Inflammation is a dynamic process that is elicited in response to mechanical injuries, burns, microbial infections, and other noxious stimuli that may threaten the well-being of the host. This process involves changes in blood flow, increased vascular permeability, destruction of tissues via the activation and migration of leucocytes with synthesis of reactive oxygen derivatives (oxidative burst), and the synthesis of local inflammatory mediators, such as prostaglandins (PGs), leukotrienes, and platelet-activating factors induced by phospholipase A2, cyclooxygenases (COXs), and lipoxygenases. Arachidonic acid is a key biological intermediate that is converted in to a large number of eicosanoids with potent biological activities. The two major pathways of arachidonic acid metabolism are the COX pathway, which results in the formation of both PGs and thromboxanes, and the 5-lipoxygenase pathway, which is responsible for the formation of leukotrienes and 5S-hydroxy-6E, 8Z, 11Z, 14Z-eicosatetraenoic acid (5-HETE). Classic examples of herbs traditionally used to treat inflammation in Western medicine are Matricaria chamomilla L. and Arnica montana L. (Asteraceae), Salix alba (Salicaceae), and Glycyrrhiza glabra (Fabaceae).
The dried capitula of Matricaria chamomilla L. (Asteraceae), or German chamomile, have been used as anti-inflammatory and antispasmodic remedies since very early times on account of its contents in bisabolol oxides the activity of which has been experimentally substantiated. The plant is listed in several European pharmacopeias, and is used in the form of tinctures, extracts, lotions, ointments, shampoos, and sunscreen products.
Arnica montana L. (Arnica) has been used for treating bruises and swelling in Western medicine on account of its ability to elaborate sesquiterpene lactones, such as hele-nalin and dihydrohelenalin, which are thought to inhibit the activation of transcription factor nuclear factor (NF)-kB, which is responsible for the transcription of genes involved in encoding mediators for the inflammatory process.
Many topical preparations containing arnica are commercially available. Arnica is most commonly prepared as a tincture that can also be used as the base for creams, ointments, compresses, and poultices. Arnica oil may also be used in topical preparations.
From: Ethnopharmacology of Medicinal Plants: Asia and the Pacific Edited by: C. Wiart © Humana Press Inc., Totowa, NJ
The effect of Salix alba L. (white willow) is largely owed to a glycoside, salicin. Salicin is antipyretic and analgesic and has been used in the treatment of rheumatic fever (salicilin tablets; British Pharmaceutical Codex, 1949). In 1893, Felix Hofmann, a chemist working for the Bayer chemical company in Germany, first synthesized acetyl-salicylic acid, the acetylated form of salicin. Aspirin is one of the most commonly used pharmaceuticals containing salicin. Today, the main commercial sources of salicin are Salix fragilis and Salix purpurea (Salicaceae), which are native to Eurasia.
The mechanism by which aspirin elicits its anti-inflammatory activity is based on the fact that it irreversibly inactivates COX by covalent acetylation.
The roots of Glycyrrhiza glabra (liquorice) were known to Roman physicians as Radixdulcis and to Arab physicians as a remedy for cough, and the plant has been cultivated in Europe since the 18th century for its peculiar taste. Glycyrrhiza glabra is listed in the British Pharmaceutical Codex (1973 ed.) and contains triterpenes glycyrrhizin (6-13%) and glycyrrhizic acid, which have anti-inflammatory activity.
Glycyrrhizic acid is mainly absorbed after hydrolysis as glycyrrhetic acid, which is a potent inhibitor of 11-p-hydroxysteroid dehydrogenase an enzyme that catalyzes the conversion of cortisol to cortisone, hence mineralocorticoid action. A large amount of commercial teas, ointments, tobaccos, and suppositories are available on the market. In cosmetology, the drug is used for sunscreen and skin-care products. Other well-known plant products with anti-inflammatory activity are the distillate of Hamamelis virginiana (witch hazel; Hamamelidaceae), Echinacea species including Echinacea angustifolia (purple coneflower; Asteraceae), and Ananas comosus (pineapple; Bromeliaceae).
