About Author:
Sandeep Kaur
M.Sc. Microbiology (Hons.) in 2012
Guru Nanak Dev University, Amritsar,
Punjab- 143001.
sandy.flowers305@gmail.com
ABSTRACT:
Medicinal plants are part and parcel of human society to combat diseases from the dawn of civilization. India is sitting on a gold mine of well-recorded and traditionally well practiced knowledge of herbal medicine. India officially recognizes over 3000 plants for their medicinal value and Terminalia plant (Baheda) is one of them. Terminalia species (Family: combretaceace) including Terminalia bellerica, Terminalia arjuna and Terminalia chebula are widely used medicinal plants throughout India and popular in various Indigenous system of medicine like Ayurveda, Sidda and Unani. Terminalia chebula, is called ‘King of Medicine’ in Tibet, because of its extraordinary power of healing. Terminalia plant has been demonstated to possess multiple pharmacological and medicinal activities, such as antioxidant, antimicrobial, antidiabetic, anti-inflammatory, anticancer & tumor and wound healing activity. In the Indian Sytem of Medicine, whole plant including stem bark, fruit, root bark and seeds are used as astringent, cooling, aphrodisiac, cardiotonic, tonic in fractures, ulcers, spermatorrhoea, leucorrhoea, cough, excessive perspiration and skin disorders. Phytoconstituents such as glucoside, tannins, gallic acid, ellagic acid, ethylgalate, gallylglucose and chebulanic acid are mainly believed to be responsible for its wide therapeutic actions. The present review is therefore, an effort to give a detailed survey of the literature on pharmacognosy, phytochemistry and pharamacological activities of the plant1.
Reference Id: PHARMATUTOR-ART-1361
1. INTRODUCTION:
The increasing failures of chemotherapeutics and antibiotics resistance exhibited by pathogenic microbial infectious agents have leads to screening of several medicinal plants for its potential antimicrobial activity (Ritch-Kro et al., 1996; Martins et al., 2001). Plants have been used in developing countries as alternative treatments to cure diseases. The revival of interest in natural drugs started in last decade mainly because of the wide spread belief that green medicines are healthier than synthetic medicines. Nowadays, there is manifold increase in medicinal plant based industries due to increase in the interest of use of medicinal plants throughout the world which are growing at a rate of 7-15% annually. Despite the major advances in the modern medicine, the development of new drugs from natural products is still considered important. This seems to be even more relevant for the developing countries, where cost to develop a drug is prohibitive. The evaluation of new drugs especially phytochemically obtained materials has again opened a vast area for research & development. Since 1980, the World Health Organization has been encouraging countries to identify and exploit traditional medicine and phytotherapy. The main Indian Traditional System of Medicine namely Ayurveda and Siddha are primarily plant based system. In India 45,000 plant species have been identified and out of which 15-20 thousand plants are of good medicinal value. According to World Health Organization (WHO) estimates, more than 80% of people in developing countries are depend on the traditional medicine for their primary health needs (Padmaa et al., 2008).
It is generally estimated that over 6000 plants in India and in use in traditional, folk and herbal medicine, representing about 75% of medicinal needs of the Third World Countries (Kumudhavalli et al., 2010). Therefore, the evaluation of rich heritage of traditional medicine is essential. Plant produces wide array of bioactive principles and constitutes a rich source of medicine. Herbal medicines are prepared from a variety of plant materials such as leaves, bark, stems and roots. They usually contain biologically active ingredients and are used primarily for treating mild and chronic ailments. Herbal drugs are prescribed widely even when their biologically active compounds are unknown because of their relatively low costs and minimal side effect (Valiathan, 1998). Despite considerable progress in therapies using expensive synthetic drugs, the search for indigenous anti-diabetic agents from medicinal plants is promising. In view of this attention has been focused on Terminalia species (Terminalia bellerica, Terminalia arjuna, Terminalia chebula) belongs to family combretaceae, which exhibited a number of medicinal activities due to presence of large number of phytoconstituents. The species of Terminalia are very well known for their therapeutic values since long and has proved by many researchers to be useful as anticancer (Kandil and Nassar, 1998), antioxigenotoxic (Chu et al., 2007), anti-inflammatory (Fan et al., 2004). The species of Terminalia also exhibited antimicrobial activity against ten pathogenic bacteria (Malekzadeh et al., 2001).
Terminalia bellerica is large deciduous tree which occurs widely in the moist valleys of India and its fruits are most commonly used in Indian traditional system of medicine (Chopra et al., 1996). They commonly knew as belleric myrobalan and locally as baheda. The fruit rind is used in different preparations, for example, as an ingredient in the popular Ayurvedic formula known as Tripula (three fruits), used for the treatment of fever, cough, diarrhea, dysentery, skin diseases and liver disorders (Kirtikar and Basu, 1933). The fruit is reported to have hepatoprotective (Nadkarni, 1954; Anand et al., 1994, 1997; Anjana et al., 2007), puragive (Chakravarti and Tayal, 1947), choleretic (Siddiqui, 1963) and hypotensive effects (Srivastava et al., 1992). In a clinical study, Terminalia bellerica was found to possess antispasmodic, anti- asthmatic and anti- tussive effects (Trivedi et al., 1979). The fruit extracts of Terminalia bellerica have been evaluated for anti- mutagenic (Kaur et al., 2002), antimicrobial and anti HIV-1 activity (Valsaraj et al., 1997). The plant is known to lower the levels of lipid in hypercholesterolemic animals and prevent the development of atherosclerosis and myocardial infarction (Tariq et al., 1977; Thakur et al., 1988). Triphala and Terminalia bellerica reduced the serum glucose level and showed marked antioxidant properties in alloxan-induced diabetic rats (Sabu and Kuttan, 2002).
Whereas Terminalia chebula is used in treatment of fevers, cough asthma, urinary diseases, piles and worms and is also useful in treating chronic diarrhea and dysentery, flatulence, vomiting, colic and enlarged spleen and liver. Terminalia arjuna is a large tree distributed throughout India and its bark is used as a cardio protective agent in hypertension and ischaemic heart diseases. The bark powder is reported to exert hypocholesterolaemic and antioxidant effect in humans.
2.Terminalia bellerica:
2.1 Botanical Description:
Terminalia bellericaalso referred to as, Beleric Myrobalan in English, Bibhitaki in Sanskrit, locally known as Bahera in India, has been used for centuries in the Ayurveda, a holistic system of medicine originating from India. It is generally cultivated on variety of soils but prefers fertile alluvial loam and deep sandy well drained soil (Nandkarni, 1976; Atal and Kapur, 1982; Handa and Kaul, 1996). The dried fruit used for medicinal purposes. It is found growing wild throughout the Indian subcontinent, Sri Lanka, and SE Asia, upto 1200 meters in elevation, in a wide variety of ecologies. It is large deciduous tree with a buttressed trunk, a thick brownish gray bark with shallow longitudinal fissures; the tree usually grows up a height of 30 meters, when matured. The leaves are crowded around the ends of branches, alternately arranged, margins entire, elliptic to elliptic- obovate, rounded tip or sub acute, midrib prominent, pubescent when young and becoming glabrous with maturity. It is considered a good fodder for cattle. The branches grow up to 10 to 12 cm in length and 7-14 cm in breadth. The flowers are pale greenish yellow with an offensive odor, which are blossom in month of May. The flowers are borne in axillary spikes longer than petioles but shorter than leaves. The fruits are ovoid grey drupes, and the amazing kernals are sweet, obscurely 5-angled, narrowed into a very short stalk (Saroya, 2011; Nandkarni, 2002). Terminalia bellerica seeds have an oil content of 40%, whose fatty-acid methyl ester meets all of the major biodiesel requirements in the USA, Germany and European Union. The seeds are called bedda nuts.
Smoke dried kernals of fruit (Baheda)
2.2 Taxonomic/ Scientific Description:
Following is the taxonomical or scientific description of this herb and how it is differentiated and known in Ayurvedic and Scientific world.
Kingdom: Plantae - Plants
Division: Magnoliophyta – Flowering plants
Class: Magnoliopsida- Dicotyledons
Order: Myrtales
Family: Combretaceae – Indian Almond family
Genus: Terminalia- tropical almond
Species: Terminalia bellerica- myrobalan
Habitat:
In India, this herb is native and abundantly found in states of Madhya Pradesh, Uttar Pradesh, Punjab and Maharashtra.
Parts Used:
Fruits of this herb are used for medicinal activity.
Fruits of Terminalia bellerica
Classical names or Synonyms:
Assam: Bhomora. Bhomra, bhaira
Eng. : Belleric Myrobalan
Guj. : Bahedam, Beheda
Hindi : Bahera
Kan. : Shanti, Shantikayi, Tare, Tarekayi
Mal. : Tanni, Tannikai
Mar. : Beheda
Ori. : Baheda, Bhara
Sank. : Vibhita, Aksa, Aksaka, Bibhitaki
Tam. : Thanakkai, Tanri, Tanri
Tel. : Tannikkaya, Vibhitakami, Tani (Saroya, 2011)
According to Dymock, Warden, Hooper: Pharmacographia Indica (1890):
"This tree, in Sanskrit Vibhita and Vibhitaka (fearless), is avoided by the Hindus of Northern India, who will not sit in its shade, as it is supposed to be inhabited by demons. Two varieties of T. bellerica are found in India, one with nearly globular fruit, 1/2 to 3/4 inch in diameter, the other with ovate and much larger fruit. The pulp of the fruit (Beleric myrobalan) is considered by Hindu physicians to be astringent and laxative, and is prescribed with salt and long pepper in affections of the throat and chest. As a constituent of the triphala (three fruits), i.e., emblic, beleric and chebulic myrobalans, it is employed in a great number of diseases, and the kernel is sometimes used as an external application to inflamed parts.
3. Terminalia chebula:
Terminalia chebula(Yellow Myrobalan or Chebulic Myrobalan) is a species of Terminalia, native to southern Asia from India and Nepal east to southwestern China and south to Sri Lanka, Malaysia and Vietnam. In Urdu and Hindi it is called Harad, Haritaki, or Harada, respectively 'Inknut. The tree is tall about 50-80 ft in height. It has round crown and spreading branches. The bark is dark brown with some longitudinal cracks. Leaves are ovate and elliptical, with two large glands at the top of the petiole. The flowers are monoecious, dull white to yellow, with a strong unpleasant odour, borne in terminal spikes or short panicles. The flowers appear May-June, the fruits July-December. The fruit or drupe is about 1-2 inches in size. It has five lines or five ribs on the outer skin. Fruit is green when unripe and yellowish grey when ripe. Fruits are collected from January to April, fruit formation started from November to January.
Part used:
Fruit; seven types are recognized (i.e. vijaya, rohini, putana, amrita, abhaya, jivanti and chetaki), based on the region the fruit is harvested, as well as the colour and shape of the fruit. Generally speaking, the vijaya variety is preferred, which is traditionally grown in the Vindhya mountain range of central India, and has a roundish as opposed to a more angular shape.
Chebulic Myrobalan
4. Terminalia arjuna:
Terminalia arjuna, commonly known as arjuna or arjun tree in English, is a tree of the genus Terminalia.The tree is about 60-80 ffet height. Arjuna is large, evergreen with a spreading crown and dropping branches. In favorable localities and especially along the banks of stream, the tree attains very large sizes. Two trees of 26 feet and 32 feet in girth at 5 feet from the ground have been recorded in the village of Manipur in J & K. Leaves sub-opposite, oblong or elliptic, coriaceous, cordate, shortly acute or obtuse at the apex. Flowers in panicled spikes. Fruits ovoid or ovoid-oblong, 2.5-5.0 cm long, nearly glabrous, with 5-7 hard, winged angles.
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Part used:
Stem bark, leaves, and fruits having medicinal activity.
· Stem bark:
It is simple, grey and smooth on the external surface. The bark is thick, soft and of red color from inside. Taste is bitter.
Stem bark (T.arjuna)
· Leaves:
Leaves are like that of guava leaves, oblong and 4-6 inch long and 2-3 inch wide, sub opposite, glabrous and often inequilateral. There is two glands near the base of the petiole. The margin is crenulate with apex at obtuse or sub acute angle. The base is rounded or cordate. Petioles run for 0.5 to 1.3 cm.
Leaves ofT. arjuna
· Fruits
The fruits are 1-1.5 inch in diameters and with 5-7 longitudinal lobes. These are glabrous with 5-7 wings, woody and fibrous. Fruit is drupe and is often notched neat the top, marked with oblique upward curving striations.
