PHYTOCHEMISTRY AND MEDICINAL ATTRIBUTES OF A. SCHOLARIS: A REVIEW

PHYTOCHEMISTRY AND MEDICINAL ATTRIBUTES OF A. SCHOLARIS: A REVIEW

Pooja Sharma ¹, Rajiv Sharma ¹, H. S. Rao ¹ and Dinesh Kumar ^*2

Sri Sai College of Pharmacy ¹, Manawala, Amritsar, Punjab, India.

Department of Pharmaceutical Sciences ², Guru Nanak Dev University, Amritsar, Punjab-143005, India.

ABSTRACT: The plant Alstonia scholaris has been used in different system of traditional medicine for the treatment of diseases. The extract of the plant showed pharmacological activities ranging from anti-malarial to anticancer properties. Alstonia scholaris is such plant who have medicinal activity against many of the ailments. In recent times, there is an upsurge of interest and focus on the importance of medicinal plants and traditional health systems in solving the health care problems of the world. In India, the bark of Alstonia scholaris is used solely for medicinal purposes, ranging from malaria and epilepsy to skin conditions and asthma. In Ayurveda, it is used as a bitter and as an astringent herb for treating skin disorders, malarial fever, urticaria, chronic dysentery, diarrhea, in snake bite. The Milky juice of the tree is applied to ulcers. An ethanol extract of the bark of Alstonia scholaris enhanced the anticancer activity of berberine in the carcinoma-bearing mice. This extract also showed cytotoxic activity. It contains echitamine and loganin as major compounds and could potentially be used as an anti-irritation agent. The methanolic extract of the bark has the analgesic activity. The bark extract also exerted a strong inhibitory effect on epididymides, seminal vesicle and prostate gland as evinced by decrease in their weights. This review complies a report on phytochemistry and pharmacological aspects of plant Alstonia Scholaris. The plant is used in traditional, Ayurvedic, Unani, Homoeopathy and Sidhha/Tamil types of alternative medicinal systems against different ailments.

Alstonia scholaris, Phytocostituents, Alstonine, Medicinal Attributes

INTRODUCTION: The genus Alstonia (Apocynaceae) is widely distributed throughout the tropical regions of Africa and Asia. The phytochemical constituents of Alstonia sp. have been extensively investigated; nearly 400 compounds have been isolated and characterized. Most of the compounds identified so far are indole and quinoline alkaloids ^1-13

Alstonia scholaris is popularly known as the “Saptaparni” or ‘Devil’s tree’ belongs to the family Apocynaceae ^{14, 15}. It is a well known remedy for the treatment of various types of disorders in the ayurvedic, homoeopathic and folklore system of medicine in India.¹⁶ It is a medium to large sized tree, of about 40 m height shown in Fig. 1 with a somewhat grey to grey-white bark.

The outer blaze is cream to yellowish in color with abundant, milky latex that flows rapidly when cut. The bark is about 1/2 inch thick ¹⁷.  It is widely distributed throughout the sub-Himalayan belt, West Bengal, Bihar, peninsular India and Southeast Asia. The bark, stem, roots and leaves have been used traditionally as folk remedies for the treatment of many diseases including diarrhea, dysentery, malaria and snake bites. ¹⁸ Bark occurs in channeled or occasionally quilled  pieces, 3-4 mm thick from branches and cut or broken irregularly into curved or flat pieces, about 7 mm thick from stem, externally younger bark dark grey to brown, older bark very rough, uneven and much fissured transversely and longitudinally, both marked with numerous rounded or transversely elongated, grey to whitish brown lenticels, internally brownish-buff to dark grayish-brown, somewhat striated and indented, fracture, short and smooth, fractured surface shows a narrow, inner portion traversed by numerous, fine, medullary rays and a varying spongy outer portion ¹⁹.

FIG. 1: ALSTONIA SCHOLARIS

Transverse section of bark shows a multi-layered, thick and thin-walled cork, a broad zone of secondary cortex composed of thin-walled, parenchymatous cells, including many rounded latex cavities, scattered throughout tissue, containing numerous rhombic to polygonal calcium oxalate crystals, numerous stone cells forming a non-continuous layer of 4-8 cells, irregular, rounded to linear, fiber-like, blunt at both ends, internal to secondary cortex a secondary phloem cells containing many sieve tubes, cork cells brick shaped to almost square in transverse and longitudinal sections and polygonal in surface view, cork cambium forms a region of two rows of cells identical to cork cells, situated in between cork and secondary cortex, secondary phloem cells smaller in dimension than cortical cells consisting of phloem parenchyma, many sieve tubes and companion cells, fibers absent. ²⁰

Extraction and isolation of Alstonic acids

An improved process for the isolation of alstonic acids from the A. scholaris, comprises of the below-mentioned steps ²¹.