Common examples of Asian anti-inflammatory plants are Curcuma domestica Val. and Curcuma longa L. (turmeric), Curcuma xanthorrhiza Roxb. (temoe-lawaq), and Zingiber officinale Rosc. (Zingiberaceae). The rhizomes of C. longa L. (turmeric) from Java were introduced in Europe probably through Arab traders. Dioskurides mentions it as an Indian plant that looks like ginger but contains a yellow dye and has a bitter taste. The Indians and Chinese have been using Curcuma longa L. for centuries as a cosmetic and for the making of curry, and it was found in a list of medicinal plants sold in Frankfurt in 1450.
The yellow principle of Curcuma longa L. is a yellow pigment, curcumin. This dye inhibits the enzymatic activity of both COX and nitric oxide synthetase (NOS) and showed clinical potentials for the treatment of inflammation. Zingiber officinale L. (ginger) is native to Gingi area near Pontichery, India and the first European to have seen the whole living plant is said to be the Venetian Marco Polo around 1285. It was used to flavor food and beverages by the Greeks and Romans, who imported it via the Red Sea. During the Middle Ages, ginger was an important economical product controlled by the Venetians. Venetians had established houses of business at Constantinople and Sudak on the shore of the Black Sea, had the monopol of ginger, which was brought by caravannes following the Silk Road. The Venetian monopol survived until the late 15th century when Portuguese navigators were able to sail via the cape to Mozambique and then direct to India to Calicut. Ginger was brought in South America for cultivation by Francisco Mendoza and was exported to Spain as early as 1547. The plant contains arylalkalones, which inhibit the enzymatic activity of COX with potentials for the treatment of inflammation.
Encompassing approx 6000 medicinal plant species, the medicinal flora of Asia and the Pacific comprise a fantastic source of pharmacologically active products, and the number of plant species principally used for the treatment of inflammation can be estimated to be more that 380. This chapter will focus on the potentials of medicinal plants of Asia as a source of original anti-inflammatory drugs, with particular interest payed to inhibitors of phospholipase A2, COX, lipoxygenases, elastase, and NOS.
Phospholipase A2 or phosphatide acylhydrolase 2, is an enzyme that catalyzes the hydrolysis of the acyl group attached to the 2-position of intracellular membrane phosphoglycerides. This hydrolysis release arachidonic acid from membrane phos-phoglycerides. Arachidonic acid is the precursor of PGs, thromboxanes, and leukotrienes (Fig. 1). In regard to the possible mechanisms observed so far, the inhibition of phospholipase A2 is mediated via lipocortine or by direct interaction with the enzyme itself. The former mechanism utilizes a protein known as lipo-cortine, the synthesis of which is commanded by steroidal hormones and steroidlike plants known as triterpenoids. Examples of lipocortine-mediated phospholipase A2 inhibitors that are of therapeutic value and potent anti-inflammatory drugs are cortisone, prednisolone, and betamethasone. The other possible mechanism involves a direct binding with the enzyme itself, a mechanism thus far unused in therapeutics, but with promise. One such compound is also a triterpene: betulinic acid (1). When looking for an inhibitor of phospholipase A2 from medicinal plants, one could look into plant species that are traditionally used as snake-bite antidotes because hemolytic and myolytic phospholipases A2 are often present in snake venom, which results in damage to cell membranes, endothelium, skeletal muscle, nerves, and eryth-rocytes.
Other medicinal features to consider when searching for plants with potential as phospholipases A2 are abortifacient, analgesic, antipyretic, and hypoglycemic uses. Such features are present in the following plant species.
The family Aristolochiaceae is a family of herbaceous plants often used in Asia and the Pacific to counteract snake poisoning, promote urination and menses, mitigate stomachache, and treat dropsy and skin diseases. During the past 20 years, members of this family, especially from the genus Aristolochia have attracted much interest and has been the subject of numerous chemical and pharmacological studies. The anti-inflammatory property of Aristolochia species is probably the result of a direct
interaction between aristolochic acid and derivatives of phospholipase A2. Aristolochia indica L., Aristolochia kaempferi, and Aristolochia recurvilabra Hance are used for the treatment of inflammatory conditions.
