Quercetin

Flavonoid Polyphenol – Flavonoid

3-O-Methylquercetin Theophylline Thymoquinone Warifteine

Flavonoid Alkaloid Quinone Alkaloid

25 mg/kg, i.p. 15 mg/kg, i.p. 14 mg/kg, i.p. 25 mg/kg, p.o. 5–20 mg/kg, p.o. 50 mg/kg, p.o. 15 mg/kg, p.o. 60 mg/kg, p.o. 10 mg/kg, p.o. 50 and 100 mg/kg, p.o. 10 mg/kg, p.o. 30 and 90 mg/kg, s.c. 1 mg/kg, osmotic pump implanted s.c 1.5 and 5 mg/kg, i.p. – – 10 mg/kg, p.o. 10 mg/ml, inhalation 7.5 mg/kg, p.o. 8 and 16 mg/kg, i.p. 3–30 ␮mol/kg, i.p. 400 mg/day, p.o. 3 mg/kg, i.p. 50 ␮g/animal, p.o.

a b

Allergic asthma in rats Allergic asthma in mice Allergic asthma in mice Allergic asthma in mice Allergic asthma in guinea pigs Allergic asthma in guinea pigs Allergic asthma in mice Allergic asthma in mice Human asthma Allergic asthma in mice Allergic pleurisy and asthma models in mice

[198] [199] [200] [109,110–112,201]

[202] [132] [203] [204]

Organized in alphabetic order. No access to the entire manuscript, no answer from the corresponding authors.

mation and gastric ulcers [114,115]. In a clinical trial, however, L. pacari methanolic extract (500 mg) failed to eradicate Helicobacter pylori in dyspeptic urease-positive patients, although the extract was well-tolerated and many patients reported relief of symptoms [116]. Employing the asthma model induced by T. canis infection, our group demonstrated that oral treatment with an ethanolic extract of L. pacari (200 mg/kg) decreased the number of eosinophils recruited to several tissues and compartments such as blood, BALF and the peritoneal cavity [31,117]. Furthermore, in the OVA-induced asthma model, L. pacari extract was effective in decreasing eosinophil recruitment and the production of IL-4, IL5, and IL-13 in BALF [118]. In addition, L. pacari extract did not demonstrate cytotoxicity, either in vitro [31] or in vivo [117]. In an attempt to identify the molecule(s) responsible for the antieosinophil activity of L. pacari extract, we have used a model of peritonitis induced in mice by exposure to the F1 fraction of the H. capsulatum yeast wall [87]. This model of acute and localized eosinophilia was suitable for the bioassay-guided fractionation of L. pacari extract. In this manner, we were able to isolate and chemically characterize ellagic acid (a polyphenol) as the major active component in L. pacari extract [119]. To our knowledge, this was the first study to demonstrate the ability of ellagic acid to inhibit eosinophil recruitment. We also showed that ellagic acid (1 and 10 mg/kg, p.o.) induced a reduction in the numbers of eosinophils found in BALF and lung parenchyma in the asthma model. Furthermore, similar to the whole L. pacari extract, ellagic acid was also effective in decreasing the concentrations of IL-4, IL-5, and IL-13 in BALF [118]. In addition to this activity, ellagic acid also demonstrates several other biologic effects, including anti-oxidant, anti-cancer, and anti-allergic activity [120–122]. Concerning its toxicity, intake of pomegranate juice (Punica granatum L., Punicaceae) with an equivalent concentration of 121 mg/L of ellagic acid

