Anti-Inflammatory Activity of Compounds Isolated from Plants

This review shows over 300 compounds isolated and identified from plants that previously demonstrated anti-inflammatory activity. They have been classified in appropriate chemical groups and data are reported on their pharmacological effects, mechanisms of action, and other properties.


INTRODUCTION
Major research efforts to find new therapeutic agents for a variety of inflammatory skin diseases are motivated mainly by the medical need to find drugs with fewer side effects than the ones currently employed. During the more than 35 years since the introduction of cortisone and phenylbutazone for the treatment of rheumatic diseases, a number of new compounds have been studied for anti-inflammatory activity. Some are also useful in the treatment of fever and gout.
In the treatment of rheumatic diseases, basically two types of drugs are used, nonsteroidal anti-inflammatory drugs (NSAIDs) and disease-modifying antirheumatic drugs (DMARDs). NSAIDs mainly inhibit the cyclo-oxygenase pathway of the arachidonic acid cascade, preventing the formation of proinflammatory prostaglandins. DMARDs are immunomodulators claimed to regulate a distorted immune system [1].
A large number of compounds of varied chemical structures isolated from medicinal plants have been shown to possess anti-inflammatory activity. In this review, over 300 compounds isolated from plants with anti-inflammatory activity are shown. This article is based on bibliographic research of Chemical Abstracts from 1950-2000. It can be helpful to researchers in the study of anti-inflammatory substances from plants. This also may serve as a guide for pharmacologists studying the mechanisms of action and anti-inflammatory effects of these substances. For only a few anti-inflammatory compounds isolated from plants has the principal mechanism of action been determined definitively.
Showed anti-inflammatory activity in several experimental models of inflammation in animals. Antitumor activity shown against ascites lymphoma in rats and mice [13]. Isolated from Thalictrum spp. (Ranunculaceae) leaves.

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Podaverine A Podoverine B Isolated from cell culture of leaves of Podophyllum versipelle Hance (Berberidaceae). Showed inhibitory activities in the mouse macrophage chemiluminescense (CL) assay and are responsible for the activity of the corresponding callus culture. Preliminary in vivo studies indicate that the compounds have anti-inflammatory activity. These inhibitory activities are comparable to those of the antioxidant compound quercetin and nordihydroguaiaretic acid [57].

Robinin
The kaempferol glycoside robinin isolated from Robinia pseudacacia Borja (Leguminosae) leaves inhibits the exudative and proliferative phases of the cotton pellet granuloma (50 mg/kg/day p.o. in 7 days) [56]. Used as an anti-inflammatory and antirheumatic agent in Spain's folk medicine. Taxifolin α α α α-Amyrin Taxifolin and α-amyrin from the seed of Cordia obliqua Wild. (Boraginaceae) showed significant anti-inflammatory activity [41]. The polar fraction of the plant extract Cedrus deodara (RoxB) Loud. (Pinaceae) was found to exhibit anti-inflammatory activity in carrageenan-induced edema in mice and its chemical examination has resulted in the isolation of dihydroflavanonols [61].

Xanthorhamnin
Isolated from the seeds of Rhamnus infectoria (Rhamnaceae). Has been patented as an antiinflammatory agent and recommended for the treatment of rheumatoid arthritis and for use in ophthalmology [63].

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Apigenin Luteolin Apigenin and luteolin showed a potency similar to indomethacin (ID 50 = 29.8 and 38.4 µ per ear, respectively). 18 h after the treatment, only luteolin maintained its effects on edema development but the three compounds decreased leukocyte infiltration [64]. Isolated from leaves of Chamomilla recutita L. (Compositae).

Wogonin
Found in the root of Scutellaria baicalensis Georgi (Labiatae). Inhibited IL-1β-induced synthesis of PGE 2 and LTB 4 considerably. In addition, these compounds exerted a moderate inhibition of collagenolytic activity and the cellular activity of fibroblast was increased remarkably [69].

Kaempferol-3-O-sophoroside (K3S)
A polyphenolic constituent isolated of the alcoholic extract of the leaves of Cassia alata L. (Leguminosae). Has been investigated for anti-inflammatory activity and the results compared with phenylbutazone. Showed a significant anti-inflammatory effect in rats in carrageenan and induced hind paw edema test [70]. C. alata is used in India for skin diseases like eczema, pruritis, and itching.

