Phytochemistry and Pharmacological Potential of Terminalia arjuna L

To cure human diseases, medicinal plants have been a major source of therapeutic agents since ancient time. Terminalia arjuna is one kind of widely used medicinal plant throughout Bangladesh and used in various indigenous system of medicine like Ayurveda, Sidda and Unani. This plant has been reported to contain active constituents including arjunolic acid, gallic acid, terminic acid, pyrocatechols, β-Sitosterol, calcium, magnesium, zinc, copper etc. which proved to be effective pharmacological agents as antimicrobial, anticancer, antidiabetic, antiacne, antihelmintic, antiinflammatory, anticholinesterase, antioxidant, antiasthmatic as well as wound healing, cardioprotective and insecticidal activities. It is considered to be an ideal agent for treating cancer, coronary artery disease, hypertension and ischemic cardiomyopathy. The present comprehensive update review is therefore an effort to give detailed information on phytochemical and pharmacological studies of T. arjuna.


Background
Terminalia arjuna is a native Bangladeshi tree with simple leaf, smooth and thick bark belonging to the family Combretaceae. Flowers are small, regular, sessile, cup-shaped, polygamous, white, creamy or greenish-white and robustly honey-scented and flowering from April to July. The inflorescences are short axillary spikes or small terminal panicles and fruits are obovoid-oblong, dark brown to reddish brown fibrous woody, indehiscent drupe and ripening from February to May (Orwa et al., 2009;Bhat et al., 2003). All the parts of the plant have been used for their therapeutic beneficiary effect from ancient times. T. arjuna helps to maintain a healthy heart and decrease the effects of stress and anxiety (Emran et al., 2011). It has antibacterial (Perumalsamy et al., 1998), antimutagenic, hypolipidemic, antioxidant and hypocholesterolaemic and anti-inflammatory effects (Tripathi et al., 2005). T. arjuna have the capability to protect the liver and kidney tissues against CCl 4 -induced oxidative stress by increasing antioxidative defense activities (Manna et al., 2006). Its chemical constituents act as a gastro-protective agent . Different types of bioactive compound have been isolated from this medicinal plant possesses enormous value in medicine among then arjunolic acid is very well known. The aim of the present study was to deliver the literal studies of T. arjuna with its phytochemical and pharmacological characteristics.

Phytochemistry
It was initially reported that the bark had 34% ash content consisting entirely of pure calcium carbonate. The water extract existence 23% calcium salts and 16% tannins, whereas the alcoholic extract contained very little coloring matter and tannins (Dymock et al., 1891). The chemical analysis of the bark showed confirmation of sugar, tannins (12%), coloring matter, glycoside, and carbonates of calcium, sodium and traces of chloride of alkali metals (Ghoshal, 1909). The chemical constituents of T. arjuna are shown in Table 1.

Bioactive compounds
T. arjuna has medicinal and economic value due to the presence of different bioactive compounds showing biological activities in human and animal body (Zaidi, 1998). Some bioactive compounds showing biological activities reported so far are summarized in Table 2. antifungal, anti inflammatory, antispasmodic, antitussive, immunoenhancer, increases coronary flow, protein kinase C inhibitor, succinic oxidase inhibitor, antihypercholesterolemic Zhou et al., 2011c Kaempferol (C 15

