Abstract: Medicinal plant Terminalia arjuna are used in folkoric system for the treatment of the various disease and disorder since ancient time. This study validated the folkoric system experimentally with modern drug approaches. The main objective of this review was to explore the pharmacological aspect of Terminalia arjuna, a indigenous medicinal plant. Medicinal plants have been recognized as major source of therapeutic agents to cure the human disease, as green medicine is healthier than synthetic products. The Arjuna was introduced into Ayurveda as a treatment for heart disease by Vagbhata (c. 7th century CE). It is traditionally prepared as a milk decoction. This plant was a known practice for thousands of years, in ancient Indian Vedas, Vagbhata mentions Arjuna in the treatment of wounds, hemorrhages and ulcers, applied topically as a powder. There is a vast variety of plants, which are rich source of bioactive compounds and several more might still be lying unexplored. The available compounds of Arjuna are more potent against snail-borne diseases and used as molluscicidal agents. Arjuna has also been found effective as an antioxidant, protect cardiovascular diseases and very helpful in regulating the hormonal system of the body. Ailments like eczema, itching, rashes scars and serious skin conditions like psoriasis can also be treated with the regular use of Terminalia arjuna. On the basis of ongoing literature and scientific reports the medicinal plant Terminalia arjuna has nature’s boon to mankind.
INTRODUCTION
Medicinal plants have been recognized as major component of all traditional system of medicine to cure the human disease, since ancient time and till today because of green medicine is healthier than synthetic counterparts. A large number of wild medicinal plants are to be brought in to cultivation in order to explore its therapeutic potential. Keeping this view the concentrate efforts are needed to make the available compound more potent against disease and safer to environment by way of improved formulations. As per WHO reported about 80% of world population relayed on traditional medicine in India1. The main Indian traditional system of medicine is primarily plant based system2. Terminalia arjuna is traditionally widely used in the medical formulation of various aliment due to the presence of large number of active phytoconstituents3. In the Indian traditional system of medicine, the bark is used as astringent, cooling aphrodisiac, cardiotonic, tonic in fracture, ulcer, spermatorrhoea, leucorrhoea, diabetes, cough, tumor, asthma, inflammation and skin disorder4,5. Primarily, the ingestion of medications prepared with bark of Arjuna ensures usual functioning of the heart, provides energy to the heart muscles, promotes the functioning of platelets as well as helps in sustaining a steady blood pressure level. Arjuna helps in thickening of the serum and the sperm that is very essential for the proper fertilization of the ovum. It is helpful in increasing the sperm count. It is capable in treating polyurea condition and is also helpful regularizing the increased urine frequency6. It is also useful to cure obesity, hypertension and hyperglycemia7. Keeping in the view of the medicinal importance of the tree in traditional and Ayurvedic system of medicine an attempt has been made to review the available literature. This aim of this comprehensive review was to provide the efficacy and advancement of Terminalia arjuna in herbal drug research covering the area of enthnomedical, phytochemical and pharmacological.
EFFICACY AND ADVANCEMENT OF T. ARJUNA
IN HERBAL DRUG
Classical names: Terminalia arjuna is known by its various classical names, such as Arjuna, Dhavala, Kaubha, Nadisaraja, Veeravrikskha, Partha and Indradru8.
Botanical description: Terminalia arjuna L. (Combretaceae) is a large evergreen deciduous tree (Commonly known as Arjuna) found throughout India growing to a height of 20-25 m. It commonly grows on banks of rivers, streams and dry watercourses and distributed throughout the greater part of Indian sub-continent, Himalayan tract of Uttar Pradesh, Chota Nagpur, Orissa, west Bengal, Punjab, Deccan and Konkan9,10. The bark of Terminalia arjuna is soft and thick with grey in colour on outer surface and tinge easily flakes off in flat large pieces inside.
Leaves of T. arjuna are simple, borne opposite shortly acute or obtuse at the apex, glabrous 4-6 inch long and 2-3 inch wide, there are two glands near the base of the petiole. There is a morphological difference in leaf traits of this plant11. It has pale yellow flowers with short auxiliary spikes or terminal panicle arrangement, which appear between March and June; its glabrous, 2.5-5cm fibrous woody fruit with smooth skinned divided into five hard wings, appears between September and November.