Fruits of T.arjuna
5. Phytoconstituents:
The pharmacological activities of Terminalia species especially Terminalia bellerica is due to presence of large number of chemical substances, called phytoconstituents. The stem bark, fruit, roots bark, seeds having phytoconstituents, which are responsible for therapeutic activity. The phytoconstituents areBeta-sitosterol, gallic acid, ellagic acid, ethyl gallate, galloyl glucose, chebulagic acid. Four lignans including termilignan, thannilignan, hydroxy-3',4 (methylenedioxy) flavan, and anolignan B identified. The fruits of T. bellerica is rich in tannins about 23.60%~37.36% and its content varies with geographical distribution. Tannins composed of chebulinic acid (C41H32O27); chebulagic acid (C41 H30 O27); 1,3,6-Trigalloylglucose and 1,2,3,4, 6-pentagalloylglucose; corilagin (C27H22 O18); terchebin (C41H30O26); glucogallin (C13H16O10); ellagic acid and gallic acid,etc. Other phytochemicals including shikimic acid, Dehydro-Shikimic Acid; Quinic acid, arabinose, fructose, sucrose, sugar, rhamnose and amino acid, triterpenes: terminoic acid; arjugenin; arjunolic acid; chebupentol. Also contains sennoside A; chebuli (C28H48O4); tannase; Polyphenol oxidase; peroxidase; ascorbic oxldase, etc. Bark contains beta-sitosterol, tannins, ellagic acid, gallic acid and catechol.
Its principle constituents are beta-sitosterol, gallic acid, ellagic acid, ethyl gallate, galloyl glucose, chebulagic acid. The fruit possesses antibacterial properties. It is employed in dropsy, piles and diarrhea. While using herbal eye drops containing T.bellirica, encouraging results have been obtained in cases of myopia, corneal opacity, pterigium, and immature cataract, chronic and acute infective conditions. The fruit possesses myocardial depressive activity.
Gallic acid: 3,4,5-Trihydroxybenzoic acid:
Chemical Formula: C7H6O5
Biological activities of gallic acid include:Analgesic, Antiallergenic, Antibronchitic, Anti-inflammatory, Antioxidant, Antiperoxidant, Antiviral, Bacteristat, Bronchodilator, Immunosuppressant or Astringent
Ellagic acid:
Ellagic acid is a phenolic compound present in fruits and nuts including raspberries, strawberries and walnuts. It is known to inhibit certain carcinogen-induced cancers and may have other chemopreventive properties. The effects of ellagic acid on cell cycle events and apoptosis were studied in cervical carcinoma (CaSki) cells. We found that ellagic acid at a concentration of 10(-5) M induced G arrest within 48 h, inhibited overall cell growth and induced apoptosis in CaSki cells after 72 h of treatment. Activation of the cdk inhibitory protein p21 by ellagic acid suggests a role for ellagic acid in cell cycle regulation of cancer cells.
Ethyl gallate:
Chemical Formula: C6H2 (OH)3COOC2H5
Synonyms: Gallic acid, ethyl ester; Ethyl 3,4,5-trihydroxybenzoate; 3,4,5-Trihydroxybenzoicacid, ethylester;
Other Constituents:
The other constituents of medicinal herb are ellagic acid; trimethyl ether of gallic acid; trimethyl ethyl of chebulic acid; chebulagic acid; chebulinic acid; chebulic acid; terchubin acid;shikimic acid; dehydroshikimic acid; quinic acid; triacontanoic acid; palmitic acid; beta-sitosterol; daucoterol; 1,3,6-trigallylglucose; 1,2,3,4,6-pentagallylglucose;corilagin; glu-cogallin; sennoside A; tannase; polyphenol oxidase; ascorbic acid oxide; arabinose; fructase; glucose; sucrose; rhamnose;vitamin C; 2alfa-hydroxymicromeric acid; maslinic acid; 2alfa-hydro-xyursolic acid; terminoic acid;arjugenin; arjunolic acid;chebupentol; punicalagin; terflavinA; terchebulin. Seeds having 14, 16-dianhydrogitoxigenin, 3-β-D-glucopyranosyl- (-1-6)-O-β-D-galactopyranoside (Yadav and Rathore, 2001).
Constituents in Volatile Oil:
The phytoconstituents of oil of T.bellerica are hexadecanoic acid; linoleic acid;9,12-octa-deeadienoic acid; heptadecane; octadecane; cis-alfa-santalol; 2,6-dimethyl hep-tadecane; 2,6-bis(1,1-dimethyl ethyl)-4-methyl phenol; eicosane; benzoic acid; pentadecane.etc.
6. Remedies and Uses Guide:
6.1. Ethnobotanical uses:
The fruit is mild laxative, stomactic, tonic, alteratives, antispasmodic. It is useful in opthalmia, hemorrhoids, dental caries, bleeding gums.The paste with water is found anti-inflammatory, analgesic and having purifying and healing capacity for wounds. Orally, Terminalia arjuna is used for cardiovascular conditions, including ischemic heart disease and angina, hypertension, and hyperlipidemia. It is also used orally as a diuretic, for earaches, dysentery, venereal and urogenital diseases, and as an aphrodisiac. Orally, Terminalia bellerica and Terminalia chebula are used for hyperlipidemia and digestive disorders, including both diarrhea and constipation and indigestion. They have also been used for HIV infection. Terminalia bellerica is also used orally as a hepatoprotectant and for respiratory conditions, including respiratory tract infections, cough, and sore throat. Terminalia chebula is also used orally for dysentery. Topically, Terminalia bellerica and Terminalia chebula are used as a lotion for sore eyes. Terminalia chebula is also used topically as a mouthwash and gargle. Intravaginally, Terminalia chebula is used as a douche for treating vaginitis. It is Astringent, Tonic, Expectorant and Laxative. It is used in coughs and sore throat. Its pulp is used in dropsy, piles and diarrhea. It promotes the receiving power of five senses. It is also useful in Leprosy, fever and hair care.
6.2.Traditional uses:
In Ayurveda, the drug is classified as an expectorant. It is an integral part of Ayurvedic laxative formulation, Tripla used in treatment of common cold, pharyngitis and constipation. The bark is midly diuretic and is useful in anaemia and lecuoderma. Unripe fruit is mild laxative and ripe fruit is an astringent. Seeds are used as aphrodisiac. Oil extract from the seed pulp is used in leucoderma and alopecia. Modern investigations have proved the laxative activity of the oil (Vaidyaratnam, 2004).
6.3.Dosage Information:
Terminalia bellericacan be used every day for overall health. It comes in various forms and is an ingredient in many products. Generally, powder: 3-6 gm; decoction: 50-100 ml (Anonymous, 1999).
6.4. Safety and Toxicity:
Terminalia bellericais generally regarded as safe for everyday consumption. There are no known safety issues or interactions associated with using this supplement. If we are taking any other supplements or medications, it is best to seek the advice of your physician before using Terminalia bellerica.
7. Pharmacological Studies:
The popularity of the plant was highly enhanced by the ideological belief in the herb as a cure for multiple diseases. The detailed pharmacological activities of Terminalia bellerica in comparision to other Terminalia species (Terminalia chebula or Terminalia arjuna) are given below:
7.1. Antioxidant and free radical scavenging activity:
Free radicals are fundamental to any biochemical process and represent an essential part of aerobic life and our metabolism. They are continuously produced by the body’s normal use of oxygen such as respiration and cell mediated immune functions. Naturally, there is a dynamic balance between the amount of free radicals generated in the body and antioxidants to quench and\ or scavenge them and protect the body against their deleterious effects (Shirwaikar et al, 2006). The reactive oxygen species (ROS) inducing superoxide anionic radical (O2 -), hydrogen peroxide (O2 -2) and hydroxyl radicals (.OH) are implemented in oxidative damage to various cellular macromolecules. Increasing number of evidence suggested that oxidative stress induced biochemical changes are crucial etiological factors in several chronic human disease such as diabetes mellitus, cancer, atherosclerosis, arthritis, inflammation and neurodegenerative disease (Soni et al., 2009). There have been many studies undertaken on how to delay or prevent the onset of these diseases. There have been many studies undertaken on how to delay or prevent the onset of these diseases. The most likely and practical way to fight against degenerative diseases is to improve body antioxidant status, which could be achieved by higher consumption of vegetables and fruits. Foods from plant origin usually contain natural antioxidants that can scavenge free radicals. The antioxidants may mediate their effect by directly reacting with ROS, quenching them or chelating the catalytic metal ions. Several synthetic antioxidants e.g. BHA and BHT are commercially available but they are suspected to cause or prompt negative health effects, and also show solubility and moderate antioxidant activity. Natural antioxidants, especially phenolic and flavonoids are safe and also bioactive. Therefore, in recent years, considerable attention has been directed towads identification of plants with antioxidant ability that may be used for human consumption.
The leaves bark and fruit of T.bellerica possessed high antioxidant activity and phenolics were responsible for this activity. Aqueous extract of T.bellerica (AETb) and ethanolic extract of T.bellerica revealed the presence of various bioactive compounds like flavonoids, sterol, terpenoids and phenolics while negative for the rest of classes of compounds. The presence of flavonoids and tannins in T.bellerica might be contributing in its antioxidant and cardiovascular effects. Badrul Alam, 2011 have postulated that the crude methanolic extract of the fruits of Terminalia bellerica along with its various organic fractions elicited both in vitro and in vivo antioxidant activity. Total antioxidant activity, scavenging free radicals, authentic peroxynitrite and reducing power assessment were performed by them and concluded that the EtOAc fraction elicited strong activity with moderate toxicity. The free radical scavenging activity of methanolic extract and other organic fractions, based on the scavenging activity of stable 1, 1-diphenyl-2-picrylhydrazyl (DPPH) free radical and was determined by method described by Braca et al., 2001. It was revealed that organic soluble fraction of T.bellerica fruits did show the proton donating ability and could serve as free radical inhibitor or scavenger, as well as a primary antioxidant that react with free radicals, which may limit free radical damage occuring in human body. Formation of reactive peroxynitrite from the combination of NO. and O2- leads to serious toxic reactions with biomolecules such as protein, lipids and nucleic acids (Yermilov et al., 1995).The reducing capacity of compound may serve as a significant indicator of its potential antioxidant activity. The reducing properties are generally associated with presense of reductones which have been shown to exert antioxidant action by breaking the free radical chain by donating a hydrogen atom (Beckman et al., 1990).
Fruits and Leaf bark of T.bellerica having antioxidant activity.
Superoxide dismutase has been reported as one of the most important enzymes in the enzymatic antioxidant defense system (Curtis and Mortiz, 1972). It removes superoxide anion by converting it to hydrogen peroxide and prevents the toxic effect caused by this radical. CCl4 Induced hepatic damage lead to decrease in percentage inhibition of SOD and after administration of plant extract/fractions increased the percent inhibition of SOD, revealed the efficient protective mechanism of this plant. Catalase, another antioxidant enzyme, is widely distributed in the animal tissues and decomposes H2O2 and protects the cells from highly reactive hydroxyl radicals (Chance and Greenstein, 1992). Yeh and Yen, 2006; reported that four different phenolic acids induced antioxidant enzymes SOD, catalase and glutathione peroxidase. Thus, increased the percentage inhibition of catalase after administration of extract/fractions probably due to the presence of the phenolic compounds in the extract/fractions. Reduced Glutathione (GSH) is a tripeptide, nonenzymatic biological antioxidant present in the liver. It protects cellular proteins against reactive oxygen species generated from exposure to CCl4 (Arivazhagan et al., 2000). The ability of plant extracts to reactivate the hepatic glutathione reductase was reflected by decreasing the level of lipid peroxidation. This result agrees with the earlier report of Bhandarkar and Khan, 2004.