produced no toxic effect in humans over 3 years and conferred the benefits of reduced common carotid intima-media thickness, blood pressure and low-density lipoprotein (LDL) oxidation [123]. Green tea, from Camellia sinensis L. (Theaceae), is widely consumed around the world and is prepared by drying and steaming fresh tea leaves. Flavonoids are the major secondary metabolites found in green tea, and epigallocatechin-3-gallate is the most abundant of these. In cancer research, phase I and/or II clinical trials have been conducted with the green tea extract [124] as well as its flavonoids (catechins) [125,126]. In addition, beneficial effects of catechins have also been reported with regard to inflammation [127], angiogenesis [128] and other processes. In the guinea pig OVA-induced asthma model, epigallocatechin-3-gallate (25 mg/kg, i.p.) reduced eosinophilic inflammation, as well as other inflammatory parameters [129]. Therefore, epigallocatechin-3-gallate might constitute an attractive molecule with potential interest for the treatment of asthma and related inflammatory and allergic diseases. In the management of obstructive airway diseases from diverse etiologies, the alkaloid theophylline is one of the oldest drugs in use [130,131], despite its weakness as a bronchodilator. Its use is often limited due to concerns regarding dose-related adverse effects, numerous drug interactions and a narrow therapeutic index. However, it has been demonstrated that a low oral dose of theophylline attenuates airway inflammatory responses to allergen inhalation in atopic asthma, extending the beneficial effect of this alkaloid to the therapy of airway diseases [132]. 5. Concluding remarks Natural products and plant derivatives used in folk medicine are of vast medical importance due to their potential as a source

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of molecules with pharmacologic properties. In fact, plant-derived drugs represent more than 30% of the current pharmaceutical market [133], including 60% of cancer drugs and 75% of infectious diseases drugs [134]. In addition, 25% of the drugs currently prescribed to patients are of plant origin, and, according to World Health Organization (WHO), 11% of the 252 drugs considered as basic and essential are derived from plants [135]. Although active plant-derived secondary metabolites can be randomly discovered, this process is laborious, with a success rate on the order of 1 new product per 10,000 plants screened [136]. Moreover, the isolation and identification of secondary metabolites requires a substantial amount of materials, financial resources and equipment [137–139]. In addition, bioassays need to be carried out in order to identify the fraction(s) that contains the active compound(s) and to quantify its purity [140]. Despite all of these obstacles, important scientific findings have been made in this area. For example, the term “medicinal plants” yielded around 50,000 entries in the U.S. National Library of Medicine (PubMed) from the National Institutes of Health as of April 2010. Several plant-derived extracts and secondary metabolites can directly influence the production of inflammatory mediators, as well as the production and activity of second messengers and the expression of transcription factors and key pro-inflammatory molecules [141–143]. In addition, some secondary metabolites provide relief of symptoms in a manner comparable to that obtained from allopathic medicines. Substances of natural origin with few or no side effects are desired as substitutes or complements to traditional chemical therapeutics [144]. Therefore, plant-derived extracts and secondary metabolites may constitute attractive therapeutic alternatives, and we expect that, in the near future, they will be used for the treatment of allergic diseases, such as asthma and related eosinophilic disorders. In this review, we presented an overall picture of the models for studying eosinophil-mediated pathologies and some of the advances in characterizing the anti-eosinophilic activity of medicinal plants and their secondary metabolites. Using these experimental models, we and others have demonstrated that plantderived products can markedly reduce eosinophil recruitment and/or eosinophilia, as well as other features involved in allergic and parasitic disorders, including the production of chemokines and TH 2 cytokines. We hope that this work will serve as a catalog of the extensive list of agents under investigation by researchers in the field of medicinal plants. Acknowledgement This study was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq Grant no. 472601/2004-0), Fundac¸ão de Amparo à Pesquisa do Estado de São Paulo (FAPESP Grant no. 2009/07169-5) and Coordenac¸ão de Aperfeic¸oamento de Pessoal de Nível Superior (CAPES). The authors would like to thank Ana Cristina Hallal Prata for her contribution in the Fig. 1. References [1] Hirsch JG, Hirsch BI. Paul Ehrlich and the discovery of the eosinophil. New York: Grune & Stratton; 1980. [2] Rothenberg ME. Eosinophilia. N Engl J Med 1998;338:1592–600. [3] Lopez AF, Begley CG, Williamson DJ, Warren DJ, Vadas MA, Sanderson CJ. Murine eosinophil differentiation factor. An eosinophil-specific colony-stimulating factor with activity for human cells. J Exp Med 1986;163:1085–99. [4] Lopez AF, Sanderson CJ, Gamble JR, Campbell HD, Young IG, Vadas MA. Recombinant human interleukin 5 is a selective activator of human eosinophil function. J Exp Med 1988;167:219–24. [5] Takatsu K, Takaki S, Hitoshi Y. Interleukin-5 and its receptor system: implications in the immune system and inflammation. Adv Immunol 1994;57:145–90.

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