Phytochemistry: The major chemical constituents analysis of different parts of T. arjuna was carried out by various standard technique like HPLC, UPLC and LC-ESI-MS/MS analysis12-15. The Terminalia arjuna bark extract revealed the presence of bio-active chemical constituents which are known to exhibit medicinal as well as physiological activities16. The chemical constituent of different classes such as; hydrolysable tannins17, triterpenoides acid (Fig. 1) and their glycosides16,18, flavonoids19, phenolics20, phytosterol21 found in stem bark portion of T. arjuna species. Arjunglucoside 1-3, arjunolic acid and terminoic acid were important constituent of bark (Table 1)22.
Ayurvedic formulation: Terminalia arjuna is tremendous plant having enormous influence in ayurvedic system of medicines. In Rigveda, the word ‘Arjuna’ used either to indicate the white colour or one of taintless fame and glow like silver41,42. It may be the first reference of Arjuna used as medicine stated in chief or principle sutra volume of Atharvaveda, Kaushiksutra (400300 B.C.). Further synonyms and properties of Arjuna are mentioned in Bhavprakash Nighantu.
| Fig. 1: | Arjunolic acid |
| Table 1: | Phytochemical and major chemical constituents of various parts of Terminalia arjuna |
Later on Chakradatta, the great ancient physician, recommended uses of Arjuna bark in form of decoction with milk (Kshirpaka) or as a ghrita (a preparation with ghee)3.
USES OF ARJUNA IN TRADITIONAL AYURVEDIC HERBALISM
Generally stem, bark, fruits and leaves of Arjuna are used in human therapeutic. Fresh leaves juice used in the treatment of earache and root paste used in headache43. Fruit paste was used topically as a traditional healer in south India44. It was also used to treat cough, sore throat and dyspepsia45. The bark was the main part used in Ayurveda as well as in allopathy for curing various diseases46. Bark ash is prescribed on snakebite and scorpion sting47. This act was astringent, cooling cardiotonic, antidysentery, urinary astringent, hypertension, hemorrhage, diarrhea associated with blood, cirrhosis of liver, hypertension inflammation and skin disorder48.
Pharmacological significance: Since the time immemorial T. arjuna has been a herb of choice in dealing with the treatment of many cogenitous disease. It serve as a blessing in Indian traditional (Ayurvedic) as well as allopathy medicinal system46 and posses the wide range of therapeutic properties and has the potential to treat many medical condition2.
Cardio-protective activity: The Arjuna plant (lat. Terminalia arjuna) has traditionally been used to treat heart disease for centuries, that is why it got the nickname “Guardian of the heart”. It was also known as hero of the famous epic “Mahabharata” because of its protective effects. Researchers studied the cardio-protective role of chronic oral administration of methanolic extract of T. arjuna bark in in vitromyocardial ischemic reperfusion injury and the induction of HSP72. The results of the study suggested that the methanolic extract of the bark powder of T. arjuna in rat induces myocardial HSP72 and augments myocardial endogenous antioxidants, without causing any cellular injury49. The ongoing researches demonstrated that T. arjuna ethanolic extract and aqueous extract both produced significant cardio-protection in isoproterenol induced mayocardial infraction animals50. The bark of T. arjuna was used in India as cardio-protective agent in hypertension and eschaemic heart disease51. The antioxidant properties of ethanol extract of bark of T. arjuna against sodium fluoride (NaF)-induced oxidative stress in murine hearts52. High amount of plant extract should not be consumed because, hepatotoxicity as well as hypothyroidism may be caused by them53. Arjunanin was very good cardio-protective drug used on the process of respiratory oxybrust54. The T. arjuna bark extract had a significant prophylactic and therapeutic beneficial effect on protection of heart against ISO-induced chronic heart failure possibly through maintaining endogenous antioxidant enzyme activities, inhibiting lipid peroxidation and cytokine levels. This cardio-protective action of T. arjuna was comparable to fluvastatin, a synthetic drug to cure heart disease55. In a study of human monocystic (THP-1) and human arotic endothelial cells (HAFECs), cell was cultured by using alcoholic and aqueous extract of T. arjuna stem bark provide a biochemical and molecular basis for the therapeutic potential against cardiovascular disease (CDV) as it significantly inhibits the lipid peroxidation and human 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA)15. Alcoholic and aqueous extracts of T. arjuna showed significant inhibition in the activity of CYP3A4, CYP2D6 and CYP2C9 enzymes. Enzyme kinetics study suggested that treatments caused rapidly reversible non-competitive inhibition of all three enzymes human liver microsomes56. The T. arjuna helps in maintaining the cholesterol level at the normal rate, as it contains the antioxidant properties similar to the vitamin E. It strengthens the heart muscles and maintains the heart functioning properly. It also improved functioning of cardiac muscle and treatment of coronary artery disease, heart failure, angina and hypercholesterolemia. Its bark powder contained asthma, diuretic, prostaglandin enhancing and coronary risk factor modulating properties50. Experimental studies on Arjuna pertaining the various aspect of its cardiovascular functions, autonomic control of myocardial functions, molecular mechanisms of its action and cardiac histopathological aspects57. A new study demonstrated the therapeutic benefit of T. arjuna in diabetes with co-existing cardio-vascular disease58.