Bromelain
A basic glycoprotein isolated from the fruit pineapple (Ananas comosus, Bromiliaceae). This proteolythic enzyme is used medicinally as an anti-inflammatory agent in soft tissue edema and injury [73].  Heptadeca-2E,8E,16-triene-4,6-dyne-10-ol Found in Bidens campylotheca Schultz Bip (Compositae). This plant is a traditional remedy in Hawaiian folk medicine for treating general weakness of the body, throat and stomach disorders, and of asthma. Showed significant in vitro inhibition of cyclo-oxygenase (CO) and 5lipoxygenase (5-LO) [75].

Magnosalicin
Obtained from the dried buds of Magnolia salicifolia (Magnoliaceae), significantly inhibited granuloma tissue formation. The inhibitory effect was particularly strong, being nearly half of hydrocortisone acetate when administered orally [78].

Nimboline
Has pronounced anti-inflammatory (rat paw edema) and fairly good antipyretic effect (pyrogeninduced hyperpyrexia in rabbits). The acute oral toxicity in mice showed a very low range of approximately 13 g/kg body weight [80,81]. Isolated from leaves of Rachta indica (Meliaceae).

Pedilanthain
A new protease isolated from the latex of Pedilanthus tithymaloides Poit Euphorbiaceae and subjected to anti-inflammatory screening. More potent than phenylbutazone. Exhibits its maximum activity at 2 nd hour of its oral administration [82].

Polysaccharide
Produced by Serratia piscatorum. Exhibited anti-inflammatory activity which was completely lost when hydrolyzed into small molecules [83].

Taspine
Croton lechleri L. (Anacardaceae), commonly called "Sangre de grado", is a tree of the upper Amazon valley of Peru. The bark, when slashed, produces a red viscous sap which is used for the treatment of rheumatism. Shown to elicit anti-inflammatory activity in different models [86]. Umbelliferone Columbianadin Caffeic acid, bergapten, columbianadin, and umbelliferone isolated from Angelica pubescens Maxim (Umbelliferae). Significantly demonstrated anti-inflammatory and analgesic activities at 10 mg/kg in the test: hindpaw, peritoneal vascular permeability, skin window, hot plate, and formalin [87]. The anti-inflammatory and analgesic activities of osthole were reported by Kosuge et al. in 1985[88] from the same plant. Caffeic acid -widespread occurrence in green and roasted coffee beans Coffea arabica, (Rubiaceae), the root bark of Chinchona cuprea, Rubiaceae), and in Conium maculatum (Umbelliferae). Also occurs in herbaceous plants such as Digitalis purpurea (Scrophulariaceae), the leaves and flowers of Papaver sommiferum (Papaveraceae), the roots of Taraxacum officinale, and the flowers of Anthemis nobilis (Compositae) and Achillea millefolium (Compositae) [89]. Umbelliferone -widespread ocurrence in the resin of various Umbelliferae: Ferula, Apium, Pimpinella, and Heracleum spp. Used in sunscreen lotions.

Cafestol
The main constituent of the unsaponifiable portion of coffee bean oil. From Coffea spp. (Rubiaceae). Showed anti-inflammatory activity against carrageenan-induced edema in rats [93].

Chamazuleno
A blue oil produced during steam distillation of chamomile with anti-inflammatory and antipyretic activities [92]. Isolated from leaves of Matricaria chamomilla (Compositae).

Cis-communic acid
Found in Cryptomeria japonica Don (Taxodiaceae). Has anti-inflammatory activity. The activity testing was done using the carrageenan-induced paw edema (CPE) method in rats [96]. The leaves of C. japonica have been used traditionally in Chinese medicine for the treatment of eczema, eruption, and swelling injury by topical application. Cis-communic acid showed antiinflammatory effect when applied topically to rats and an inhibitory effect on histamine-induced ileum contraction [86].

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Ginkgolide A Found in the root bark and leaves of maidenhair tree, Ginkgo biloba (Ginkgoaceae). Used medicinally to treat allergic inflammation and asthma [91].

Guaiazulene
A blue oil produced during steam distillation of chamomile with anti-inflammatory and antipyretic activities [92]. Extracted from Matricaria chamomilla (Compositae).