The other species of Terminalia plant also exhibited antioxidant activity.The methanolic extracts of T.chebula leaves exhibited the highest quantity of total phenolic and flavonoid content, followed by those of T. bellerica and T.arjuna. T.arjuna contained more tannin than T.bellerica did, but less than that of T.chebula. The scavenging capacity of T.chebula for the antioxidant DPPH was the highest of the extracts tested.as it recorded the lowest IC50 valves of all three extracts (Arya et al., 2012). T. chebula fruits have been found to contain higher amounts of total pheonolics, total flavonoids and total tannin, and are reprented to contain gallic acid, chebulic acid, 1,6-di-O-gallonyl-β-D-glucose, punicalagin, 3,4,6-tri-O-gallonyl-β-D-glucose, casuarinin, chebulanin, chebulagic acid, chebulinic acid and 1,2,3,4,6-penta-O-gallonyl-β-D-glucosein, which might be responsible for its high antioxidant activity. Aqueous extract of T. chebula inhibited xanthine\ xanthine oxidase activity and was also an excellent scavenger of DPPH radicals (Naik et al., 2004). T.chebula in a polyherbal formulation (Aller-7/ NR-A2) inhibited free radical induced hemolysis and also significantly inhibited nitric oxide release from lipopolysaccharide stimulated murine macrophages (Mahesh et al., 2009). Six extracts and four compounds of T.chebula fruit exhibited antioxidant activity at different magnitudes of potency (Hazra et al., 2010). Strong antioxidant activity of aqueous extract of T.chebula observed by studying the inhibition of radiation induced lipid peroxidation in rat liver microsomes at different doses and methanolic extract was also found to inhibit lipid peroxide formation and to scavenge hydroxyl and superoxide radicals in vitro (Lee et al., 2005). Acetone extract has stronger antioxidant activity than alpha-tocopherol and HPLC analysis with diode array detection indicated the presence of hydroxybenzoic acid derivatives, hydroxycinnamic acid derivatives, flavonol aglycones and their glycosides, as main phenolic compounds (Chen et al., 2011).
The antioxidant and free radical scavenging capacities of arjunic acid, an aglycone obtained from the fruit of Terminalia was evaluated. It reported that arjunic acid was a strong antioxidant and a free radical scavenger, more potent than ascorbic acid, in microsomes lipid peroxidation, DPPH, hydrogen peroxide induced RBCs hemolysis and 2’, 7’-dichlorodihydrofluorcin diacetate (DCFH(2)-DA) aasay. However, no significant difference was observed in the RBCs autoxidative hemolysis assay (Sun et al., 2008). The study was designed to assess the ability of casuarinin, extracted from T.arjuna, to protect cultured Madin-Darby canine kidney (MDCK) cells against H2O2.-mediated oxidative stress. Casuarinin caused a decrease in intracellular peroxide production. After 3 h exposure to 8mM H2O2, the percentage of intracellular glutathione (GSH)-negative cells was reduced in the casuarinin-treated group. Addition of 32 mM H2O2 to MDCK cells for 3 h induced an increase in the percentage of cells declined in casuarinin-treated cells. The data suggest that casuarinin attenuates H2O2-induced oxidative stress, decreases DNA oxidative damage and prevents the depletion of intracellular GSH in MDCK cells (Chen et al., 2004). Hence, Terminalia species are very efficient as antioxidant agent.
7.2. Antimicrobial activity:
Various reports on antimicrobial activities of Terminalia species were scanty, particularly on these strains of microorganisms and their biochemical processes. Therefore, an attempt has been made to study of antimicrobial activity of crude and methanol extract of dry fruit of Terminalia species on certain pathogenic microorganisms. Antimicrobial activities of Terminalia species fall under various categories such as antibacterial, antifungal, antiprotozoal, antiviral, anticaries activities.
7.2.1 Antibacterial activity:
Terminalia speciesexhibited antibacterial activity against a number of both Gram-positive and Gram-negative human pathogenic bacteria (Khan, 2009; Malckzaden et al., 2001). So these have been found to be effective against some pathogenic microorganisms involved in wounds, burns and skin infections (Babayi et al., 2004). In all Terminalia species, T. bellerica and T.chebula showed more antimicrobial compounds than other tested species of Terminalia. The Terminalia species have tested against Staphylococcus aureus, Streptococcus pneumoniae, Salmonella typhimurium, Escherichia coli (entero pathogen), E.coli (uropathogen), Pseudomonas aeruginosa andYersinia enterocolitica. Disc diffusion method was performed to determine the antibacterial activities of plant (Elizabeth, 2002). It reported that, both crude and methanol extracts of T.bellerica were strongly inhibitory to S.aureus wheras the crude extract was less effective against Yersinia enterocolitica. Coagulase is major virulence factor of S.aureus, which converts the host plasma fibrinogen to fibrin, forming blood clots. This enzyme was inhibited by this herbal extract which was confirmed when S.aureus grown in the presence of T.bellerica extract was unable to form coagulation of normal human plasma indicating either inactivation of coagulase enzyme or absence of protein product. It was observed that when a drop of S.aureus culture was added to a mixture (a drop of normal saline, a drop of normal human plasma and a drop of fruit extract), the coagulation of plasma was arrested indicating that T.bellerica, naturally may act as an anti-coagulant. Similarly,this herb effective against against Salmonella typhi, S.typhimurium, E.coli and Pseudomonas aeruginosa, in which Terminalia bellerica produces morphological alternations where the actively motile organisms S.typhi, S.typhimurium, E.coli and Pseudomonas aeruginosa have showed less motility.
The DNase enzyme activity was inhibited when these organisms were treated with T. bellerica. Similarly, there were alternations in several enzymatic reactions such as urease, tryptophanase, fermentation of sugars in these pathogens indicating that active compounds of this fruit extracts have interfered with the enzymes involved in those biochemical reactions. The inhibitory effect of fruit extracts of T. bellerica can be attributed to the chemical substances such as gallic acid and ethyle gallate, which were present in the fruits (Rastogi and Mehrotra, 1999). It has been recently reported that tannins and propyle gallate, were inhibitory to food-borne, water-borne and off-flavour producing microorganisms. The antimicrobial activity of propyle gallate was associated with the hydrolysis of ester linkage between gallic acid and polyols that occurs when the fruit ripe (Chung et al., 1998). It was evident from this study that T.bellerica fruit extract can be used against fever, superficial skin infections, urinary tract and diarrheal infection.
Elizabeth et al., (2001), have reported the similar results with T.chebula, since both plants belong to same family and fruit taste the same and possessed a few similarly phytochemical substances.T. chebulaexhibited antibacterial activity against a number of both Gram-positive and Gram-negative human pathogenic bacteria. Ethanedioic acid and ellagic acid isolated from butanol fraction of T. chebula fruit extract had strong antibacterial activity against intestinal bacteria, Clostridium perfingens and Escherichia coli(Kim et al., 2006). It is effective in inhibiting the urease activity of Helicobactor pyroli, and ubiquitous bacterium implicated in the development of gastritis, ulcers and stomach cancers(Malckzadehet al.,2001).Gallic acid and its ethyl ester isolated from ethanolic extract of T. chebula showed antimicrobial activity against methicillin-resistant Staphylococcus aureus(Sato et al., 1997).Ripe seeds of T. chebula also exhibited strong antibacterial activity against S. aureus. The aqueous extract of T. chebula strongly inhibited the growth of Streptococcus mutans, salivary bacteria. Diffusate of T. chebula showed an inhibitory effect against strain X-100 of the bacterium Xanthomonas campestris pv. citri indicating its usefulness for the management of citrus canker disease. It has also growth inhibitory action against Salmonella typhi,Klebsiella, Shigella and intestinal bacteria. Ethanol extract of T. chebula fruit showed strong antibacterial activity against multidrug-resistant uropathogenic Escherichia coli and phenolics were found to be responsible for this antibacterial activity (Bag et al., 2011).
Hexane and dichloromethane extracts have shown more antibacterial components than acetone extract suggesting the antibacterial activity in T.arjuna extracts (Shinde et al., 2009). Strong antibacterial activity was shown by the methanol extracts of T.arjuna against multi-drug resistant Salmonella typhi (Rani and Khullar, 2004). Thus, Terminalia species exhibited broad spectrum activity.
Zone of antibacterial inhibition of T. arjuna leaves organic extracts against S. aureus by (A), acetonic, (B) methanolic and (C) ethanolic extract.
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7.2.2 Anticaries activity:
Dental caries is common oral bacterial pathology that has been associated with Streptococcus spp., mainly Streptococcus mutans and Lactobacillus spp. Anticaries activities of Terminalia chebula has been reported (Aneja and Joshi, 2009). Only Terminalia chebula shows anticaries activity.Acetone, ethanol, methanol and aqueous extracts of T.chebula showed antimicrobial activity against two dental caries causing bacteria onlyi.e. S.mutans andS. aureus. Candida albicans is also the most common yeast isolated fromthe oral cavity, and is associated with fungal oral infections, endocarditis and septicemia (Bagg, 1999). S. aureus, a major human pathogen, is responsible for a number of hospital acquiredinfections and propagates mainly in mouth and hands acquired in the hospital environment (Knighton, 1960; Piochi and Zelante, 1975). Saccharomyces cerevisiae considered to be an opportunistic pathogen in the oral cavity, may induce significant oral risks by acting as a tertiary colonizer in dental caries and causing both superficial and invasive infections. The acetonic extract of T. chebula was more potent against both S. mutans and S. aureus compared to other tested extracts. The acetone and ethanol extracts of fruits of T. chebula showed greater antimicrobial activity than the corresponding water and methanolic extracts. This finding is interesting, because in the traditional method of treating a microbial infection, decoction of the plant parts or boiling the plant in water was employed. Whereas, according to the present study, preparing an extract with an organic solvent (acetone and ethanol) showsa better antimicrobial activity (Cowen, 1999). Since all the tested extracts of T. chebula were highly effective against two of thetested dental caries causing bacteria,purification and toxicological studies of theplant and in vivo trials should be carried out so that it can be used as a potential source for the development of a phytomedicine to act against dental caries causing bacteria (Nair et al., 2005).
7.2.3. Antifungal activity
Terminalia speciesexhibited antifungal activity against against a number of dermatophytes and yeast. Antifungal activities of the aqueous, alcoholic and ethyl acetate extract of leaves of Terminalia species were recorded with plant pathogenic fungi i.e. Aspergillus flavus, A.niger, Alternaria brassicicola, Alternaria alternate andHelminthosporium tetramera (Shinde et al., 2009). Antifungal activity of extracts of T.arjuna was recorded higher than other plants. Generally in all plants the activity of aqueous leaf extracts were relatively less than the activity of ethyl acetate extracts, while the alcoholic extracts possessed the highest activity against all plant pathogens. Earlier, Thippeswamy and Lokesh, 1997; Elsamma et al., 1996 have reported antifungal activity of alcoholic leaf extracts against fungal pathogens. Antifungal activity of leaves extracts of T.bellerica, T.chebula and T.arjuna and its active constituents would be helpful in treating various kinds of plant diseases and seed borne diseases. Aqueous extract of T.chebula effective against the pathogenic yeast Candida albicans and dermatophytes such as Epidermophyton, Floccosum, Microsporum gypseum and Trichophyton rubrum (Vonshak et al., 2003). Its inhibitory effect on three dermatophytes (Trichophyton spp.) and three yeasts (Candida spp.) has also been documented. An aqueous extract of galls of T. chebula showed inhibitory effects on three dermatophytes (Trichophyton spp.) and three yeasts (Candida spp.). In vitro anticandidal activity of methanol extract of T. chebula was observed against clotrimazole resistant Candida albicans (Bonjar, 2004). Seed extract exhibited antifungal activity against Trichophyton glabrata (Vonshak et al., 2003).
7.2.4. Antiviral activity:
An extract of Terminalia bellerica showed significant inhibitory activity on human immunodeficiency virus-1 reverse transcriptase, with IC50 NMT 50 micrograms/ml (Gambari and Lampronti, 2006). Four lignans (termilignan, thannilignan, hydroxy-3', 4’-(methylenedioxy) flavan, anolignan B) possessed demonstrable anti-HIV-1 in vitro. T. chebula fruits afforded four immunodeficiency virus type 1 (HIV-1) integrase inhibitors, gallic acid (I) and three galloyl glucoses (II-IV). Their galloyl moiety plays a major role for inhibition against the 3'–processing of HIV-1 integrase of the compounds (Jeong et al., 2002). T. chebula has also retroviral reverse transcriptase inhibitory activity (Lee et al., 2011). It protects epithelial cells against influenza A virus, supporting its traditional use for aiding in recovery from acute respiratory infections (Badmaev and Nowakowski, 2000). The methanol and aqueous extracts of T. chebula showed a significant inhibitory activity with IC50 ≤ 5 μg/ml on human immunodeficiency virus- 1 reverse transcriptase. It also demonstrated therapeutic activity against Herpes Simplex Virus (HSV) both in vitro and in vivo tests (Suthienkul et al., 1993). These finding prompted a team of Japanese researchers to investigate T. chebulas’s effect on humancytomagalovirus (CMV). They found that T. chebula was effective in inhibiting the replication of human cytomagalovirus in vitro and in an AIDS model with immunosuppressed mice and concluded that it may be beneficial for the prevention of CMV diseases and immonocompronised patients. It is also helpful in sexually transmitted diseases and AIDS. Tannins from T. chebula are effective against potato virus x (Ma et al., 2010).