• Air-dried, powdered leaves (8.5 kg) of A. scholaris were soaked with Ethanol: Water (25 L × 3, 95:5, v/v, with each soaking for 3 days) at room temperature and filtered.

• The filtrate was concentrated in vacuum to give a residue around 500 g.

• The above residue was subjected to silica gel column chromatography (CC) with a gradient elution system of petroleum ether–acetone (100:0-0:100) to obtain fractions.

• Fraction-4 (3.0 g) mainly contained the triterpene acids, eluted with petroleum ether–acetone (90:10), was repeatedly separated.

• The above separated fraction was purified by silica gel (Petroleum ether: Ethyl acetate = 20:1).

• Fractions were subjected to recrytallization to get the pure compounds.

Phytoconstituents:

The analysis of phytochemical analysis of    Alstonia scholaris have been reported by many authors. These species are rich in alkaloids, steroids, terpenoids and these are responsible for the toxicity. Alkaloids are one of the major constituents of the species. ^{8, 22, 23}  The phytochemical investigation of the leaves of A. scholaris has led to the isolation of alstonic acids A and B (1–2), new 2,3-secofernanetype triterpenoids, as well as a new monoterpene indole alkaloid, N¹-methoxymethyl picrinine (3), together with six known alkaloids, picrinine (4) ⁶, 5a-methoxystrictamine (5) ⁹, picralinal (6) ¹³, 19,20-(E)-vallesamine (7) ⁸, leuconolam (8) ²⁴, and scholaricine (9) ⁷ shown in Fig. 2

FIG.2: STRUCTURES OF CONSTITUENTS ISOLATED FROM A. SCHOLARIS

Among different alkaloids Alstonine (10) Echitamine ¹⁹ (11) in Fig. 3, Scholarine ²⁶, Scholaricine⁷, Dihydrocondylocarpine²⁷, 19, 20-Z-Vallesamine and 19, 20-(E)-vallesamine ⁸, Picrine ²⁸, Alsschomine and Isoalschomine ⁶ Mataranine A and B ²⁹, Monoterpenoid indole alkaloids ⁹, Picrine type alkaloids ¹, N¹-methoxymethyl Picrine ²¹ have been reported.

FIG.3: STRUCTURE OF ALSTONINE AND ECHITAMINE

One flavonoid glycoside, quercetin 3-O-β-D-xylopyranosyl (12), β-D-galactopyranoside and one lignin glucoside, (-)-lyoniresinol 3a-O-β-D-glucopyranoside (13), as the active principles, together with another lignin glucoside, (+)-lyoniresinol 3a-O-β-D-glucopyranoside (14) shown in Fig. 4. with no inhibitory activity are also obtained from the Alstonia scholaris ³⁰.

FIG. 4:

Three new triterpenoids, two of the urs-ane type, 3β -acetate- 24-nor-urs-4, 12-diene ester triterpene and 3β -hydroxy-24-nor-urs-4, 12,28-triene triterpene , and one of the oleanane type, 3,28-β - diacetoxy-5-olea-triterpene and two triterpenes, α-amyrin acetate and ursolic acid have also been recorded. ³¹ Ursolic acid (pentacyclic triterpene acid) ³², lupeol acetate ³³. Apart from those, two C-13-norisoprenoids namely megastigmane-3β, 4α, 9-triol, 7-megastigmene-3, 6, 9-triol, C-13-norisoprenoid have been found. The isolation of a new secoiridoid glucoside alstonoside , together with two known isoflavone apioglucosides, formononetin 7-O-β-D-apiofuranosyl-(1,6)-β-D-glucopyranoside  and biochanin A 7-O-β-D-apiofuranosyl-(1,6)-β-D-glucopyranoside are reported ³⁴. Recently, Xing-Wei Yang et. al. in 2014 isolated the three monoterpenoid indole alkaloids, alstolactines A–C (1–3) shown in Fig. 5, from the leaves of Alstonia scholaris.^{35, 36}

FIG.5: STRUCTURE OF ALSTONINE (A-C) AND FORMONONETIN 7-O-β-D-APIOFURANOSYL-(1,6)-β-D-GLUCOPYRANOSIDE.

Pharmacology:

Medicinal attributes of Alstonia scholaris reported by various researchers are given in Table 1.