Hepatoprotective activity: The preventive role of arjunolic acid against arsenic induced cytotoxicity in isolated murine hepatocytes was evaluated by Manna et al.59. The aqueous extract of T. arjuna bark could protect the liver and kidney tissue against CCl4 induced oxidative stress probably by increasing anti-oxidative defense activity51. The anti-oxidative effect of T. arjuna bark against DEN-induced liver cancer was also studied60. It was found that aqueous and ethanol extract of T. arjuna bark showed the hepatoprotective potential against paracetamol/CCl4 induced liver damage in Wistar albino rats. Pre-treatments of the rats with the ethanol and aqueous extract prior to paracetamol/CCl4 administration caused a significant reduction in the value of serum glutamic pyruvic transaminase (SGPT), serum glutamic oxaloacetic transaminase (SGOP) and serum alkaline phosphatase (SALP) and serum bilirubin (SB) almost comparable to silymarin, standard hepatoprotective agent. Hepatoprotective activity was confirmed by histopathological examination of control and treated rats61. The extract of T. arjuna bark was investigated for its hepatoprotective and antioxidative effect on cadmium provoked toxicity and the result of the experiment indicated that Terminalia arjuna (200 mg kg–1) significantly reversed the effect of cadmium and proved that it has hepatoprotective and antioxidant potential62. The T. arjuna bark aqueous extract was found to be a potential therapeutic agent against alcohol induced oxidative/nitrosative stress mediated hepato and nephrotoxicity in rats63. Alcohol administration significantly raised the plasma concentrations of nitrogenous compounds and increased activities of alcoholic marker enzymes. Administration of aqueous bark extract to alcoholic rats significantly brought these alterations in plasma to normal and also significantly reduced the levels of lipid peroxidation and restored the enzymatic and non-enzymatic antioxidants in liver. Co-administration of alcohol along with bark extract offered protective effect against alcohol-induced stress in rats. Further, it was reported that the methanolic extract of Terminalia arjuna stem bark and its purified flavonoids (baicalein and quercetin) exhibit hepatoprotective effect against CCl4 induced hepatic damage5. Its hepatoprotective role was due to its flavonoids content. Quercetin showed more protective effect than bicale in in vitro5. Arjunolic acid a major active constituent of Arjuna gives a promising result in the treatment of non-alcoholic fatty acid liver disease as it significantly reduced the lipid level in palmitate-oleate induced HePG2 cell and also reduced the level of LDH, ALT, AST and GGT in HFD rats64.
Anti-inflammatory and analgesic activity: Anti-inflammatory activity of T. arjuna bark powder was investigated by Halder et al.65. Constituents from the stem bark of Arjuna showed potent antioxidant activity and inhibited Nitric Oxide (NO) production in lipopolysaccharide (LPS) stimulated rat peritoneal macrophages32. The poly herbal formulation of ethanolic extract of Datura stramonium (leaves), Terminalia arjuna (bark) and Withania somnifera (root), have anti inflammatory effect and inhibits the enzyme cyclooxygenase (COX) leading to inhibition of prostaglandin synthesis using inflammation at third stage. The result proved the polyherbal formulation showed significant anti-inflammatory and analgesic activity66. The extract of Terminalia arjuna was used in the study of Carrageenan-induced paw edema method to study the anti-inflammatory activity and observed that extract significantly reduced the formation of edema induced by carrageenan. The extract was also used to evaluate the centrally acting analgesic potential using formalin, hot plate and peripheral pharmacological actions using acetic acid induced writhing test in mice. The extract of the plant was found to have significant (p<0.01; p<0.001) analgesic activity at the oral dose of 250 and 500 mg kg–1 b.wt., in the tested models67. The anti-inflammatory activity of Arjuna Kaseera paka an ayurvedic formulation of T. arjuna (prepared in cow milk) and compared with hydroalcoholic extract. The result of the study showed that AKP has higher efficacy that could be due to the presence of milk solids. Milk solids act as adjuvant to T. arjuna phytoconstituents contributing to their sustained bioavailability leading to higher efficacy at lower drug concentration68.