Casuarinin isolated from bark of T.arjuna was investigated for its antiviral active Herpes simplex type 2 (HSV-2) in vitro. Casuarinin also exhibited an activity in inhibiting the viral penetration. Interestingly, casuarinin was virucidal at a concentration of 25 mM, reducing viral titers up to 100,000-fold which suggest that casuarinin possesses anti-herpesvirus activity in inhibiting viral attachment and penetration and also distribing the late events of infection (Cheng et al., 2002).
7.2.5.Anti-diarrhoeal Activity:
Diarrhoea is the passage of loose or watery stools, usually atleast three times in a 24-hour period. Scientists usually define diarrhoea as excessive fluid weight with 200g per day representing the upper limit of normal stool water weight for healthy adults in the western world. Aqueous and ethanolic extracts of T.bellerica exhibited anti-diarrheal activity. The AQETB (Aqueous extract of T.bellerica) and ETETB (Ethanolic extract of T.bellerica) might be enhancing the absorption of water, electrolytes and glucose and also brings the antisecretory effect of intestinal mucosa as a result of this antidiarrhoeal effect occured. These extracts might be also inhibiting secretory effect of NO. The gastrointestinal tract is innervated by both the parasympathetic and sympathetic fibers of the autonomic nervous system. The peristalsis movement of gastrointestinal tract is myogenic in character and is mainly initiated by the local reflexes and can occur without neural connections to the brain and spinal cord. The extrinsic nerves to the intestine appear to have a minor role in modulating the peristalsis activity of the organ (Prakash, 2002). As cholinergic stimulation often cause diarrhea by increasing GI motility the significant inhibition of GI motility by the extract suggested its probable mode of action to be the prevention of cholinergic transmission or its anticholinergic effect on gastric mucosa (Shaphiullah et al., 2003). Both the extracts have an ability to inhibit the peristaltic movement of GIT results the anti-motility effect which in turn allows the absorption of water and electrolytes as a result of this anti-diarrheal effect occur. This effect of the extracts might be due to inhibition of acetylcholine and/or histamine effect on gut.Many plants contain tannins and tannic acid which denature proteins by forming a complex (Protein tannate). This complex coats the intestinal mucosa and makes it more resistant while simultaneously diminishing gastric secretions .It concluded that, Terminalia bellerica contains pharmacologically active substances with anti-diarrhoeal properties. Thus we presume that AQETB and ETETB can be developed to use for the treatment of diarrhea. But the T.chebula and T.arjuna does not show such activity.
7.2.6. Anthelmintic activity:
In recent years, several reports of apparent failures in the treatment of human nematodes have been published (Reynoldson et al., 1997). Although the interpretation and the implications of these studies are still being debated, they have led to an increased awareness of the potential problem of anthelmintic resistance (AR) in the treatment and control of human helminths. The concerns about AR are not superfluous in the context of serious issues of development of drug resistance in majority of the nematodes infesting animals (Waller et al., 1996; Wyk et al., 1997). It would, therefore, be imperative to explore possibilities of developing new anthelmintic compounds. This has drawn attention of researchers to the validation of traditionally used botanical anthelmintics. Terminalia arjuna, known for its ethnomedicinal significance. The present study was carried out to evaluate the anthelmintic activity of Terminalia arjuna (Roxb.) bark locally used as an anthelmintic. Lethal median concentration (LC50 values) of methanolic extract of T. arjuna bark in egg hatch and larval development tests against Haemonchus contortus ova and larva were found. In adult motility assay, efficacy of the extract was evident by the mortality of H. contortus at different hours post exposure. In vivo results revealed maximum (87.3%) egg count percent reduction (ECR) in sheep treated with crude methanolic extract.The data revealed dose-dependent anthelmintic activity both in the in vitro and in vivo studies, thus justifying its use in the traditional medicine system of India (Iqbal et al., 2003).
Though, condensed tannins have been reported to exert direct anthelmintic effects, other phytochemicals like alkaloids, flavonoids and oleane type triterpenes (Anjaneyulu and Prasad, 1982; Tripathi et al., 1992; Irobi et al., 1994) of T. arjuna may also have their independent or synergistic effect. The phytochemicals noted above are known for their antimicrobial activity and may have their application as an anthelmintic as well. In conclusion, the use of T. arjuna bark as an anthelmintic in the form of decoction seems valid in the light of results of the current study. Therefore, quality controlled extracts of T. arjuna bark or possibly isolated bioactive compounds could be promising alternatives to conventional anthelmintics in the future (Cowan, 1999).
7.2.7. Antiprotozoal activity:
A combination of T. chebula and four other botanicals (Boerhavia diffusa, Berberis aristata, Tinospora cordifolia, and Zingiber officinale) had a maximum cure rate of 73% in experimental amoebic liver abscess in hamsters (Dwivedi et al., 2008) and 89% in experimental caecal amoebiasis in rats showing its antiamoebic activity against Entamoeba histolytica. The acetone extract of T. chebula seeds showed anti plasmodial activity against Plasmodium falciparum (Bagavan et al., 2011).
7.3. Acute and Sub acute toxicities:
The study was carried out to evaluate acute and subacute toxicities of the 95% ethanol extract from Terminalia bellerica. A single oral administration of the ethanol extract at a dose of 5,000 mg/kg did not produce signs of toxicity, behavioral changes, mortality and differences on gross appearance of internal organs. In the subacute toxicity, all rats were received a repeated oral dose of 1,000 mg/kg of the ethanol extract over 14 days. The satellite group was given the ethanol extract in the same period but kept for further 14 days without dosing in order to detect the delayed effects or reversibility of toxic effects. The results showed that the extract did not cause changes in terms of general behaviors, mortality, and weight gain, hematological or clinical blood chemistry parameters. The results of gross and histological examinations showed normal appearance of the internal organs when compared to those of the control group (Thanabhorn et al., 2006). In both male and female animals, neither sign of toxicity nor death among the rats wasobserved during 14 days of experimental period after administration of a single oral dose at 5,000 mg/kg of the 95% ethanol extract from the fruits of T. bellerica. Toxicity evaluation was further carried out byobserving body weight gain and internal organ weights of the animals. The body weight of the maleand female extract-treated rats on the seventhday was slightly decreased, yet no significant change in the body weight gain was detected on the fourteenth day. There was no difference in gross and weight examinations of the internal organs. These results suggest that the 95% ethanol extract from the fruits of T. bellerica is practically not toxic after an acute exposure (Kritikar and Basu, 1993). Intravascular effect and bone marrow activity of the extract suggested that the extract this not cause hematological defect.
The total protein level is a combined measurement of two blood protein molecules, albumin and globulin. Albumin is normally produced by the liver. We often see albumin levels depressed when the animals have liver diseases. The bilirubin is by-product of the breakdown of hemoglobin. Therefore, bilirubin levels may be higher than normal when excessive numbers of red blood cells are breaking down, or if the liver is diseased. The clinical blood chemistry studies showed that the female treated groups had a significant increase in the levels of total protein, total bilirubin and direct bilirubin, but these values remained within the normal ranges (Caisay and king, 1980). Moreover, all of the rats did not have any the signs of the impaired function of liver as confirmed by the histopathological examination. The histopathological analysis of internal organs, livers and kidneys, heart, lungs, thymus, spleen, adrenals, small intestine, stomach and duodenum, muscle with sciatic nerve, thoracic spines, brain, eyes, sex organs, uterus and epididymis did not reveal pathological features in all groups. Thus, these results suggest that the 95% ethanol extract from the fruits of T. belerica does not produce signs of oral acute or subacute toxicity in rats.
7.4. Antisecretory and Analgesic activity:
The crude extracts of Terminalia bellerica (Tb.Cr).exhibited antisecretory and analgesic activities.Based on the medicinal use of T. bellerica in diarrhea, it was tested for the possible protective effect against castor oil-induced intestinal secretion in mice. The plant extract dose-dependently suppressed the castor oil stimulated intestinal fluid accumulation, like that caused by positive control drug, loperamide, thus showing antisecretory effect and explains the T. bellerica use in gut hypersecretion. For the anti-nociceptive activity, acetic acid induced writhing test was employed. Various peripheral analgesic drugs such as diclofenac sodium ibuprofen and aspirin have been reported to inhibit acetic acid induced writhing (Okpo et al., 2001). In this study, the tested plant extracts reduced the nociception induced by acetic acid. Abdominal writhing in response to acetic acid is postulated to be mediated through stimulation of local peritoneal receptors related to prostanoid system, indicating increased levels of lipoxygenase products as well as prostaglandins in peritoneal fluid (Deraedt et al., 1980). The inhibitory effect of the plant extracts against acetic acid induced writhing, suggests that it may have occurred through inhibition of lipoxygenase and/or cycloxygenase pathways. The flavonoids are known for their antisecretory and analgesic actions (Bukhari et al, 2007) and the presence of such compounds in T. bellerica (Khan and Gilani, 2010) is likely to account for their observed effects. In conclusion, the present study, by reporting the antisecretory and analgesic activities of T. bellerica, contributes towards evidence based phytomedicine, as well as validates its effectiveness in diarrhea and pain.
T.arjunabark powder significantly reduced the duration of licks and bites in both phases of formalin-induced pain response and showed significant increase in tail flick latency at higher dose. These effects were anatgonised by pretreatment with naloxone. In another series of experiments, mice pretreated with morphine for three days in increasing doses, showed a decrease response in antinociceptive activity of morphine. Further, these findings support the hypothesis that T.arjuna has antinociceptive action probably measured via central opioid receptors (Halder et al., 2009).
7.5. Antihypertensive activity:
Terminalia bellericahas been used as a folk medicine in a variety of ailments including hypertension. The crude extract of Terminalia bellerica fruit (Tb.Cr) which tested positive for flavonoids, sterols and tannins induced a dose-dependent (10-100 mg/kg) fall in the arterial BP of rats under anaesthesia. In isolated guinea-pig atria, Tb.Cr inhibited the force and rate of atrial contractions. The vasodilator effect of Tb.Cr was endothelium-independent as it was not opposed by Nω-nitro-L-arginine methyl ester in endothelium-intact rat aortic preparations and it occurred at the similar concentration in the endothelium-denuded tissues. These results indicate that Terminalia bellerica lowers BP through Ca++ antagonist mechanism and thus provides a sound mechanistic background for its medicinal use in hypertension (Khan and Gilani, 2010). A water soluble fraction obtained from the defated fruits of Terminalia bellerica caused hepatoprotection against CCl4-induced hepatotoxicity (Anand et al., 1994). Srivastava et al, 1992; Dwivedi et al, 1994, reported that T.bellerica lowers blood pressure but the precise mode of action remains to be elucidated. Blood pressure (BP) is considered the product of cardiac output and peripheral resistance (Johansen, 1992), hence the extract was further studied in isolated heart and vascular preparations. In guinea-pig atria, Tb.Cr exhibited a negative inotropic and chronotropic effect, similar to that caused by verapamil, a standard Ca++ channel blocker (Fleckenstein, 1977). Calcium antagonists are known to cause cardiac depression through inhibiting the slow inward current during the action potential plateau (Roden, 2006). The cardiac inhibitory action of the extract may be due to the Ca++ antagonist effect leading to decrease in cardiac out put and thus falling BP.
The plant extract was tested in two different types of vascular tissues. Rabbit aorta is routinely used for screening of Ca++ antagonists (Okmura et al., 1993). Tb.Cr inhibited the high K+ and PE-induced contractions of rabbit aorta at similar concentration, indicating that it was equipotently blocking the Ca++ influx through voltage- and receptor-operated calcium channel (Musha et al., 2005). In addition to the Ca++ influx through membrane bound calcium channels, smooth muscle contraction also occurs via Ca++ release from the intracellular sarcoplasmic reticulum (Hall et al., 2006). The second type of vascular preparation used was rat aorta, which is a prototype tissue for evaluating the endothelium-dependent vasodilation (Chan et al., 2006). The vasodilator effect of Tb.Cr was endothelium-independent, evident from the fact that its inhibitory effect on the endothelium- intact tissues was resistant to L-NAME, a nitric oxide synthase inhibitor (Thorin et al., 1998) and that the effect occurred in endothelium-denuded preparations at the same concentration, similar to the fashion of a standard Ca++ channel blocker.Terminalia bellerica extract was found to contain flavonoids, sterols and tannins. Flavonoids and tannins are reported to possess Ca++ antagonist effect (Ajay et al, 2003) and the presence of such compounds in Terminalia bellerica might be contributing in its cardiovascular effects. From all above reports, it showed that Terminalia bellerica exhibits BP-lowering effect possibly mediated through inhibition of Ca++ influx via membranous calcium channels and its release from the intracellular stores and thus explains its medicinal use in hypertension.