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Helenalin Sesquiterpene lactones have previously been shown to possess anti-inflammatory and antiarthritic activities in rodents. The α-methylene-γ-lactone moiety of this chemical class is required for activity as well as the β-unsaturated cyclopentenone ring. The helenalin showed significant inhibitory activity against carrageenan-induced edema [90]. Isolated from Helenium autumale, H. anaphalis, H. balduinea, and H. gaillardia (Compositae).

Hydroxyachillin
Found in the aerial parts of Tanacetum microphyllum (Compositae). Used in the Iberian peninsula since ancient times in Spanish traditional medicine as an anti-inflammatory and antirheumatic agent, and for its beneficial effects on the digestive tract. Showed a marked anti-inflammatory activity in carrageenan-induced paw edema in mice [98].

Trans-dehydrocrotonin
Occurs in Croton cajucara Benth. (Euphorbiaceae). Widely known in traditional phytotherapy for the treatment of diabetes, diarrhea, gastrointestinal disorders, and liver diseases. Also indicated for controlling high cholesterol levels. Its vernacular name is sacasa and it occurs widely in the Amazon region (Brazil). Produced a significant inhibition of carrageenan-induced paw edema and cotton pellet granuloma in rats. It also inhibited the writhing in mice induced by acetic acid [108].
The essential oil of Bupleurum fructicosum L. (Umbelliferae) has shown significant antiinflammatory activity in carrageenan-induced rat paw edema model and the activity is attributed in part to the major components, α and β pinene. It has also been shown that thymol and carvacrol, although present in extremely low levels, potentiate the pharmacodynamic action [106].

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Tirotundin Diversifolin Sesquiterpene lactones from Tithonia diversifolia (Hemsl) A. Gray (Asteraceae). In Central America, leaf extracts from this plant are used for the treatment of hematomas and wounds. Inhibit cyclo-oxygenase1, phospholipase A 2 , or the transcription factor NF-KB [110].

Cyanidin-3-O-galactoside
Has anti-inflammatory activity and is used in the prevention of capillary fragility [114]. Isolated from leaves of Fagus sylvatica (Fagaceae).

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Euglobal-1ª Showed granulation inhibitory activity. One of a series of related compounds from Eucalyptus globulus (Myrtaceae) having the same activity [115].

Curcumin
A constituent of turmeric. Has been shown to be an effective anti-inflammatory agent. As potent as phenylbutazone in the carrageenan edema test but half as potent in chronic tests. The mechanism of anti-inflammatory activity is found to be multifactorial. Inhibited lysosomal enzymes (acid phosphatase and cathepsin D) and was effective in inhibiting lipid peroxide formation [89]. Has cytotoxic and antioxidant activities. Reduces cholesterol level and helps control blood sugar. Isolated from rhizomes of Curcuma longa, C. aromatica, and C. xanthorrhiza (Zingiberaceae).

Fagaramide (piperonyl-4-acrylicisobutylamide)
Effective against carrageenan paw edema in rats and was approximately 20 times less potent than indomethacin. Effective against the prostaglandin phase of an acute experimental inflammatory reaction. It is thus suggested that at least part of the anti-inflammatory activity of fagaramide is mediated via inhibition of prostaglandin synthesis [125]. The roots of Zanthoxylum zanthoxyloides and Fagara xanthoxyloides (Rutaceae) have been used to treat allergic and anti-inflammatory diseases. The activity is due a fagaramide, a phenylpropanoid, that inhibits the edema of the rat paw induced by carrageenan [89]. Occurs in Calcolaria ascendens Lind. (Scrophulaiaceae). Has anti-inflammatory activity and enhanced production of cyclo-oxygenase products [124].

Myristicin
The fruit of Myristica fragrans Houtt (Myristacaceae) has been used in Indonesian folk medicine as aromatic stomachics, analgesics, and a medicine for rheumatism. The anti-inflammatory activity in carrageenan-induced edema in rats and vascular permeability in mice is due to the major principle myristicin [126].

Plantamajoside
Occurs in the leaves of Plantago major and P. asiatica (Plantaginaceae). Inhibits 5-lipoxygenase and cyclic adenosine monophosphate diesterase, thus explaining the anti-inflammatory activity of Plantago plants [89].