A. indica L. Indian Aristolochia, also known as Indian birthwort, ishvara (Sanskrit), or adagam (Tamil), is a bitter climber native to India. The medicinal material consists of the rhizome, which is to resolve inflammation (India), counteract insect poison, and as an antipyretic (Philippines and Vietnam). The rhizome contains aristolochic acid, which inhibits in vitro and dose-dependent phospholipid hydrolysis by the human synovial fluid phospholipase A2, snake venom phospholipase A2, porcine pancreatic phospholipase A2, and human platelet phospholipase A2
Aristolochia kaempferi Willd. (Aristolochia chrysops [Stapf] E.H. Wilson ex Rehder, Aristolochia dabieshanensis C.Y. Cheng and W. Yu, Aristolochia heterophylla Hemsl., Aristolochia kaempferi f. heterophylla S. M. Hwang, Aristolochia kaempferi f. mirabilis S. M. Hwang, Aristolochia neolongifolia J.L. Wu and Z.L. Yang, Aristolochia mollis Dunn, Aristolochia shimadae Hayata, Isotrema chrysops Stapf, Isotrema heterophyllum [Hemsl.] Stapf, and Isotrema iasiops Stapf), or yellow mouth Dutchman's pipe, ma tou ling, yi ye ma dou ling (Chinese), is a perennial climber that grows to a height of 1 m in forests, thickets, and the mountain slopes of China, Taiwan, and Japan. The plant is herbaceous and develops small yellow flowers in the summer. The fruits are cylindrical or ovoid, 3-7- X 1.5-2-cm, dehiscing capsules. The drug consists of the fruit, which is shaped like human lungs, and is therefore recommended in China for all forms of pulmonary infections. Other diseases for which they are prescribed are hemorrhoids, ascite, and heartburn. The plant is known to contain phenanthrene alkaloid derivatives
Fig. 2. Aristolochiaceae recurvilabra.
including aristoliukine-C, aristofolin A and E, aristolochic acid-Ia methyl ester, and aristolochic acid, as well as kaempferol-3-O-rutinoside and quercetin kaempferol-3-O-rutinoside (3,4).
The plant is known elaborate a series of quite unusual phenanthrene alkaloid derivatives, of which aristoliukine-C, aristofolin A and E, aristolochic acid-Ia methyl ester, and aristolochic acid. Other chemical constituents found in this plant are flavonoid glyco-sides such as kaempferol-3-O-rutinoside and quercetin kaempferol-3-O-rutinoside (3,4). Exposure to Aristolochiaceae family is associated with the development of cancer in humans. A significant advance is the toxicological effects of aristolochic acid has been provided by the work of Pezzuto et al. They showed that aristolochic acid is a mutagen
Aristolochia recurvilabra Hance (Aristolochia debilis Sieb. et Zucc, Aristolochia sinarum Lindl., Aristolochia longa L.), or ch'ing-mu-hsiang, pai-shu, ma dou ling, sam pai liang yin yao (Chinese), is a climber that grows to a height of 1.5 m in thickets, mountain slopes, and moist valleys to 1500 m altitude in China, Taiwan, and Japan by roadsides, in thickets, and in meadows. The flowers are tubular and dark purple at the throat (Fig. 2). The drug consists of the rhizome. It is highly esteemed and was, at one time, worth 300 silver taels. The rhizome can be easily mistaken for ginger. It is used to treat digestive disorders, fluxes, diarrhea, dysentry, and snake bites. Levi et al. reported cases of hepatitis following ingestion of teas containing aristolochic acid (6).
Hong et al. showed that a methanol extract of Aristolochia debilis is a potent inhibitor of COX-2 activity (7).