7.6. Antidiabetic activity:
Diabetes is a common metabolic disease characterized by abnormally high plasma glucose levels, leading to major complications, such as diabetic neuropathy, retinopathy and cardiovascular diseases. T.bellerica found to be beneficial to prevent diabetes. Effect of continuous administration of dried 75% methanolic extract of fruits of T.bellerica suspended in water was studied in alloxan induced hyperglycemia in rats. Oxidative stress produced by alloxan was found to be significantly lowered by the administration of T.bellerica extract. This was evident from a significant decrease in thiobarbituric acid reactive substances, conjugated dienes and hydroperoxides in blood and liver respectively. Similarly, decreased gluthathione level produced by alloxan was increased by the administration of extract in blood and liver. So, T.bellerica helps to reduce diabetes. Other effects of plant extract, such asα-Glucosidase inhibitor, glucoamylase activity are discussed below:
7.6.1. α-Glucosidase inhibitor activity:
Diabetes is a common metabolic disease characterized by abnormally high plasma glucose levels, leading to major complications, such as diabetic neuropathy, retinopathy and cardiovascular diseases (Gao et al., 2008).The key enzyme which catalyses the final step in the digestive process of carbohydrates in mammalian is α-glucosidase (α-D-glucoside glucohydrolase, EC: 3.2.1.20), which is located in the brush-border surface membrane of intestinal cells. Hence, α-glucosidase inhibitors can retard the liberation of D-glucose of oligosaccharides and disaccharides from dietary complex carbohydrates and delay glucose absoption, resulting in reduced postprandial plasma glucose levels and suppressed postprandial hyperglycaemia (Gao et al., 2008). Terminalia species was considered as potential α-glucosidase inhibitor as the IC50 values are below. All the Terminalia species tested contains flavonoids and mostly contains steroids/terpenoids except Terminalia kaerbachii.So, T.kaerbachii is most active α-glucosidase inhibitor, followed by T.catappa, T.arjuna, T.chebula, T.bellerica. Gao et al. (2008) reported that isolation of maltase inhibitory principles, chebulanin, chebulagic acid and chebulinic acid from the fruits of T.chebula. T.chebula contains tannins, hence, the finding supports Gao’s idea that the antidiabetic activity ofT.chebula is due to the maltase inhibitory principles. Bajpai et al. (2005) stated that the leaves, bark and the fruits of T. arjuna, T. bellerica andT. chebula had high total phenolic contents and high antioxidant activity. Fruits of T.bellerica andT.chebula were good source of gallic acid, meanwhile bark of T. arjuna, leaves and fruits of T.bellerica are rich source of ellagic acid.
T.bellericacontains triterpenoids and glucosides. It has been used for treatment of diabetes (Chadha, 1976) and has been reported to contain gallic acid, ethyle gallate, gallonyl glucose, mannitol, glucose, galactose, fructose and rhamnose (Nandy et al., 1989). Sabu and Kuttan (2002) evaluated the combination of T.chebula, T.bellerica and Emblica officinalis, known as Triphala for their antidiabetic activity and their relation with their antioxidant activity. T.bellerica, was found to be most active plant to reduce serum glucose level followed by E.officinalis and T.chebula. Triphala which is a combination of all the three produced a significant action in reducing the alloxan induced diabetic.They concluded that T.chebula has higher α-glucosidase inhibitory activity compared to T.bellerica. Rao and Nammi (2006), reported that the chloroform extract of the seeds of T.chebula having antidiabetic properties. The evaluation data also confirmed the traditional indications. The seed extract of T. chebula indicated a potent action in short term study and a prolonged duration of antidiabetic action in long term study and this could be due to multiple sites of action possessed by active principles of T.chebula. The study also revealed that T.chebula is more effectively inhibited the incidence of diabetic neuropathy (Rao and Nammi, 2006).
The study by Ahmed et al. (2005) indicates that T. catappa leaves extracts have antidiabetic activity. Aqueous and cold extracts of Terminalia catappa exhibited significant anti hyperglycemic activities in alloxan-induced hyperglycemic rats without significant change in body weight. The number of functionally intact β-cells in the islet organ is of decisive importance the development course and outcome of diabetes mellitus. The renewal of β-cells in diabetes has been studied in several animal models. The total β-cell mass reflects the balance between the renewal and loss of these cells. It was also suggested that regeneration of islet β-cells following destruction by alloxan may be the primary cause of the recovery of the drug and vinca rosea extract have also shown to act by β-cell regeneration (Ahmed et al., 2005).
7.6.2. In vitro glucoamylase activity:
T.bellericafruit rind powder was assessed for its antimicrobial activity by using Chloroform-Ethyl Acetate fractions. Maximum zone of inhibition was observed in both fractions. The fractionized compounds Epigallo catechin gallate showed significant antimicrobial activity against E.coli, B.subtilis and S.aureus (Meshram et al., 2011). In Type-2 diabetes, the body does not produce enough insulin or properly use it. The cause of diabetes is a mystery although both genetic and environmental factors such as obesity and lack of exercise appears to play a role. Currently available therapies for diabetes include insulin and various oral anti-diabetic agents such as Sulphonyl Ureas, biguanides, α-glucosidase inhibitors and glinides, which are used as monotherapy or in combination to achieve better glycemic regulation. Many of these oral antidiabetic agents have a number ofserious adverse effects; thus managing diabetes without any sideeffects is still a challenge (Saxena and Kishore, 2004). Therefore thesearch for more effective and safer hypoglycaemic agents hascontinued to be an important area of investigation. The glucosidasetransferase debranching system may be regarded as an integral partof the overall phosphorylase pathway for the degradation ofglycogen. An attempt has been made to isolatebioactive component Epigallocatechin gallate from Terminaliabellericaand the effect of on glucoamylase in vitro.and concluded that,Epigallocatechin gallate at very low concentration being promising inhibitor of glucoamylase, may be useful agent to control the level of blood glucose in diabetic conditions.
7.6.3. Streptozotocin induced Antidiabetic activity:
Terminalia bellericais extively used in Indian traditional systems of medicine to treat various diseases including diabetes mellitus. Latha et al., (2010) investigated that hexane, ethylacetate and methanol crude extracts of T.bellerica fruits at doses of 200, 300 and 400 mg/kg, respectively, for 60 days to Streptozotocin induced diabetic rats significantly induced the plasma insulin, C-peptide and glucose tolerance levels, body weight, serum total protein. The effect was more pronounced in methanol extract treated rats. In addition, the plant extracts significantly decreased the serum level of total cholesterol, triglycerides, low density lipoprotein cholesterol, urea, uric acid and creatinine in diabetic rats. It indicated that T.bellerica fruit extracts restored all the biochemical parameters related to the patho-biochemistry of diabetes mellitus and prevented diabetic neuropathy, dyslipidemia and other diabetes-induced complications. These beneficial therapeutic effects of T.bellerica fruits may be due to the synergistic action of more than one bioactive compound and due to the significantly increased C-peptide in extract treated diabetic rats (Latha et al., 2010).
Administration of various crude extracts of T.bellerica fruit brought back the levels of serum lipids to near normal values in diabetic rats. Among the three solvent extracts, hexane extract produced maximum significant reduction in total cholesterol, triglycerides and LDL- Cholesterol and increase in HDL-Cholesterol in diabetic rats. Serum total protein was reduced and serum urea, creatinine and uric acid levels were significantly elevated in STZ-diabetic rats when compared to the normal rats. Administration of various crude extracts of T.bellerica for 60 days to diabetic rats significantly increased serum total protein and lowered all the three Non-Protein Nitrogenous (NPN) substances. Streptozotocin is well known for its selective pancreatic isletβ-cell cytotoxicity and has been extensively used to induce diabetes mellitus in animals. Daily administration of various crude extracts of T.bellerica fruits produced gradual decrease in the blood glucose level. Maximum reduction in the serum glucose level was found in methanol extract treated diabetic rats followed by ethylacetate and hexane extract. The increase in plasma C-peptide levels also followed the same pattern. C-peptide and insulin are the products of the enzymatic cleavage of pro-insulin and secreted into the circulation in equimolar concentrations. The measurement of both C-peptide and insulin levels have been reported to be valuable index of insulin secretion rather than insulin alone (Doda, 1996).
The antidiabetic effect of crude extracts of T.bellerica fruits may be due to the presense of more than one antihyperglycemic principle and their synergistic properties. T.bellerica fruit extracts revealed phenolic compounds and tannins as major constituents. Fruit contains 23.60 to 37.36% tannins such as Chebulinic acid; Chebulagic acid; 1, 3, 6- Trigalloylglucose and 1, 2, 3, 4, 6-pentagallonyl glucose; glucogallin; ellagic acid; gallic acid; etc, (Row and Murty, 1970). The hypoglycemic activity of T.bellerica fruit extracts might be due to the presence of polyphenolic compounds that suppress the increase in plasma glucose, tannin molecules which were found to be responsible for the insulin-like glucose transport stimulatory activity and more specifically the presence of gallotannins such as Pentagalloyl glucose (PGG), found to be more potent and efficacious in Insulin Receptor (IR) binding, IR activation and glucose transport induction (Klein et al., 2007). The hypolipidemic and cardioprotective activity of T.bellerica fruit extracts in hypercholesterolemic rats have been reported by Tariq et al., 1977 Thakur et al. 1988) which might be due to the presence of beta-sitosterol, as plant sterols are well known for its cardioprotective properties (Jones et al., 1997). Therefore, it may be concluded that hypoglycemic and protective role of T.bellerica fruit extract in preventing secondary complications of uncontrolled diabetes mellitus may be due to the highly significant increase in plasma C-peptide levels in extract treated diabetic rats.
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7.7. Immune response in vitro:
In vitro Phagocytic activity and lymphocyte proliferation assay were carried out in methanolic extract of on the mouse immune system. In both assay, stimulation of macrophage phagocytosis through the production of superoxide anions and acid phosphatase,and maximal activation of phytohemagglutinin were observed.With concanavalin A, lipopolysaccharide, and pokeweed mitogen, similar activation of lymphocyte proliferation was observed. However, at low concentrations, T. bellerica extract with concanavalin A and pokeweed mitogen caused suppressant activity. The results suggested that the effect of extract on T-lymphocyte proliferation occurred through the same mechanism as phytohemagglutinin, concanavalin A and B-lymphocyte proliferation through T-cell independent and T-cell dependent mechanisms, in manners similar to lipopolysaccharide and pokeweed mitogen respectively. It might be concluded that the methanolic extract of T. bellerica affected the mouse immune system, specifically both the cellular and humoral immune response in vitro, corresponding with its folklore applications. The compounds which are responsible for phagocytic activity may be either gallic acid or other phytochemicals present in T.bellerica (Saraphanchotiwitthaya et al., 2008).
Immune activation is an effective and protective approach against emerging infectious diseases (Hackett et al., 2003), and alternative medicine is becoming more popular for the treatment of these illnesses. T. bellerica has been used as a traditional remedy in Thailand (Bunyapraphatsara, 2000) and various pharmacological activities has been reported. Among the array of medicinal properties attributed to it, a significant one is its therapeutic immunomodulating activity. So, that the activity of extract of T. bellerica fruit has been determined for any immunomodulatory activity. It is well known that macrophages play a significant role in the defense mechanism against host infection and proliferation of tumour cells. The modulation of macrophage antitumour properties by various biological response modifiers is an area of interest for cancer chemotherapy (Kang et al., 2002). Although the phagocytic activity of the T. bellerica extract has never been reported, the superoxide anion production response of gallic acid, an active component isolated from T. bellerica extract, has been discussed. It reported that, the slight increase of reactive oxygen species (ROS)production in macrophage RAW 264.7 cells in response to gallic acid. However, the suppressant effect on macrophage chemiluminescence (Tam et al., 1990) and the inhibition of superoxide scavenging of gallic acid (Sabu and Kuttan, 2002) were also presented.