Aethiopinone
An o-naphthoquinone diterpenoid isolated from Salvia aethiopis L. (Labiatae) roots. Commonly used in folk medicine for a wide variety of remedies. Exhibited sizeable antinociceptive and antiinflammatory effects in rodents. Produced a strong anti-inflammatory effect on an acute inflammatory process like that induced by carrageenan, which was in the same order of magnitude as that observed after poroxicam or ibuprofen administration and its antinociceptive effects were specially important against thermal painful stimuli [128].

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Abruquinones F The pharmacological activities of the five isoflavanquinones isolated from the leaf of Abrus precatorius L. (Leguminosae) have been evaluated. The results indicate that abruquinones A, B, and D exhibited remarkable inhibitory effects on the platelet aggregation. The compounds A, B, D, and F showed strong anti-inflammatory and antiallergenic effects. The IC50 of abruquinones A, B, D, and F for the inhibition of superoxide formation were less than 0.3 µg/ml for the inhibition of the release of both β-glucuronidase and lysosyme from rat neutrophils [129]. This plant is used as a folk-medicine in China for the treatment of laryngitis, hepatitis, and bronchitis, indicating that it exhibits anti-inflammatory activity.

Chimaphillin
Anti-inflammatory and analgesic principles were isolated from the methanol extract of the whole herb of Pyrola rotundifolia L. (Pyrolaceae). Based on bioassays of the inhibitory activities on carrageenan-induced hindpaw edema in rats on acetic acid-induced writhing in mice. The principles were identified as ursolic acid and chimaphillin [88]. P. rotundifolia is found in the group of Chinese crude drugs called Qu-feng-shi-yao, which has long been used as a remedy mostly for arthritic diseases in traditional Chinese medicine.

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Shikonin Acetylshikonin Shikonin and acetylshikonin are active ingredients in the traditional Chinese drug Zi-Cao (Arnebia euchroma Royle, Boraginaceae). Both of these compounds inhibit the usual increase of capillary permeability induced in rats by histamine and have significant anti-inflammatory effects in rats on edema of the paws induced by acute exposure to formalin [132].

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Asteryunnanoside C Found in Aster yunnanensis (Compositae). Used as drug for the treatment of fevers, colds, tonsillitis, snake bites, and bee stings in Chinese medicine. Showed potent analgesic and antiinflammatory activity [136]. Isolated from the ethanol extract of Bumelia sartorum Mart. (Sapotaceae) leaves and has been shown to be responsible for anti-inflammatory activity [133].

Boswellic acid
In India, the oleogum resin of Boswellia serrata Roxb. Ex Coleb (Burseraceae) has been released for therapeutic use under trade name "Sallaki" for the treatment of rheumatism and nervous diseases. It has been established that anti-inflammatory and antiarthritic activities are due to the presence of boswellic acid and other related pentacyclic triterpene acids [137].

Chiisanoside
Used in Korean folk medicine, leaves and stem bark of Acanthopanax chiisanensis Nakai (Araliaceae) have been used as an antirheumatic. Chiisanoside, a glycosilated 3,4-secotriterpene of lupane-type with significant anti-inflammatory activity has been isolated from A. chiisanensis [138].

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R 1 = glucose (1→2)-glucoronic acid R 2 = glucose Chikusetsusaponin V The rhizomes of Panax japonica C.A. Meyer (Araliaceae) have been used for a long time in Japan as a substitute for P. ginseng roots of Chinese medicine. A saponin glucoside, chikusetsusaponin V isolated from the rhizomes of the plant, has shown significant antiinflammatory activity [139].

Cucurbitacin
The fruit juice of Ecballium elaterium L.A. Rich (Cucurbitaceae). Used in Turkish folk medicine for the treatment of sinusitis. Has been investigated for its anti-inflammatory activity. The active principle isolated from chloroform extract showed significant anti-inflammatory activity (69.6% inhibition of edema) [141].

Dulcin
Found in Pitchecellobium dulce (Leguminosae). Showed anti-inflammatory activity [142]. Echinocystic acid Possesses activity capable of preventing various chemically induced edemas in rats and abdominal writhings following acetic acid injection in mice [143]. Isolated from Baccharis trimera (Asteraceae) leaves. This South American plant is used in traditional medicine, internally, for the treatment of rheumatism, hepatobiliary disorders, and diabetes.