Thottea grandiflora Rottb. is a shrub that grows in the primary rainforests of Malaysia, Thailand, and Singapore. The stems are terete and hairy. The leaves are simple, alternate, thick, glossy, and glaucous underneath and grow up to 25 cm long. The flowers are axillary, 15 cm long, purple, membranaceous, and three-lobed. The fruits are linear follicles (Fig. 3). The roots are used to invigorate, break fevers, treat agues, and as a postpartum remedy. The pharmacological potential of this plant is unexplored.
The Myristicaceae family has attracted a great deal of interest on account of its ability to produce series of unusual phenylacylphenols—of possible symbiotic origin—that might have some potential for the treatment of inflammation. One such compound is YM-26567-1 from Horsfieldia amygdalinia (Wall.) Warb. isolated by Mikaye et al. (8) Horsfieldia amygdalinia (Wall.) Warb (Myristica amygdalina Wall, Horsfieldia tonkinen-sis H. Lecomte, Horsfieldia thorelii H. Lecomte, Horsfieldia tonkinensis var. multiracemosa H. Lecomte, Myristica glabra auct. non Blume, Horsfieldia glabra auct. non (Blume)
Warb, Horsfieldia prunoides C.Y. Wu), or feng chui nan (Chinese), is a timber tree that grows to a height of 25 m in hilly, sparse forests or dense forests of mountain slopes and groves in China, India, Laos, Burma, Pakistan, Thailand, Vietnam, Malaysia, and Indonesia. The bark is grayish-white and exudes sticky blood-like latex. The mature fruits are ovoid to elliptical drupes that are orange and to 2.5 cm long. The seeds are oily and completely enclosed in a crimson tunic (Fig. 4). The leaves and bark are used to make a tea to treat intestinal discomfort, and the bark is used to heal sores and pimples. The anti-inflammatory property of Horsfieldia amygdalinia (Wall.) Warb is confirmed in vitro. Mikaye et al. reported that YM-26567-1 from the fruit of this plant competitively inhibits the enzymatic activity of phospholipase A2. In the course of further screening for YM-26567-1 derivatives, YM-26734 was selected, and inhibited phospholipase A2 from rabbit platelets with an inhibition concentration 50% (IC50) value of 0.085 mM (8).
Horsfieldia valida (Miq.) Warb. (Myristica valida Miq., Endocomia macrocoma [Miq.] de Wilde subsp. prainii [King] de Wilde; Horsfieldia merrillii Warb.; Horsfieldia oblongata Merr., Horsfieldia prainii [King] Warb., Myristica prainii King.), or yunnan feng chui nan (Chinese), is a buttressed tree that grows to a height of 25 m and a girth of 50 cm in the
primary rainforests of Indonesia, Malaysia, and the Philippines. The bark is red-brown and minutely scaly. Red sap is present. The stems are terete, pubescent to puberulous, lenticelled, and longitudinally fissured. The leaves are simple, spiral, and exstipulate. The petiole is 2.3 cm X 3 mm, woody, and cracked. The blade is obovate-oblong, 19 cm long by 6 cm large, 24 cm long by 8 cm large, 24 cm long by 6 cm large, and shows 18-25 pairs of secondary nerves prominent on both surfaces. Male flowers are yellowish or subglobose, three- to five-lobed, and minute. The female flowers are ovoid-globose and 2.5-2.8 mm long. The fruits are red, ovoid, edible, and resinous in flavor, and 6 X 3.5 cm on a 5-mm-long pedicel. The seeds are 2-4 cm long and enclosed in a waxy, orange aril (Fig. 4). In Indonesia, the bark is used to treat sprue. Pharmacological properties are unexplored.
The family Caprifoliaceae comprises approx 400 species, of which Lonicera japonica Thunb., Lonicera affinis Hook and Arn, Lonicera confusa DC, Sambucus javanica Reinw. ex. Bl, Sambucus sieboldiana (Miq.) Graebn, and Weigela floribunda (Sieb. and Zucc.) K. Koch. are used to treat inflammatory conditions in Asia and the Pacific. There is an expanding body of evidence to suggest that biflavonoids from this family might hold some potential as phospholipase A2 inhibitors. One such compound is ochnaflavone from Lonicera japonica Thunb.