Therefore, the compounds responsible for phagocytic activity may be either gallic acid or other phytochemicals present in T. bellerica. The release of nitric oxide, superoxide anion, hydrogen peroxide and lysosomal enzyme from activated macrophages is an enzyme-controlled process. So it is possible that the extract may induce some alteration in the mechanism of activation of the related enzyme such as phosphotyrosine phosphatase, which could result in an increase of O2– (Carreras et al., 1997). Moreover, the effect of the extract at high concentrations on the stimulation of phagocytic activity may be due to a significant amount of active ingredients contained in T. bellerica extract. These observations suggest a possible application of T. bellerica to the treatment of microbial infections and cancer. Besides gallic acid, there were other phytochemical compounds present in the fruit of T. bellerica, such as ellagic acid, ethyl gallate, chebulagic acid and beta-sitosterol (Nandy et al., 1989). Three lignans and one flavan from the T. bellerica extract showed significant anti-HIV, antimalarial and antifungal activity in vitro (Valsaraj et al., 1997). Therefore, it is possible that other compounds contained in T. bellerica extract might be responsible for the immunomodulatory activity as well.
7.8. Anti-inflammatory and anti-arthritic activity:
Cardiovascular diseases have witnessed a surge in incidence and prevalence in the last few decades. Atherosclerosis is one of the most common disorders involving the cardiovascular system. Atherosclerosis is now recognized as an inflammatory disorder rather than due to hyperlipidemia alone (Meng et al., 2006). Recent studies have also suggested that the role of immune response in the pathogenesis of atherosclerosis as evidenced by the immunomodulatory effects of statins in the treatment of atherosclerosis (Sugano et al., 2005). With the limitation of the currently available molecules, indigenous treatments options are being currently explored for cardiac disorders like atherosclerosis. In Ayurveda also, there is reference of a few drugs available for treatment (Chopra et al., 1994). One such agent is Terminalia species especially bark of Terminalia arjuna. Animal experiments and clinical studies, have also reported the beneficial effects of dried bark powder of T.arjuna in ischaemic heart disease (Bharani et al., 2002). Some polyherbal preparations, CapHT2 and BHUx, containing T. arjuna among other constituents, have been reported to possess antiatherogenic, hypolipidemic and anti-inflammatory activity (Mary et al., 2003). Pain is frequently associated with inflammation and is feature of numerous cardiovascular diseases like angina and myocardial infarction. Drugs with anti-inflammatory effect very often possess analgesic property as well. The experience of pain is the final product of complex information processing network involving the central and peripheral pathways. Many clinical trails, have also demonstrated the beneficial effects of T.arjuna in ischaemic cardiomyopathy and in patients with stable angina. However, the effect of T.arjuna bark powder per se, has not been studied on inflammation, immunomodulation and nociception which may provide a better understanding of its role in atherosclerosis.
The anti-inflammatory property of T.arjuna was screened in formalin and carrageenan models of paw oedema. T.arjuna (400 mg/kg) significantly decreased formalin-induced paw oedema. However, did not have significant effect in reducing carrageenan-induced paw oedema. Anti-inflammatory compounds can act on various levels of the pathophysiological process viz., (a) by blocking the biosynthesis of proinflammatory mediators, by decreasing the enzyme expression or by reducing substrate levels; (b) by inhibiting the release of preformed stored mediators; (c) by blocking mediator-receptor interaction on target cells and (d) immunostimulation which results in less aggressive response to allergen challenge (Safayhi et al., 1997). T.arjuna is known to contain antioxidant constituents such as flavones (arjunolone), tannins and oligomeric proanthrocyanidins (OPCs). Nair et al. (1998) have reported that T.arjuna tree bark contains high amount of flavonoids. Arjunolic acid, a new triterpene isolated from the bark of T.arjuna has been shown to have antioxidant and cardioprotective activity in rats (Sumitra et al., 2001). Another mechanism contributing to the efficacy of T.arjuna in cardiovascular ailment, especially ischemic heart disease is the antiatherosclerotic and hypolipidemic activity of the plant. The hypolipidemic property has been confirmed in various clinical trails. CapHT2, a polyherbal formulation containing among other constituents, T.arjuna has been shown to have antiatherogenic, hypolipemic, anti-inflammatory and antioxidant activity (Mary et al., 2003). Another polyherbal formulation BHUx containing T.arjuna was shown to have anti-inflammatory and antioxidant activity (Tripathi et al., 2004).
Pain is a feature of numerous cardiovascular diseases like angina and myocardial infarction. In the present study, antinociceptive response was assessed by tail flick model and formalin-induced pain response model, which employ thermal and chemical noxious stimuli respectively. In present study, significant reduction in the duration of pain response by T.arjuna (400 mg/kg) in both early and late phases was observed. The abilityof T.arjuna bark powder to inhibit both the phases of formalin-induced pain response, in addition to prolong the tail flick latency further indicates the involvement of central opioidergic mechanisms as the antinociceptive activity of T.arjuna in both the tests is significantly anatagonised by an opioid antagonist, naloxone (Halder et al., 2009). Whereas, Aqueous extract of dried fruit of T. chebula and T.bellerica showed anti-inflammatory by inhibiting inducible nitric oxide synthesis (Moeslinger et al., 2000). Chebulagic acid from immature seeds of T. chebula significantly suppressed the onset and progression of collagen induced arthritis in mice (Nair et al., 2010). T. chebula in a polyherbal formulation (Aller-7) exhibited a dose dependent anti-inflammatory effect against Freund’s adjuvant induced arthritis in rats (Pratibha et al., 2004).
7.9. Hepatoprotectiveactivity:
Shuklaet al., (2006), were evaluated the protective effect of T.bellerica fruit extract and its active principle, Gallic acid against CCl4 intoxication. Treatment with extract and gallic acid showed dose-dependent recovery in biochemical parameters such as lipid peroxidase and glutathione but the effect was more pronounced with gallic acid (Shukla et al ., 2006). The importance of fruit powder of Terminalia bellerica has also been investigated for its hepatoxicity effect in rats against CCl4 induced hepatic damage. Oral administration of 1 gm/kg body weight of powder of Terminalia bellerica fruit recovered the CCl4 induced liver damage.. The administration of Terminalia bellerica plant material recovered the enzyme levels like normal rats. The biochemical observations were supplemented by histoapthological examination of liver. The results of blood and tissue biochemical parameters like Aspartate aminotramferase, Alanine Aminottramferase, Alkaline phosphatase, etc reveled that Terminalia bellerica fruit powder could regenerates liver cells and offered protection against CCl4 induced hepatic damage. The observation of markers as well as Light and electron microscope photographs supports the regeneration process of liver parenchyma (Pingale, 2011)
Liver has an important place in toxicology by virtue of its function, both qualitatively and quantitatively. It plays a major role in detoxification and excretion of many endogenous and exogenous compounds, any injury to it or impairment of its functions may lead to many implications on one’s health. Management of liver diseases is still a challenge to the modernmedicine (Reddy et al., 1993). The modern medicines have little to offer for alleviation of hepatic ailments, whereas most important representatives are of phytoconstituents. Many organs in body account for any toxic action, liver is one of them. Attempts have been carried out to reveal the efficacy of T.bellericafruit powder in the form of aqueous slurry against CCl4 induced biochemical and histopathological changes in liver rats. Literature survey reveals that CCl4 has direct destructive effect on membranes of the hepatocyte and on consequent interface with cellular metabolism and transport. It damages the membranes of the hepatocyte causing leakage of the enzymes present in the cell. This results in elevation of the levels of plasma tramaminase (Pingale, 2008). It leads to fat decomposition in the liver due to blockage of secretion of hepatic triglycerides into plasma. The toxicity of CCl4 depends upon the cleavage of C-Cl bond to generate a trichloromethyl a free radical (CCl3O2). This cleavage occurs in the endoplasmic reticulum and is mediated by the cytochrome P-450 mixed function oxidase system.
The product of the cleavage binds irreversibly to hepatic proteins and lipids. The metabolism of CCl4 releases CCl3 a free radical, which initiates per oxidation and clevage of fatty acids in the membranes. The CCl4 derived free radicals initiates the process of peroxidations by attacking Methylene Bridge of unsaturated fatty acid side chains of microsomal lipids. This results in early morphological alteration of endoplasmic reticulum and eventually to ultimate cell death through series of changes listed below besides as yet underlined pathways like loss of activity of P-450 xenobiotics metabolizing system, loss of glucose-b-phosphatase activity, loss of protein synthesis, loss of capacity of liver to form and excrete VLDL (Very Low Density Lipoproteins). Alterations in these parameters are used to monitor the course and extent of CCl4 induced liver damage (Pingale, 2010). A single dose of CCl4 leads to centrilobular necrosis and fatty liver. Within a few minutes, there is injury to the endoplasmic reticulum lending to functional defects of the hepatocyte and multiple biochemical manifestations of hepatic injury. Irrespective of the route of administrations it leads to centrilobular necrosis and steatosis. Biochemical changes in the blood reflect injury.
Many clinical conditions that causes an increase in cholesterol levels also cause increase in triglycerides enzymes sensitive to cytotomic injury are serum glytamic pyruvic transaminase (SGPT) now called Alanine amino transferase (ALT) and serum glytamic oxaloacetic transferase (SGOT) now known as Asparatate amino transferase (AST). Asparatate and Alanine amino transferases are present in high concentration in liver. Due to hepatocyte necrosis or abdominal membrane permeability, these enzymes are released from the cells and their levels in the blood increase. ALT is a sensitive indicator to acute liver damage and elevation of this enzyme in hepatic disease is unusual. Alkaline phophatase, although is not a liver specific enzyme, the liver is major source of this enzyme. Also the levels of this enzyme increase in cholestasis, elevated serum gamma-glutamyl transpeptidase levels appear to be indicative of diseases of the liver, biliary tract and pancreases. Bilirubin levels in blood also increases in liver disease. (Cirrhosis and hepatitis).
T. bellericafruit powder in the form of aqueous slurry treatment significantly reduced cholesterol in all rats (Pingale, 2010).
7.10. Antispasmodic activity:
Many reports have provided the pharmacological basis for the medicinal use of Terminaliabellerica in hyperactive gastrointestinal and respiratory disorders. In medicine a spasm is a sudden, involuntary contraction of a muscle, a group of muscles, or a hollow organ, or a similarly sudden contraction of an orifice. It most commonly refers to a muscle cramp which is often accompanied by a sudden burst of pain, but is usually harmless and ceases after a few minutes. There is a variety of other causes of involuntary muscle contractions, which may be more serious, depending on the cause. The word "spasm" may also refer to a temporary burst of energy, activity, emotion, stress, or anxiety unrelated to, or as a consequence of, involuntary muscle activity. New type of antispasmodics is used for smooth muscle contraction, especially in tubular organs of the gastrointestinal tract. The effect is to prevent spasms of the stomach, intestine or urinary bladder. Both dicyclomine and hyoscyamine are antispasmodic due to their anticholinergic action.But due to range of complications due to use of currently available medicines, many researchers have found that medicinal plant are beneficial for antispasmodic activity.
Crude extract of Terminaliabellerica fruit (Tb.Cr) was studied in in vitro and in vivo. Gilani et al., (2008) were postulated that the Tb.Cr caused relaxation of spontaneous contractions in isolated rabbit jejunum. Tb.Cr inhibited the carbachol and K+-induced contractions in a pattern similar to that of dicyclomine, but different from nifedipine and atropine. Tb.Cr shifted the Ca++ concentration–response curves to right, like nifedipine and dicyclomine. In guinea-pig ileum, Tb.Cr produced rightward parallel shift of acetylcholine-curves, followed by non-parallel shift at higher concentration with the suppression of maximum response, similar to dicyclomine, but different from nifedipine and atropine. Tb.Cr exhibited protective effect against castor oil-induced diarrhea and carbachol-mediated bronchoconstriction in rodents. In guinea-pig trachea, Tb.Cr relaxed the CCh-induced contractions, shifted CCh-curves to right and inhibited the contractions of K+. Anticholinergic effect was distributed both in organic and aqueous fractions, while CCB was present in the aqueous fraction (Gilani et al., 2008).
T.chebulaalso demonstrated for its ‘anti-vata’ or ‘anti-spasmodic’ properties by the reduction of abnormal blood pressure as well as intestinal spasms. This confirms its traditional usefulness for spastic colon and other inrestinal disorders (Seyyed et al., 2011).
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7.11. Wound Healing activity:
Despite recent advances in antimicrobial chemotherapy and wound management, several types of wounds and ulcers still prove recalcitrant to treatment. Thus, wound healing continues to be one of the major public health problems in the world and wound management still remains a matter of research. The complex cascade of cellular and biochemical events that occurs after injury determines the successful outcome of wound repair. Fibroblasts are the primary synthetic element in the repair process and are responsible for production of large quantities of collagen. They also help in the production of other matrix constituents including hyaluronic acid, fibronectin and glycosaminogly can repair by connective tissue involves four important steps,
(i) Migration and proliferation of fibroblasts,
(ii) Deposition of extracellular matrix
(iii) Formation of new blood vessels (angiogenesis) and
(iv) Maturation and organization of the scar, also known as remodeling.