Anti-tumor and cytotoxic activity: Terminalia arjuna is herbal medicine against environmental carcinogenicity as the T. arjuna bark extract protects DNA against ADR induced damage69. The aqueous extract of stem bark showed anti-oxidant action on anti-carcinogenic activity by reducing the oxidative stress along with inhibition of anaerobic metabolism70. The arjunic acid was significantly activated against human oral, ovarian and liver cancer cell lines suggesting its role in anti-cancer treatment71. It was reported that the ethanolic extract of bark of T. arjuna has significant analgesic and cytotoxic effect67. Arjunolic acid isolated from T. arjuna showed the cytotoxic activity against carcinoma and lymphoma cancer cell72. The anti-carcinogenic anti-mutagenic potential of Terminalia arjuna extract in vivo and in vitro was also studied73. Anti-cancer potential of T. arjuna bark extract against some human cancer cell line was studied by Singh et al.74. The methanolic extract of Arjuna was rich in the flavonoids content responsible for its antiproliferative effect. It was studied that phytosome complex of methanolic extract of Terminalia arjuna bark has antiproliferative effect on human breast cancer cell lines (MCF-7) as compared to methanolic extract75.
Gastric activity: The methanolic bark extract of T. arjuna showed a significant increase in the adherent mucus of the gastric wall and in the protein bound carbohydrate complexes of the gastric juice in rats treated with diclofenac sodium76. Anti-ulcer effect of methanol extract of T. arjuna against Helicobacteron pylori lipopolysaccharide induced gastric damage in rat were evaluated by Devi et al.77. The findings of the result suggested that Arjuna has ability to combat factor that damage the gastric mucosa.
Wound healing activity: The topical application of T. arjuna bark hydroalcohol extract on rat dermal wounds using in vivo models was assessed the wound healing capacity of T. arjuna. The result strongly documented that the beneficial effect was due to its tannin content78. Herbal formulation of Himax ointment and lotion containing T. arjuna extract was evaluated for its wound healing potential and the result was comparable to the standard drug nitrofurazone79. The T. arjuna bark powder mix with coconut oil was found to be potentially effective against chronic wound80.
Antibacterial activity: Strong antibacterial activity was shown by the methanol extracts of T. arjuna against multi drug resistance salmonella typhi 81. The T. arjuna plant extract have great potential to been developed as herbal ear drops to control bacterial ear infection. The leaves and bark extract as potent and effective medicine against tested bacterial responsible for ear infections than that of standard ear drop82. Antibacterial and cytotoxic activity of T. arjuna bark aqueous and methanolic extract was experimentally carried out by using the agar gel diffusion method against Escherichia coli, Klebsiella sp., Pseudomonas sp. and Staphylococcus sp. Aqueous and methanolic extract of T. arjuna showed inhibition against all the mentioned organism in dose dependent manner83. Antibacterial, antifungal brine shrimp lethality and phytotoxic effect of Terminalia arjuna was performed by Javed et al.84. The results showed that methanolic extract of T. arjuna leaves has moderate antifungal effect against Microsporm canis and fruit extract posses good antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa. Moreover, dichloromethane extract of T. arjuna bark and fruit posses moderate phytotoxic activity. A recent study find that the T. arjuna bark and leaves ethanolic extract and its different solvent fraction show strong antimicrobial activity against Bacillus subtilis, staphylococcus aureus, Eschericia coli, Klebsiella pneumonia, Pseudomonas aeruginosa and Salmonella typhi, respectively85.
Antioxidant activity: Antioxidant and free radical scavenging capacity of T. arjuna were studied by various scientist. Comparative study the antioxidant potential of T. arjuna bark and leaves ethanolic extract and its different solvent fraction was carried out by Kumar et al.85. The study demonstrated that the antioxidant properties due to presence flavonoids, tannins and oligomeric proanthocyanidins. It was observed that arjunic acid and aglycone isolated from the fruit were strong antioxidant or free radical scavenger and more potent then ascorbic acid86. Casuarinin extracted from T. arjuna protect Cultured Madin Darby Canine Kidney (MDCK) cell against H2O2 mediated oxidative stress decrease DNA oxidative damage and prevent the depletion of intracellular GSH in MDCK cells87.