Lonicera japonica Thunb. (Lonicera chinensis Wats, Lonicera brachypoda DC. var. repens Sieb.), or Chinese honeysuckle, kim ngam, day nhan dong (Vietnamese), jen-tung (Chinese), is a climbing shrub. The flowers are tubular, up to 4 cm long, and white when fresh but yellow when dry. In China, the flowers, stems, and leaves are used in medicine as febrifuge, correctives, and astringents and are used to treat infections and poisoning. The dried flowers are a common sight in the Chinese pharmacies of Malaysia, where they are prescribed as an antipyretic. In Vietnam, a decoction of stems or flowers is drunk to treat syphilis and rheumatism. The anti-inflammatory and antipyretic properties of Lonicera japonica Thunb. are confirmed and involve a biflavonoid, ochnaflavone, strongly inhibited the enzymatic activity of rat platelet phospholipase A2 (IC50 approx 3 (iM). This activity was strong and dependent of the pH, noncompetitive, and irreversible. In addition, the inhibitory activity of ochna-flavone is rather specific against group II phospholipase A2 than group I phospholipase A2 (IC50 approx 20 (iM). These results indicate that the inhibition of phospholipase A2 by ochnaflvone may result from direct interaction with the enzyme (9).
Sambucus javanica Reinw. ex Bl. (Sambucus hookeri Rehd, Sambucus thunbergiana Bl.), or so tiao, chieh ku ts'aois (Chinese), or kambiang beriak (Indonesian), is a deciduous shrub of open spaces of land in town or countryside that are abandoned and where plants can grow freely, village outskirts, and wasteland. The flowers are white, starry, and small, and the fruits are red berries (Fig. 5). In Indonesia, the leaves and bark are used to cure itching. The plant is also used to treat rheumatism, assuage pain, reduce fever, and resolve swellings. The pharmacological potentials of this plant are unknown.
Weigela floribunda (Sieb. & Zucc.) K. Koch. (Diervilla versicolor Sieb. & Zucc.), crimson weigela, or Japanese wisteria, is a deciduous shrub that grows up to 2.5 m in Asia and was introduced as an ornamental shrub in the United States. The flower appears from May to June, and is large and purplish (Fig. 6). The plant is medicinal in China and Indonesia, where it is used to wash sores. The pharmacological potentials of the plant are unknown.
Classical examples of anti-inflammatory Asteraceae are Arnica montana and Calendula officinalis, both used in European medicine to treat bruises and contusions. There is an expanding body of evidences to suggest that Asteraceae could be a useful source of anti-inflammatories, such as sesquiterpene lactones and/or triterpene alcohols, the latter being known to inhibit 12-O-tetra-decanoylphorbol-13-acetate (TPA)-induced inflammation in mice as efficiently as commercial indomethacine by possible inhibition of phospholipase A2
One of the most exiting findings in this area is perhaps the isolation of Bt-CD, a neoclerodane diterpenoid from Baccharis trimera (Less) DC or carqueja (Brazil) used to treat rheumatism and diabetes that shows anti-phospholipase A2 activity (11). Note also the anti-phospholipase A2 and anti-inflammatory activity of Santolina chamaecy-parissus (12). Cirsium japonicum DC, Crossotephium chinense L. Makino, Inula chinensis Rupr. ex Maxim., and Sigesbeckia orientalis L. are used in Asia for the treatment of inflammatory conditions.
Cirsium japonicum DC (Cnicus japonicum Maxim, Cnicus spicatus ), or Japanese thistle, azami (Japanese), ta chi, hu chi, ma chi, tz'u chi, shan nin p'ang, chi hsiang ts'ao, yeh hung hua, and ch'ien chen ts'ao (Chinese), is an herb that grows to 2 m in height. The plant is spiny and produces conspicuous purple capitula (Fig. 7). The drug consists of the root and is used to treat menstrual difficulties, irritable uterus, wounds, and snake bites. A decoction of the aerial part is used to stop bleeding from the nose. In Taiwan, the plant is used to heal burns. In Cambodia and Laos, the root is applied to ulcers and abscesses. The pharmacological properties of this herb are unknown.