Pharmacological Values
A number of previous studies reported a wide number of pharmacological activities of T. arjuna. It can be used to treat diabetics, heart diseases as well as for the treatment of wound. It has antiviral, antibacterial, anticancer and other potential anti-ailment properties.
(i) Antimicrobial activity: Perumalsamy et al (1998) reported that the aqueous extracts of T. arjuna bark holds major antimicrobial activity against Proteus vulgaris, Klebsiella aerogenes, Escherichia coli and Pseudomonas aerogenes. The presence of antibacterial activity in the bark of T. arjuna exhibiting selectively maximum activity against S. epidermidis (Singh et al., 2008). Antimicrobial activity of different solvent extracts from T. arjuna reported previously are summarized in Table 3.  (Sarveswaran et al., 2006). (v) Antidiabetic activity: The T. arjuna extracts have potential effects on diabetic. In the experimental diabetic rats model treated with T. arjuna extracts showed two enzymes (glucose-6-phosphatase, fructose-1, 6-diphosphatase) significantly reduced in liver and kidney. This has effects on increasing insulin secretion which can effects on repression of the gluconeogenic key enzymes (glucokinase and phosphofructokinase) (Ragavan et al., 2006). Terminalia arjuna bark extract exhibited antidiabetic activity by enhancing the peripheral utilization of glucose which have the ability to kidney glycolysis and correcting the impaired liver and by decreasing its gluconeogenic formation as like as insulin. This effect may be due to the presence of tannin, saponin, flavonoids and other constituent's presence in the bark, which could act synergistically or independently in enhancing the activity of glycolytic and gluconeogenic enzymes (Ragavan et al., 2006). Manna et al (2009a;2009b) have investigated the prophylactic role of arjunolic acid against streptozotocin (STZ) induced diabetes in the pancreatic tissue of Swiss albino rats. STZ administration (at a dose of 65mg/kg body wt, injected into the tail vein) causes an increase in the production of both ROS and reactive nitrogen species (RNS) in the pancreas of experimental animals. Formation of these reactive intermediates decreases the intracellular antioxidant defense, increases the levels of lipid peroxidation, protein carbonylation, serum glucose and TNF-α (Puvanakrishnan et al., 2010).
(vi) Antiacne activity: Topical formulations (cream) of T. arjuna extract containing flavonoid (FF-I to III) and tannin fraction (TF-I to III) have been developed, which were examined for antimicrobial activity against Propionibacterium acnes and Staphylococcus epidermidis. The formulation of FF-III (cream containing 2% flavonoid fraction) has showed higher antibacterial activity against P. acnes (zones of inhibition >17 mm) and S. epidermidis (zones of inhibition >20 mm) than other formulations and which is comparable to that of standard marketed topical herbal preparation (Vijayalakshmi et al., 2011). Herbal anti-acne cream is non-toxic, safe, effective and improves patient compliance by the utilization of herbal extracts from T. arjuna would be highly acceptable (Vijayalakshmi et al., 2011).
(vii) Anthelmintic activity: Crude methanolic extracts of T. arjuna bark exhibited anthelmintic activity both in vitro (eggs, larvae and adult of Haemonchus contortus and in vivo studies against mixed gastrointestinal trichostrongylid nematodes of sheep (Bachaya et al., 2009). Anthelmintic activity of T. arjuna bark may be mainly attributed to its tannin content that binds with a free protein existing in the tubes for larval nutrition and reduced nutrient availability resulting in larval starvation or decreased gastrointestinal metabolism by directly inhibiting the oxidative phosphorylation thereby causing larval death (Bachaya et al., 2009).
(viii) Wound healing activity: The hydroalcoholic extract of T. arjuna bark phytoconstituents was reported to be used in topical application on healing rat dermal wounds. Wounds created on the back of rats under anesthesia have been treated with various fractions applied topically as simple ointment. Results prove that fraction III prepared as 1% simple ointment shows complete epithelialization on day 20, whereas fraction I show complete epithelialization on day 9, which essentially consists of tannins (Puvanakrishnan et al., 2010). Mengi et al (2003) reported the capability of T. arjuna to complete epithelisation of excision wounds and increased tensile strength of incision wounds.
(ix) Cardioprotective activity: There are different types of therapeutic use of T. arjuna for cardiac disease that based on empirical explanation recorded in various treatment of ancient medicine.
(a) Cardiotonic activities: Arjunolic acid is used as a cardiac tonic in ayurvedic medicine for centuries and it has been first isolated from T. arjuna. The bark extracts have major component triterpenoid saponin is an arjunolic acid (Puvanakrishnan et al., 2010). Physiological studies carried on the isolated rabbit and frog heart exposed that T. arjuna bark had cardiotonic and stimulatory effect (Ghoshal, 1909). It was consequently found that intravenous administration of the glycoside, obtained from the bark of T. arjuna, resulted in rise in blood pressure (Ghosh, 1926). It was indicated that the bark powder has a cardiotonic property, also possessed diuretic properties. Consequent experimental studies in isolated frog heart exposed that the aqueous extract of the bark had chronotropic and inotropic activities. The aqueous extract of the bark is isolated from rat atria that confirmed positive inotropic activity (Radhakrishnan et al., 1993). Aqueous extract of the bark was isolated from rat atria that was again confirmed in consequent work where produced inotropic action which was abolished by propanolol and cocaine (Karamsetty et al., 1995). The new compound 16,17-Dihydroneridienone, 3-O-β-Dglucopyranosyl-(1-6)-O-β-D-galactopyranoside is isolated from arjuna root and used as a cardiotonic (R.N. Yadav et al., 2001).
(b) Coronary flow: Bhatia et al. (1998) reported to inject aqueous extract of the bark injection into isolated rabbit heart (Langendorff's) to increase in coronary flow. The dose was 1024 µg/ml that causes highest increase in coronary flow.
(c) Hypotensive effects: Singh et al. (1982) reported intravertebral and intracerebro-ventricular injection of alcoholic and aqueous extract of bark that was dose-dependent persistent bradycardia and hypotension. Further the alcoholic extract causes the hypotensive effect in dogs was abolished by pre-treatment with atropine. In another study the observation in dogs where intravenous administration of aqueous extract of T. arjuna resulted in dose-dependent fall in blood pressure (Srivastava et al., 1992).
(d) Effect on aortic prostaglandins: Aortic prostaglandin E 2 like activity was enhanced in those rabbits that were administered T. arjuna compared to those who were on placebo. The finding of raised PGE 2 like activity was significant because PGE 2 is known to produce coronary vasodilation. This may possibly explain the pharmacological basis of the increased coronary flow following T. arjuna infusion (Bhatia et al., 1998). This may also be contributing to the beneficial effect of T. arjuna in coronary artery disease (CAD) patients. (xi) Insecticidal property: Arjunolic acid isolated from the stem of T. arjuna exhibits significant inhibitory activity towards fourth instar larvae of Spilarctia obliqua. Effective concentration to reduce feeding and growth of the larvae has been found to be 617.8 and 666.9 ppm, respectively (Puvanakrishnan et al., 2010).
(xii) Antioxidant activity: In antioxidant activity test, the methanol extract of T. arjuna bark exhibited significant antioxidant activities with the IC50 value of 7.05 µg/ml. Methanol extract of T. arjuna has intense antioxidant activity and may have potential use in medicine (Rahman et al., 2011).
(xiii) Antiasthmatic activity: Arjunolic acid and alcoholic extract of T. arjuna have significant mast cell stabilization activity and specifically, arjunolic acid exhibits comparatively better stabilization activity than alcoholic extract of TA (Prasad et al., 2004). The antiasthmatic and antianaphylactic activity may be due to the mast cell stabilizing potential and inhibition of antigen induced histamine and acetylcholine release (Prasad et al., 2004;Puvanakrishnan et al., 2010).
(xiv) Gastroprotective effect: T. arjuna acts as an gastroprotective agent probably due to its free radical scavenging activity and cytoprotective nature .