In recent years, considerable interest in the use of alternative therapies and natural remedy is attracting the attention of many researchers. Many plants maily, Terminalia species (T.bellerica, T.chebula andT.arjuna) having wound healing activityand.Wound healing is a complex but orderly phenomenon involving a number of processes which include migration and proliferation of both epithelial and connective tissues, synthesis of extracellular matrix (ECM) proteins, remodeling of connective tissue and parenchymal components and collagenization and acquisition of wound strength. Synthesis of collagen is initiated by DNA transcription from specific gene coding for the polypeptide chains. This is followed by synthesis of alpha chains on ribosomes. The alpha chains then come off the ribosome into the cisternae of the rough endoplasmic reticulum (RER).
Thereafter, they undergo a series of biochemical modifications; one important change being the hydroxylation of the amino acid proline. This provides collagen with its characteristic high content of hydroxyproline and provides tensile strength to healing wounds since collagen content was always higher in the combined treated groups. The activation of collagen synthesis was globally more efficient than catabolism. Wound remodeling is however, an important feature of the healing process. Increased level of hydroxyproline suggests higher collagen content in the granulation tissue in experimental animals treated with paste of Terminalia spp. Since fibroblasts are responsible for the synthesis of collagen in the newly formed granulation tissue, one would expect that any increase in fibroblasts proliferation would more or less result in an increase in collagendeposition (Aljady et al., 2000). The beneficial effect of herbal paste on scar management appears to be the stimulation of naturation of the scar by the production of collagen and the resulting decrease in the inflammatory reaction and myofibroblast production (Widgernow et al., 1999).
Combined application with Terminalia chebula and Terminalia bellerica significantly increased the cells proliferation in nearly formed granulation tissues as evidenced by higher levels of DNA and corroborated the findings of (Suguna et al., 2002). An early and rapid fibroblastic and angiobalstic activity was also observed in Terminalia chebula applied wounds. It might be expected that combined treatment may stimulate the growth factors resulting in increased DNA synthesis in competent cells. Under certain conditions, fibroblasts can differentiate into a cell type structurally and functionally similar to smooth muscle and that this cell, the ‘myo-fibroblast’, plays an important role in connective tissue contraction. Glycosominoglycans are made up of repeating disaccharides containing uronic acid and hexosamine. These are the first components of extracellular matrix (ECM) to be synthesized during wound healing and form the template for collagen and elastin deposition. The higher level of uronic acid in combined T. chebula and T. bellerica treated animals indicates an increased synthesis of glycosaminoglycans. Since fibroblasts are responsible for the synthesis of glycosaminoglycans, it is expected that its synthesis doesn’t occur until fibroblasia is established. It is the fat that glycosaminoglycans, especially hyaluronic acid and small proteoglycans, play a major role in the healing process and contribute to the organization and strength of the fibrillar network of the wound (Scott et al., 1988). Glycosaminoglycan which is a part of proteoglycan retains fluid in the tissue and their major function is to maintain the normal shape and volume of connective tissue.
Thus, they regulate the structure and permeability of connective tissue and subsequently modulate cell growth. In conclusions, the paste obtained from T. chebula and T. belerica stimulate fibroblast function, enhance synthesis of glycoseminoglycans and deposition of collagen and offers a distinct advantage to wound healing and as such, may be a useful adjuvant in wound healing. The wound healing activity of two herbal formulations (Himax ointment and lotion) containing Indradaru extract, i.e. Arjuna bark (Terminalia arjuna), extract was evaluated for its wound healing potential in two types of wound models (1) excision wound model and (2) incision wound model. Both the formulations responded significantly in both the wound model tested. The results were also comparable to that of the standard drug nitrofurazone. The result was comparable in terms of wound contracting ability, epithelialization period, tensile strength and regeneration of tissues at the wound area. Thus, this investigation confirms the use of the Himax ointment and lotion containing T.arjuna extract as a wound healing agent (Mukherjee et al., 2003).
7.12. Anti-ulcerogenic activity:
Gastric ulcer, one of the most widespread, is believed to be due to an imbalance between aggressive and protective factors. The gastric mucosa is continuously exposed to potentially injurious agents such as acid, pepsin, bile acids, food ingredients, bacterial products (Helicobacter pylori) and drugs. These agents have been implicated in the pathogenesis of gastric ulcer, including enhanced gastric acid and pepsin secretion, inhibition of prostaglandin synthesis and cell proliferation growth, diminished gastric blood flow and gastric motility. Drug treatment of peptic ulcers is targeted at either counteracting aggressive factors (acid, pepsin, active oxidants, platelet aggravating factor “PAF”, leukotrienes, endothelins, bile or exogenous factors including NSAIDs) or stimulating the mucosal defences (mucus, bicarbonate, normal blood flow, prostaglandins (PG), nitric oxide). The goals of treating peptic ulcer disease are to relieve pain, heal the ulcer and prevent ulcer recurrence. Currently there is no cost-effective treatment that meets all these goals. Hence, efforts are on to find a suitable treatment from natural product sources. The anti-ulcer activity of methanolic extract of Terminalia chebula fruits was investigated in pylorus ligation and ethanol induced ulcer models in rats. In both models the common parameter determined was ulcer index. METC produced significant inhibition of the gastric lesions induced by Pylorusligation induced ulcer & Ethanol induced gastric ulcer .The extract showed significant reduction in gastric volume, free acidity and ulcer index as compared to control. In Terminalia species, T. chebula indicates that fruit extract have potential anti ulcer activity in the both models. These results may further suggest that methanolic extract was found to possess antiulcerogenic as well as ulcer healing properties, which might be due to its antisecretory activity. (AlKofahi et al., 1999).
The etiology of peptic ulcer is unknown in most of the cases, yet it is generally accepted that it results from an imbalance between aggressive factors and the maintenance of mucosal integrity through the endogenous defence mechanisms (Piper et al., 1986). To regain the balance, different therapeutic agents are used to inhibit the gastric acid secretion or to boost the mucosal defence mechanisms by increasing mucosal production, stabilising the surface epithelial cells or interfering with the prostaglandin synthesis. The causes of gastric ulcer pyloric ligation are believed to be due to stress induced increase in gastric hydrochloric acid secretion and/or stasis of acid and the volume of secretion is also an important factor in the formation of ulcer due to exposure of the unprotected lumen of the stomach to the accumulating acid (Dhuley, 1999). Pylorus ligation induced ulcer was used to study the effect of fruit extracts on gastric acid secretion and mucus secretion. The ligation of the pyloric end of the stomach causes accumulation of gastric acid in the stomach. This increase in the gastric acid secretion causes ulcers in the stomach. The original Shay rat model involves fasting of rats for 36 hours followed by ligation of pyloric end of the stomach. The ulcer index is determined 5 hours after pylorus ligation. The lesions produced by this method are located in the lumen region of the stomach. Many authors have modified the original model.
In the present study, the Shay rat model described by Kulkarni was followed. The METC and Omeprazole significantly decreased the total acidity and free acidity; this suggests that it having an antisecretory effect. Its antiulcer activity is further supported by histopathological study shows that protection of mucosal layer from ulceration and inflammation. Ethanol induced gastric ulcer was employed to study the cytoprotective effect of the extracts. Ethanol induced gastric lesion formation may be due to stasis in gastric blood flow which contributes to the development of the haemorrhage and necrotic aspects of tissue injury. Alcohol rapidly penetrates the gastric mucosa apparently causing cell and plasma membrane damage leading to increased intracellular membrane permeability to sodium and water. The massive intracellular accumulation of calcium represents a major step in the pathogenesis of gastric mucosal injury. This leads to cell death and exfoliation in the surface epithelium (Surendra, 1990). The extract shows protection against characteristic lesions produced by ethanol administration this antiulcer effect of methanolic extract of T.chebula may be due to both reductions in gastric acid secretion and gastric cytoprotection.
The anti-ulcer effect of methanol extract of T.arjuna against Helicobacter pylori lipopolysaccharide (HP- LPS) induced gastric damage in rats was evaluated. The efficacy of T.arjuna on gastric secretory parameters such as volumes of gastric juice, pH, free and total acidity, pepsin concentration and cytoprotective parameters such as protein-bound carbohydrates complexes in gastric juice and gastric juice and gastric mucosa were assessed. The protective effect of T.arjuna was also confirmed by hispathological examination of gastric mucosa. HP-LPS-induced alternations in gastric secretory parameters and gastric defence factors were altered favorably in rats treated with T.arjuna, suggesting that T.arjuna has an antiscretory role. These results also suggested that the severe cellular damage and pathological changes caused by HP-LPS are mitigated by T.arjuna. The anti-ulcer effect of T.arjuna may reflect its ability to combat factors that damage the gastric mucosa and to protect the mucosal defensive factors (Soll, 1990).
7.13. Cytoprotective activity:
Gallic acid (GA) and chebulic acid (CA) were isolated from the extract of the herbal medicine Kashi (myrobalan, the fruit of T. chebula) as active principal that blocked the cytotoxic T- lyphocyte (CTL)-mediated cytotoxicity. Granule exocytosis in response to anti-CD3 stimulation was also blocked by GA and CA at the equivalent concentrations (Chang et al., 2010). The ethanolic extract of T. chebula fruit exhibited a notable cytoprotective effect on the HEK-N/F cells. In addition its extract exhibited significant cytoprotective effect against UV-induced oxidative damage. These observations were attributed to the inhibitory effect of the T. chebula extract on the age dependent shortening of the telomere length as shown by the Southern Blots of the terminal restriction fragments (TRFs) of DNA extracted from sub-culture passages (Minkyun et al.,2004). It exhibited the development of duodenal ulcers and appeared to exert a cytoprotective effect on the gastric mucosa in vivo (Lee et al., 2005). Cytoprotective effect on oxidative stress and inhibitory effect on cellular aging of its fruits have also been documented (Na et al., 2004).
7.14. Anticarcinogenic and antitumor activity:
Malignancy is one of the most serious diseases that damage human health in the modern world. There exists close relationship between the occurrence, growth and decline of tumor and immune states. The low immune function of an organism may not only result in the generation and development of a tumor, but also be one of the most important factors that prevent the tumor patients’ recovery. Immunomodulation through natural or synthetic substances may be considered an alternative for the prevention and cure of neoplastic diseases. The enhancement of host immune response has been recognized as a possible means of inhibiting tumor growth without harming the host. Therefore, it is very important to investigate novel antitumor substances with improving immunity potential. A group of researchers have reported the inhibitory action on cancer cell growth by the phenolics of T. chebula Retz fruit and found that chebulinic acid, tannic acid and ellagic acid were the most growth inhibitory phenolics of T. chebula (Saleem et al., 2002). Ethanol extract ofT. chebula fruit inhibited cell proliferation and induced cell death in a dose dependent manner in several malignant cell lines including human (MCF-7) and mouse (S115) breast cancer cell line, human osteosarcoma cell line (HOS-1), human prostate cancer cell (PC-3) and a non-tumorigenic immortalized human prostate cell line (PNT1A). Besides, acetone extract of bark and fruit powder of T. chebula harbors constituents with promising anticarcinogenic activity.
The effect of a bark extract of T.arjuna was studied on the alternations of adriamycin (ADR)-induced micronuclei formation in cultured human peripheral blood lymphocytes. Pretreatment of lymphocytes with extract of T.arjuna before ADR treatment resulted in a significant decline in micronuclei formation. Prior exposure of lymphocytes to extract of T.arjuna significantly reduced the frequency of lymphocytes bearing one, two and multiple micronuclei when compared with ADR-induced control. Extract of T.arjuna inhibited the induction of hydroxyl, superoxide, DPPH (1, 1-diphenyl-2-picrylhydrazyl), ABTS (2, 2-azino-bis-3-ethyl benzothiazoline-6-sulphonic acid) radicals in a dose-dependent manner. These results demonstrate the T.arjuna extract protects DNA against ADR-induced damage (Reddy et al., 2009). isolated from the bark of T.arjuna were evaluated for cytotoxicity.
The effect of aqueous extract of T.arjuna on antioxidant defence system in lymphoma bearing mice was evaluated. Oral administration of different doses of aqueous extract of T.arjuna causes significant elevation in the activities of catalase, superoxide dismutase and glutathione S transferase. T.arjuna is found to down the activity of lactate dehydrogenase in lymphoma bearing mice. The results indicate the antioxidant action of aqueous extract of T.arjuna, which may play a role in the anti-carcinogenic activity by reducing the oxidative stress along with the inhibition of anaerobic metabolism (Verma and Vinayak, 2009). Arjunic acid, arjugenin, arjunetin and arjunoglucoside ds, arjunic acid was significantly active against the human oral (KB), ovarian (PA 1) and liver (HepG-2 and WRL-68) cancer lines suggesting its role in anticancer treatment (Saxena et al., 2007).