Crossotephium chinense L. Makino (Crossostephium artemisoides Less, Artemisia judaica sensu Lour, Artemisia loureiro Kostel.) is a sub-shrub growing in crevices in the rocks in Japan and is cultivated in other Asian countries as pot ornamental. The plant is glaucous with dissected fleshy leaves (Fig. 8). In China, the leaves are used to calm itching. In Taiwan, the leaves are applied to contusions and wounds. In Vietnam, Cambodia, and Laos, an infusion of the plant is drunk to treat congestion. The plant is known to elaborate taraxerol, taraxeryl acetate, and taraxerol, which might participate in the medicinal uses (13). It would be interesting to know whether further studies on this herb discloses inhibitors of phospholipase A2.
An example of a medicinal plant used for the treatment of inflammation based on its activity on COX is Harpagophytum procumbens DC (Pedaliaceae), or devil's claw, which has long been used in South Africa for the management of pain and inflammation. Two isoforms of COX, designated COX-1 and COX-2, are known to catalyze the synthesis of PGs from arachidonic acid (Fig. 1). A body of evidence suggests that PGs are involved in various physiopathological processes including carcinogenesis. COX-1 is present in most tissues, whereas COX-2 is inducible by carcinogens, cytokines, and tumor promoters, and therefore involved not only in inflammation, but also the growth of cells. Thus, compounds that inhibit the activity of COX-2 might also be an important target for cancer chemoprevention. Nonsteroidal anti-inflammatory drugs are widely used in the treatment of pain and inflammation associated with acute injury or chronic diseases, such as rheumatoid arthritis or osteoarthritis. Classic examples of COX inhibitors of therapeutic value are aspirin, paracetamol, ibuprofen, and recently introduced and withdrawn "coxibs" such as celecoxib (Celebrex®) and rofe-coxib (Vioxx®). Coxibs abrogate the formation of cardioprotective PGI2, leading to a rise in blood pressure, atherogenesis, and heart attack by the rupture of an atherosclerotic plaque.
There is, therefore, a need for original coxibs, and one might think to look into the medicinal flora of Asia and the Pacific, as an increasing body of evidence suggests the families Apocynaceae, Clusiaceae, Asteraceae, Polygonaceae, Lamiaceae, and Con-volvulaceae to elaborate ast sources of biomolecules which are able to inhibit the enzymatic activity of COX.
The family Apocynaceae consists of about 250 genera and 2000 species of tropical trees, shrubs, woody climbers, or herbs classically known to elaborate monoterpenoid indole alkaloids of therapeutic usefulness, such as vinblastine and vincristine characterized from the aerial part of Catharanthus roseus G. When looking for such principles, one might investigate members of the subfamily Plumerioideae, which includes the Plumerieae (Alstonia, Aspidosperma, Catharanthus), Tabernaemon-taneae (Crioceras, Tabernaemontana, Tabernanthe, Voacanga), Rauvolfieae (Ochrosia, Rauvolfia, Kopsia, Vallesia), and Carissae (Hunteria, Melodinus, Picralima). About 80 species of plants classified within the family Apocynaceae are medicinal and are often used to treat gastrointestinal ailments, reduce fever and pains, and treat diabetes and infectious diseases. Alstonia scholaris (L.) R. Br, Plumeria rubra L. sensu lato, (Plumeria acuminata Ait, Plumeria acutifolia Por, Plumeria alba L.), Ervatamia divaricata (L.) Burk. (Ervatamia coronaria Stapf, Tabernaemontana coronaria Willd, Tabernaemontana divaricata R. Br.), Trachelospermum jasminoides (Lindl.) (Rynchospermum jasminoides Lindl.), and Trachelospermum asiaticum (Sieb. & Zucc.) Nak. are used in Asia to treat inflammation and have virtually been unstudied as a source of COX inhibitors.