Ant diabetic activity: The T. arjuna has known to be posses the anti-diabetic activity. The effect ethanol extract of T. arjuna bark in alloxan induced diabetic rats and its lipids peroxidation enzymatic and non-enzymatic activity was investigated in the liver and kidney tissue. The results of the study clearly validate the traditional used of this plant in diabetic animal88. The anti diabetic effect of T. arjuna in co-existing with cardiovascular disease was study by Borde et al.58. The result of the study demonstrated that T. arjuna has beneficial effect in experimental model of myocardial infarction co existing with cardiovascular disease.
Anti-viral activity: Casuannin extracted from T. arjuna bark was investigated for its antiviral activity against Herpes simplex type II in vitro. The results showed that casuarinin was virucidal and possesses anti herpesvirus activity in inhibiting viral attachment and penetration89.
Anthelmintic activity: Anthelmintic activity of T. arjuna methanol extract against the hatched egg and larvae of Haemonchus contortus were found to be toxic at 645.65 and 467.65 μg mL–1 of dose, respectively. The data revealed dose dependents antihelmintic activity both in vitro and in vivo studied, thus justifying its use in the traditional medicine system90. Anthelmintic activity of T. arjuna may be only attributed to its tannin content. Antihelmintic effect of T. arjuna bark was also studied on Pheretima posthuma. The effectiveness of drug was judge on the basis of loss of spontaneous movement and death of trematode91.
Molluscicidal activity: The molluscicides activity of T. arjuna bark and its different organic extract against fasciolosis vector snails Lymnaea acuminata and Indoplanorbis exustus were studied by Soni and Singh24,25. The results of their findings demonstrated that toxicity of column purified fraction was higher among all the treatments of Terminalia arjuna bark against L. acuminata (96h LC50 = 3.12 mg L–1) and I. exustus (96h LC50 = 14.53 mg L–1). The TLC analysis demonstrated the presence of arjunolic acid in column purified fraction and cause of its molluscicidal activity. In vivo and in vitro mode of action of molluscicidal component on key enzymes AChE, ACP and ALP activities in the nervous tissue of snail L. acuminata were studied by Soni et al.92. The results of the study proved that plant have concentration dependent inhibition in key enzymes i.e., AChE, ACP and ACP activities. The maximum inhibition in AChE (60.17% of control) ACP (34.66% of control) and ALP (24.01% of control) activity was observed in snail exposed to 96 h exposure of 80% of 96 h LC50 of arjunolic acid. Percent enzyme inhibition both in vivo and in vitro condition indicated that inhibition of ALP was more pronounced than ACP and AChE against all the treatments. The study of kinetics of inhibition of AChE, ACP and ALP by column purified fraction and arjunolic acid of T. arjuna bark were also studied92. The findings of the work clearly indicated that inhibition of AChE was non-competitive, inhibition of ACP was uncompetitive and inhibition of ALP by column purified fraction and arjunolic acid of T. arjuna bark were competitive-non-competitive as it is clearly from Km and Vmax values of uninhibited and inhibited enzymes on Line weaver plot93. The safety of this plant derived molluscicidal drug were evaluated against non-target aquatic biota i.e., fish Colisa fasciatus. The result of the work were found that toxic concentration (24h LC90 against L. acuminata and I. exustus) of arjunolic acid and column does not exert any effect on nervous tissue of fish94.
Apoptosis: At least two modes of cell death can be distinguished: apoptosis and necrosis. Apoptosis is a strictly regulated (programmed) device responsible for the systematic removal of superfluous, aged, harmful, abnormal or misplaced cells. Studies were conducted to establish the effects of Terminalia arjuna bark extract on apoptosis of human hepatoma cell line HepG2. It was found that T. arjuna induced cytotoxicity in HepG2 cells in vitro. Apoptosis effect of T. arjuna on HepG2 cells may be due to the DNA damage and expression of apoptotic proteins. Depletion of GSH may be involved in the induction of apoptosis of HepG2 cells95.
CONCLUSION
Virtually every part of the plant has a great ethnopharmacological value with wide array of the traditional as well as pharmaceutical application due to the presence of large number of bio-active chemical constituents. Experimental study has demonstrated its cardio-protective, hepatoprotective, antioxidant, anticancerous, anti-inflamatory, analgesic, antidiabetic antihelminthic, antimicrobial, antiviral and molluscicidal effects. However, further, detailed clinical research appears worthwhile to explore the full therapeutic potential of various parts of Terminalia arjuna in order to establish it as a standard drug.
SIGNIFICANCE STATEMENT
This study efforts to give every aspect of literature such as; pharmacognosy, phytochemistry, pharmacological, ayurvedic traditional and clinical studies on plant and updating available research data. It can be beneficial for the new researcher and students to collect the informative knowledge of plant in comprehensive form.