The effect of ethanolic extract of T.arjuna on carbohydrates metabolizing enzymes of N-nitrosodiethylamine induced hepatocellular carcinoma in rats was studied. The plasma and liver glycolytic enzymes such as hexokinase, phosphoglucoisomerase, aldolase were significantly increased in cancer induced animals while glyconeogenic enzymes; glucose-6-phosphate were decreased. These enzymes were reverted significantly to near normal range in treated animals after oral administration of T.arjuna for 28 days. The modulation of enzymes constitutes the depletion of energy metabolism leads to inhibition of cancer growth. The inhibitory activity may be due to the anticancer activity of constituents present in ethanol extract of T.arjuna (Sivalokasnathan et al., 2005). Similarly results were performed with the chloroform, acetone, methanol, diethyl ether and ethyl acetate extracts of T.arjuna bark. The 4-NQO mutagenicity inhibited by more than 70% in the Salmonella/microsome test at highest nontoxic extract dose of ethyl acetate, chloroform, acetone and methanol. The results suggested that T.arjuna bark contains some nonpolar as well as polar compounds with antimutagenic activity against 4-NQO (Pasquini et al., 2002).
7.15. Adaptogenic and antianaphylactic activity:
Terminaliaplant has also found to have adaptogenic and antianaphylactic activity.T. chebula fruit was one of the six Ayurvedic herbs administered to animals to test their adaptogenic potential. All six traditional rasayana plants were able to aid the animals against a variety of different stressors working in different ways (Shin et al., 2001). Besides, animal studies show that when extract of T. chebula was administered following induction of anaphylactic shock, the serum histamine levels were reduced, indicating its strong antianaphylactic action. Water soluble fraction of T. chebula had a significant increasing effect on anti-dinitrophenyl IgE-induced tumor necrosis factor – alpha production from rat peritoneal mast cells indicating its strong antianaphylactic action. (Rege et al., 1999).
7.16. Anti-allergic activity:
Allergic rhinitis is a global health issue affecting 10% to 25% of the world’s population and Its prevalence is increasing over the last three decades (Sibbald et al., 1993). Allergic rhinitis is a significant cause of morbidity, which impairs work performance and has a significant economic impact, through the cost of treating associated conditions (asthma, sinusitis, otitis media and lower respiratory tract infections). Epidemiological studies have identified causes for the increase in prevalence of allergic rhinitis. The postulated reasons are environmental pollution4 and an increased predisposition in individuals who produce excessive immunoglobulin E (IgE) (through a major change in the gene pool) leading to increased expression of allergic rhinitis (Howarth and Holmberg, 1995). The available treatment options for allergic rhinitis have major limitations either due to less efficacy, associated adverse events or compliance issues. Antihistamines are commonly used as first-line treatment for symptom management, but they do not prevent recurrent episodes6. Use of intranasal glucocorticosteroids is questionable due to long-term adverse effects. Decongestant drugs are effective in the treatment of nasal obstruction; however, these do not improve other symptoms of rhinitis, have high incidence of adverse effects (nasal burning, stinging, dryness and mucosal ulceration) and a prolonged use (>10 days) of decongestants may lead to rebound swelling of the nasal mucosa (rhinitis medicamentosa).
Studies with the leukotriene receptor antagonist as a sole therapy in allergic rhinitis, have proved disappointing (Salib et al., 2003). Ayurveda, an Indian system of medicine, has described several drugs from indigenos plant sources for use in the treatment of bronchial asthma and allergic disorders. HK-07 is one such polyherbal formulation containing mainly the extracts of Curcuma longa, Ocimum sanctum, Adhatoda vasica, Trikatu, Terminalia chebula, &T.arjuna, T.bellerica,Embelia ribes, Cyperus rotundus,. The dry rhizome of Curcuma longa contains curcumin, the main bioactive component, demethoxycurcumin, and bisdemethoxycurcumin. The traditional uses of turmeric or natural curcuminoids in folk medicine are multiple, and some are based on their antioxidant, antiinflammatory and antiallergic properties which have been confirmed by various experimental studies. Terminalia bellerica demonstrated potent antiperoxidative activity and inhibited lipid peroxide formation by scavenging hydroxyl and superoxide radicals in vitro (Sabu and Kuttan, 2002).HK-07 prolonged the latent period of preconvulsive dyspnea (PCD) in guinea pigs following histamine aerosol. This may be suggestive of an antihistaminic activity following treatment with HK-07. It also offered protection against anaphylactic shock-induced bronchospasm in rats.
Aller- 7, a polyherbal formulation of seven medicinal plants T.chebula exhibited potent in vitro anti-allergic activity in isolated guineapig ileum substrate (Pratibha et al., 2004).
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7.17. Antifertility activity:
Despite many achievements in human health care in the twenty first century, population in developing countries lack regular access to affordable essential drugs. For these people, modern medicine is never likely to be a realistic treatment option. In contrast medicinal plants are widely available and affordable, even in remote areas. The cost of modern medicine is increasing by modern health technology and in many cases is inappropriate to the immediate needs of people in developing countries. Traditional medicine is sometimes the only affordable source of health care especially for the world’s poorest patients. There is no thorough scientific investigation on most of the claims made by the traditional medicine practitioners. One of the main challenges is lack of coherent national health policies and development plans that will include traditional medicine research and development, allocation of financial and other resources of traditional Medicine research. In addition there is deficiency of systematic plans for developing research capacity in traditional medicine leading to lack of a critical mass of traditional medicine researchers including traditional health practitioners.
The magic of Terminalia plants in reducing fertility of mammalian species is well established. A number of plants from Indian origin have been experimentally tested using modern techniques for their antifertility activities. Maurya et al. (2004) have also given a review to provide an account of the studies carried out on traditional plants which are used for fertility regulation. Phytochemical screening has revealed many bioactive as well as toxic agents such as alkaloids, tannins, phlobatannins and anthraquinones, phenolics, flavonoids, cardenolides and dienolides, glycosides, saponins, steroids and triterpenes of plant extract of Cnidoscolous aconitifolius leaves and fruits of Terminalia bellerica affect the regulation of oestrous cycle, conception and reproduction.Terminalia belericahave anti-implantation activity (Maurya et al., 2004).
7.18. Antimutagenic activity:
Phytoconstituents of Terminalia plants have been screened for antimutagenic activity. The benezene, chloroform, acetone and mrthanol extracts of T.arjuna have high antimutagenic efficacy. The antimutagenic effect of benzene, chloroform, acetone and methanol fractions from Terminaliaarjuna, a well-known medicinal plant, was determined against Acid Black dye, 2-aminofluorene (2AF) and 4-nitro-o-phenylenediamine (NPD) in TA98 Frameshift mutagen tester strain of Salmonella typhimurium. Among the different fractions, the antimutagenic effect of acetone and methanol fractions was more than that observed with other fractions. Moreover, these fractions inhibited the S9-dependent mutagens, 2AF and Acid Black dye more effectively than the direct-acting mutagens. Studies are under way to isolate and elucidate the nature of the antimutagenic factor in acetone and methanol fractions (Kaur et al., 2002). Alongwith T.arjuna, antimutagenic activity of aqueous extract and hydrolyzable tannins from T. chebula in Salmonella typhimurium has been documented (Grover and Bala., 1992). Gamma radiation induced strand breaks formation in plasmid PBR322 DNA was inhibited by aquesous extract of T. chebula (Naik et al., 2004). The administration of aqueous extract of T. chebula prior to whole body irradiation of mice resulted in a reduction of peroxidation of membrane lipids in the mice liver as well as a decrease in radiation induced damage to DNA. It also protected the human lymphocytes from undergoing the gamma radiation-induced damage to DNA exposed in vitro (Gandhi and Nayaret al.,2005). T. chebula showed chemopreventive effect on nickel chloride -induced renal oxidative stress, toxicity and cell proliferation response in male Wistar rats (Prasad et al., 2002).
8. Clinical studies:
Several studies have been to assess the efficacy of T.arjuna bark in cardiac disorders.Decoction of bark powder was found more useful in hypertensive heart disease as compared to congestive heart failure. Alcoholic decoction of bark was found to be beneficial in stable cases of ischemic heart disease. Prolonged use of drug brought sense of well being in patients and increased euglobulin lysis time and prothrombin time. The drug also showed electrocardiographic improvement (Anand, 1994). Solidified aqueous extract of Arjuna bark when administrated in doses of 500 mg B.D. for 3 months along antianginal drugs proved useful in reducing tread mill test positivity and increase in exercise tolerance in 25 angina patients. However, there was no reduction in the consumption of antianginal drugs (Sharma et al., 2005). A clinical trail was taken on 51 pateints of coronary heart disease to assess the effect of T.arjuna. All patients were administrated with 2 capsules of 500 mg in morning and in evening with milk for 4 months followed up each month. Reduction in systolic and diastolic blood pressure, pulse rate, serum cholesterol and HDL and LDL cholesterol was noticed (Arora et al., 1995). To evaluate the antioxidant and hypercholesterolaemic effects of T.arjuna bark and to compare it with a known antioxidant, vitamin-E a randomized controlled trail was performed on 105 patients with Coronary Heart Disease (CHD). There was a significant decrease in total cholesterol and LDL cholesterol with the drug group. Lipid peroxide levels decreased significantly in both the treatment groups. This decrease was more in vitamin E group as compared to the T.arjuna group. T.arjuna tree bark powder has significant antioxidant action that is comparable to vitamin E. In addition, it also has a significant hypocholesterolaemic effect (Gupta et al., 2001).
Oral rinsing with extract of T. chebula was found to significantly reduce both total bacterial counts and streptococcal counts in saliva samples. The protective effect lasted for about 3 hours. After rinsing, demonstrating the potential role of T. chebula in the prevention of dental caries (Kannan et al., 2009). A short term clinical trials have been carried out on patients with simple constipation. T. chebula increases the stools and has got property of evacuating the bowel completely. Besides, some Ayurvedic drugs, consisting of T. chebula as one of the constituents have been subjected to clinical trials regarding their effects on constipation, mental and physical disability, allergic rhinitis and mental stress. In all the case T. chebula containing drugs showed good effects in the treated groups when compared to their normal control patients (Mukherjee et al., 2006).
9. Conclusion:
The extensive survey of literature revealed that Terminalia species (T.bellerica, T.arjuna, T.chebula), are important medicinal plants having a wide spectrum of pharmacological and medicinal activities. Terminalia bellerica is widely used in Ayurveda, Siddha, Chinese medicine etc. The vast study done on the plant proved that the plant has many important phytoconstituents like Gallo-tannic acid, bellericanin, ellagic acid, gallic acid, termilignan, thanni lignin, flavones and anolignan B, Tannins, ellargic acid, ethyl gallate, gallonyl glucose and chebulaginic acid, phenyllemblin, beta-sitosterol, mannitol, glucose and rhamnose. These compounds are responsible for many of the pharmacological activities such as antimicrobial, antiocidant, antidiarrhoeal, antidiabetic, analgesic, immunomodulatory, antihypertensive, antisalmonella, hepatoprotective, antispasmodic and bronchodilatory activities, cardiovascular activities, antimutagenic and anticancer activities and wound healing activities. Further the plant is used in the treatment of gastric ulcer, constipation, general debility, piles. In a same way, T.chebula and T.arjuna having wide spectrum diverse pharmacological spectrum. Though it has a number of pharmacologicalactivities due to the presence of various types of bioactive compounds, very little work has been done on the plausible medicinal applications of this plant against the diseases particularly on multidrug resistant bacterial pathogens. Hence, extensive investigation is needed to exploit their therapeutic ability to combat diseases including drug resistant infections. As the global scenario is now changing towards the use of nontoxic plant products having traditional medicinal use, a drug development programme should be undertaken to develop modern drugs with the compounds isolated from T. chebula effective against different types of diseases and also to overcome the problem of drug resistanceafter extensive investigation of its bioactivity, mechanism of action, pharmacotherapeutics, toxicity and after proper standardization and clinical trials. Hence, these plants provide a significant role in the prevention and treatment of disease. Further evaluation needs to be carried out on order to explore the concealed areas and their practical clinical applications, which can be used for the walfare of the mankind.
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