Trachelospermum asiaticum (Sieb. & Zucc.) Nak. (Trachelospermum divaricatum K. Schum), or Asian jasmine, is a climber native to Southeast Asia. The stems are smooth and reddish-brown and exude a milky liquid when cut. The small, leathery leaves are glossy, deep green, and arranged in opposite pairs along the stems. The flowers are light yellow and fragrant (Fig. 9). The plant is used in Korea to treat rheumatism, heal
abscesses and ulcers, and sooth laryngitis. To date, this anti-inflammatory property is not confirmed, and it will be interesting to learn whether it is be mediated via inhibition of the enzymatic activity of COX as measured with an ethanol extract of stem of Trachelospermum jasminoides (Lindl.) (14). If confirmed, this activity might involve alkaloids or lignans, such as arctigenin, and/or flavonoids or iridoids, which are known to occur in the plant (15).
The family Clusiaceae, or Guttiferae, consists of 50 genera and 1200 species of tropical trees, climbers, or herbs. Regarding the chemical constituents of Clusiaceae, there is a massive body of evidences, which cleary demonstrate that neoflavonoids, prenylated xanthones, dipyra-nocoumarins, and quinones are common in member of thus family. Perhaps no other Clusiaceae has contributed antiviral research than Calophyllum teysmanii var. inophylloides from the rainforest of North Borneo. This tree produces series of dipyra-nocoumarins, or calanolides with anti-HIV potentials (Fig. 10). If the antiviral properties of Clusiaceae are being investigated, less work has been done in regard to the central nervous system properties of this family, although monoamine oxidase (MAO; of MAO A and, to a lesser extent, of MAO-B) activities have been measured experimentally, hence its potential to fight depression. An example of central nervous system-active Clusiaceae is Hypericum perforatum L. (St. John's Wort), the flowering tops of which can be found in several over-the-counter products, and the safety of which is controversial. One such compound is 7-mangostin from Garcinia mangostana L., which is found to directly inhibit activity of both COX isoforms in microsomal preparations (16). The family Clusiaceae and the genera Garcinia therefore represent an interesting source of potential COX inhibitors.
Garcinia atroviridis Griff., or asam geluggur (Malay), som khaek, som ma won (Thai), is a tree that grows to a height of 15 m. The leaves are decussate and glossy, long (25 X 6.5 cm), and show about 18 pairs of secondary nerves. The flowers are dark red and the fruits are pumpkin-like berries that are edible and sour (Fig. 11). In Malaysia, a decoction of leaves and roots is used to mitigate earaches; the sap of the leaves is used as a postpartum remedy. One might give the hypothesis that the anti-inflammatory property of the plant involves atroviridine, a xanthone structurally related to mangostin. Is atroviridin an inhibitor of COX?
An example of Asteraceae reported to inhibit COX is Cichorium intybus L., or chicory (17). In Asia, Chrysanthemum sinense Sab. (Chrysanthemum morifolium Ramat) and Bidens bipinnata L. are used as anti-inflammatories on account of their likely ability to inhibit COX.
Chrysanthemum sinense Sab. (Chrysanthemum morifolium Ramat), or chrysanthemum or chu-hua. (Chinese), is a herb native to China and Japan that grows to a height of 30 cm. The plant is ornamental, aromatic, and a perennial herb. The leaves are pinnately lobed and toothed. The capitula are small, yellowish-pink, and globose (Fig. 12). The flowers are used to treat colds and headaches, to soothe inflamed eyes, and to prevent hair loss. A tincture of flowers is used to promote digestion and blood circulation, and to treat nervousness. A decoction of the whole plant is drunk to promote menses and applied externally to heal infected and cancerous sores. The medicinal properties mentioned here have not been confirmed experimentally; however, the plant is known to elaborate a series of sesquiter-penes, such as chrysanthediol A, which might have some level of activity against COXs, as demonstrated with Chrysanthemum parthenium (L.) Bernh. (18,19). Note that the plant has antivenom properties, and this is not surprising because celecoxib, an inhibitor of COX-2, attenuates the action of venom phospholipase A2 (20).