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Fruticesaponin A Fruticesaponin B Fruticesaponin C Occur in the dry root of Bupleurum fruticescens (Umbelliferae). Listed officially in the Chinese and Japanese pharmacopoeias and used in Asian traditional medicine to treat certain disorders, are accompanied by inflammation. In vivo anti-inflammatory activity (antidematous activity) [144]. Ginsenoside Ro An oleanane-type saponin that has been screened for activity in experimental models of inflammation. Inhibited an increase in vascular permeability in mice induced by acetic acid and reduced an acute paw edema in rats induced by carrageenan [145]. Isolated from roots of red Panax ginseng C.A. Meyer (Araliaceae). Widely prescribed in Chinese medicine in general practice and has been considered to be effective in the management of psychosomatic diseases such as indefinite complaints, stress ulcer, and anxiety neurosis. In addition, ancient literature indicates that ginseng root alleviates some types of inflammatory diseases.

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Glycyrrhetinic acid glucoside 3β β β β-p-Hydroxybenzenzoyldehydrotumulosic acid Occur in the sclerotium of Poria cocos Wolf (Polyporaceae). Used in Chinese herbal prescriptions as a diuretic and a sedative. The 50% inhibitory doses of the compounds were 0.27 and 1.25 mg per ear on TPA-and AA-induced inflammation [146].

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3β β β β-Hydroxy-2,3-dihydro-withanolide F Anti-inflammatory activity of 3β-hydroxy-2,3-dihydro-withanolide F has been assessed and has marked effects in subacute inflammation. A comparison of the anti-inflammatory properties showed it is approximately 5 times more active than phenylbutazone and equally active to that of hydrocortisone on weight basis. The withanolide did not exhibit any effect on CNS [147]. Isolated from Withania coagulans Dunal (Solanaceae) leaves. This plant is used in India for skin afflictions, inflammatory conditions, chronic liver complications, and as a sedative.

Mi-saponin A
A bisdesmoside of an olean-12 ene-type sapogenol protobassic acid. Obtained from seed kernels of Madhuca longifolia L. Macbride (Sapotaceae). The activity of anti-inflammatory activity was found to be ¼ of phenylbutazone [148].

Quillaic acid
Obtained from the acid hydrolysis of the saponin fraction from the bark of Quillaja saponaria (Rosaceae). The saponin-rich bark of Q. saponaria (10%) is used in shampoo liquids. Shown to have analgesic and anti-inflammatory activity [141].

Ruscogenin
Occurs in Ruscus aculeatus. Used in the local treatment of hemorrhoids. Showed antiinflammatory effect [8].

Saikosaponin A
The roots of Bupleurum falcatum L.B. chinense (Umbelliferae) are used in Chinese medicine for the treatment of inflammation of the diaphragm and enlargement of the liver caused by hepatitis. A number of saikosaponins have been isolated and the aglycone part was found to have oleananetype structure with a characteristic unsaturation at C-11 and 13β,28-oxide system. The administration of saikosaponins has no side effect such as shrinking of the adrenal gland that often occurs with the administration of prednisolone [106].

Sasanquol
Found in the seed of Camellia sasanqua Thumb (Theaceae). The 50% inhibitory dose of this compound against TPA-induced ear inflammation (1 µg per ear) in mice was 0.4 per ear [155].

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Betulin Betulinic acid Ursolic acid Three anti-inflammatory triterpenes -betulin, betulinic acid, and ursolic acid -were isolated from Diospyros leucomelas L. (Ebenaceae) leaves. They showed anti-inflammatory activity in the carrageenan and serotonin paw edema tests and TPA and EPP ear edema tests. The blockade of their effects by progesterone, actinomycin D, and cycloheximide has served to determine the mechanism of action in relationship with that of glucocorticoides [167].

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Mangiferin Mangostin Xanthone mangiferin and phenylated xanthone mangostin have been found to exert pronounced anti-inflammatory activity when tested against different models of experimental inflammation [170]. Isolated from leaves of Swertia chirata Buch-Ham (Gentianaceae). This plant is used in the Indian system of medicine as an antimalarial, and liver tonic. Mangiferin exhibits significant anti-inflammatory properties at a dose of 50 mg/kg. They do not have analgesic or antipyretic effects but show antiulcer activity [169]. Isolated from leaves of Canscora decussata Schult (Gentianaceae) and Cratoxylua prunifiorus Kurz (Guttiferae).