Traditional use
T. arjuna is widely used and known as ayurvedic plant. Physicians used it for its curative properties in different types of heart problems including hypertension, angina and blocks in arteries. It is also very useful in the treatment of any sort of pain in heart such as falls, spermatorrhoea, ecchymosis and sexually transmitted diseases as gonorrhea and thought to be a useful astringent, cooling, aphrodisiac, cardio-tonic, and is used for ulcers, leucorrhoea, diabetes, cough, tumor, excessive perspiration, asthma, inflammation and skin disorders etc (Parakh, 2010).

In vitro Propagation of T. arjuna
There are different types of species that are being threatened and are endangered (IUCN 2011) because of logging practices, non-optimal management strategies, exchange to agricultural lands and generally deforestation rates that cannot keep up with natural regeneration of native forests. In vitro propagation of arjuna from different parts has been reported by Pijut et al. (2012). Arjun was propagated from nodal explants of a mature tree on half-strength MS medium with 4.44 µM BA and 0.53 µM NAA. Seasonal variations were found to affect the proliferation rates with the best rate obtained from material collected during April or May. Rooting was obtained on medium with 4.92 µM IBA and plants were acclimatized (Pandey et al., 2006).

Conclusion
The present review reveals that T. arjuna is a very important plant for its large number of phytochemical and pharmacological properties as well as medicinally important chemicals. The plant was found to be very useful in antibacterial, antiviral, antimutagenic, anti-inflammatory and wound healing activities. The most exciting aspects of the plant were treatment of diabetics, cancer and heart diseases. This compendium literature supports various potential medicinal characteristics of T. arjuna. Thus this review can be a preliminary authentic source for the researchers willing to carry out further research and systematic study to develop herbal and poly-herbal drugs from T. arjuna.

Authors' contributions
Khan ZMH and Faruquee HM conceived the work; Shaik MM designed the project; Shaik MM and Faruquee HM analyzed the data; Shaik MM, Faruquee HM and Khan ZMH wrote the paper.