Bidens bipinnata L., or Spanish needles, is an herb that grows to a height of 80 cm. The plant is native to the United States and grows wild in tropical regions. The stems are quadrangular and dichotomously branching from tap roots. The leaves are deeply bipinnatifid. The capitula are yellow. The fruits are needle-like, hence the common name (Fig. 13). In China, the plant is used to counteract snake bites and insect stings. In Taiwan, a decoction of the plant is drunk to treat diarrhea. The antivenom property may involve inhibitors of phospholipase A2 and possibly COXs because extracts of Bidens pilosa L. inhibit the enzymatic activity of COX in vitro (21).
Polygonaceae are interesting because they elaborate a series of stilbene derivatives including resveratrol, which has displayed so far a broad array of pharmacological effects, including the inhibition of the enzymatic activity of rat polymorphonuclear leukocytes lipoxygenase and COX (22). A classic example of anti-inflammatory Polygonaceae is Polygonum amphibium L.
Polygonum amphibium L., or water smartweed, water knotweed, or t'ien Xiao (Chinese), is a common temperate herb that grows in marshes and around ponds and lakes. The plant is erect, may be both branched or not, and grows up to 1 m in height. The leaves are dark green, glossy, are characterized by a conspicuous yellowish midrib and lanceolate, and the flowers are arranged in pinkish spikes (Fig. 14). In China, the juice expressed from the rhizomes and stems is used to heal infected sores and to treat rheumatism. To date, the pharmacological potential of this plant is unexplored, and it will be interesting to learn whether or not it holds any potential as a COX inhibitor.
The family Lamiaceae comprises 200 genera and 3200 species of aromatic herbs including Mentha piperita, (peppermint, British Pharmaceutical Codex, 1954), Lavendula officinalis (lavender oil, British Pharmaceutical Codex, 1963), Salvia officinalis (sage, British Pharmaceutical Codex, 1934), and Rosmarinus officinalis L. (rosemary oil, British Pharmaceutical Codex, 1963). About 60 species of Lamiaceae are of medicinal value in Asia and the Pacific and, in regard to the potentials of Lamiaceae against COX, one might set the hypothesis that the stockhouse of diterpenes present in this family could be an interesting source of COX inhibitors. A signicant advance in that field of research has been provided by the work of Pang et al. Using ionophore-stimulated rat peritoneal leukocytes, they identified from Sideritis javalambrensis, a labdane called labdane F2, which inhibits the generation of COX and 5-lipoxygenase products of arachidonate metabolism (23). An example of anti-inflammatory Lamiaceae where COX could be involved are Ocimum basilicum L. and Glechoma brevituba Kuprian which are described next.
Ocimum basilicum L., or basil, selaseh (Malay), telasih (Javanese), manglak luk (Thai), basilic (French), tiruni-tru (Tamil), babul (Hindi), barba (Sanskrit), badruj (Arab), or hsiang ts'ai (Chinese), is an erect herb that grows to a height of 90 cm. The stem is purplish and the leaves are lanceolate, glossy, and fragrant. The flowers are tubular, bilabiate, purplish, and packed in whorled racemes (Fig. 15). In China, the seeds are used to soothe pain and inflammation. In India, the juice expressed from the leaves is used as nasal douche, and the plant is used to treat inflammation and assuage chronic pain in the joints. In Malaysia, the juice expressed from the leaves is drunk to calm cough, and the plant
is used to abrogate pregnancy. In Cambodia, Vietnam, and Laos, the leaves are used to break fever. The anti-inflammatory property of the plant is confirmed by Singh et al. They showed that the fixed oil inhibits carrageenan-induced and arachidonic acid- and leukotriene-induced paw edema, possibly by blockade of the enzymatic activity of both COX and lipoxygenaseas demonstrated for Ocimum sanctum L. and Holy basil (24). Possible constituents responsible for COX inhibition might be phenolic compounds, such as phenylpropanes. Phenylpropanes are simple alkylated phenolic substances, which inhibit the PG synthesis. Such compounds are responsible for the anti-inflammatory properties of several medicinal plants in the family Con-volvulaceae (25,26).
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