TABLE 1: VARIOUS MEDICINAL ATTRIBUTES OF ALSTONIA SCHOLARIS

1.1: Anticancer activity:

In treatment of neoplastic diseases, use of herbal extracts are of particular relevance because of their cytotoxic, cyto-protective and chemo-preventive activities. Herbal drugs with their long history are the only answer to provide an integrated health care for the suffering populations of humanity, particularly in the developing world at affordable cost. The Echitamine chloride from Alstonia scholaris has anticancer activity. ³⁷ Recently, Ganesh Chandra Jagetia et al. in 2005 evaluate the seasonal variation as well as cytotoxicity of different fractions of Alstonia scholaris. The exposure of HeLa cells to different extracts prepared from the stem bark collected in monsoon, winter and summer seasons resulted in a dose dependent increase in the cell killing effect of ASE and the highest cell killing effect was observed for the extract prepared from the summer collections. The extract of ASE was more powerful than the active principle echitamine present in ASE. ^{38, 50}

1.2: Antimicrobial activity:

Antimicrobial are compounds which protect the living organisms from microbial infection. There is a continuous and urgent need to discover new antimicrobial compounds with diverse chemical structures and novel mechanisms of action due to an alarming increase in the incidence of new and reemerging infectious diseases and development of resistance to the antibiotics in current clinical use ³⁹. Acetone extract gave relatively wide spectrum of activity (37.5% – 87.5%) against the test bacterial strains compared to methanol extract (12.5 % - 75 %). This was screened out by the agar diffusion method. ^{40-43, 50}

1.3: Antidiabetic and Antihyperlipidemic activity:

Alstonia scholaris has been used in traditional and folklore medicine for the treatment of diabetes. Diabetes mellitus (types 1 and 2) is recognized as a serious global health problem, often resulting in substantial morbidity and mortality. Type 2 diabetes mellitus is a group of disorders characterized by hyperglycemia and associated with microvascular i.e. retinal, renal, possibly neuropathic, macrovascular i.e., coronary, peripheral vascular, and neuropathic i.e., autonomic, peripheral complications. Unlike type 1 diabetes mellitus, the patients are not absolutely dependent upon insulin for life, even though many of these patients ultimately are treated with insulin. According to the World Health Organization estimate 3% of the world’s populations (194 million) have diabetes and is expected to double (6.3%) by the year 2025 and that of Ethiopia was about 800,000 cases in 2000, and the number is expected to increase to 1.8 million by 2030.

The management of type 2 diabetes mellitus often demands combined regimens, including diet and/or medicines, including sulfonylurea, and biguanide, as well as insulin. The aqueous extract of Alstonia scholaris significantly reduced elevated blood glucose level in STZ diabetic rats without showing any hypoglycemic effect in normal rats. Since STZ effectively destroys pancreatic beta cells and causes persistent hyperglycemia, the mechanism of action of Alstonia scholaris might involve actions other than pancreatic beta cells insulin release or secretion. The antidiabetic effect of the extract could be due to increased utilization of glucose by peripheral tissues, improved sensitivity of target tissues for insulin or it may be due to improved metabolic regulation of glucose.

Alstonia schoalris bark also reduced serum triglyceride levels in STZ diabetic rats support its long term use not only for better control of blood glucose but also for normalization of disturbances in lipid metabolism which may prevent further predisposition of the patients to cardiovascular complications. On repeated administration of aqueous extract of Alstonia scholaris L. for 28 days, a sustained and significant (p<0.01) decrease in blood glucose level of diabetic rats was observed in dose dependent manner as compared to diabetic control group. In diabetic rats blood glucose level was  reduced by 30.3% and 45.79% at 150 and 300 mg/kg doses of the extract respectively and the extract (300 mg/kg) and glibenclamide (4 mg/kg) reduced the LDL-cholesterol  by 53.79% and 64.13%.Also the extract significantly  improved the HDL- cholesterol level at 300 mg/kg. ⁴⁴

Sinnathambi Arulmozhi et al. reported the effect of ethanolic extract of the leaves of A. scholaris in streptozotocin-induced diabetic rats. Results were found to significantly reduce the blood glucose level and glycosylated haemoglobin ⁴⁵. Besides the use of multiple approaches, α -glucosidase inhibitors are one of the alternative therapeutic approaches. The inhibition of intestinal α -glucosidases, would delay the digestion and absorption of carbohydrates and consequently suppress postprandial hyperglycemia.

Nilubon Jong-Anurakkun et al. evaluated α-glucosidase inhibitory activity using aqueous methanol extract of dried Devil tree (Alstonia scholaris) leaves. An inhibitory activity against both sucrose and maltase. This preliminary observation will provide the basis for further examination of the suitability of Alstonia scholaris as a medicinal supplement that contributes toward the treatment and prevention of diabetes.^45-47

1.4: Analgesic and Anti-inflammatory activity:

Recently, Jian-Hua Shang et al.. in 2010 established the analgesic activities were investigated using acetic acid-induced writhing, hot-plate and formalin tests in mice. The anti-inflammatory activities were carried out in vivo and in vitro, including xylene-induced ear edema and carrageenan-induced air pouch formation in mice, and COX-1, COX-2 and 5-LOX inhibition ⁴⁸.

Thankamani V. et al. in 2011, reported that the rat immersion test indicated that the methanolic extract of this drug had potent analgesic effect which was mediated via peripheral and an inhibitory mechanism Thus the use of this plant can be evidence as an efficient therapeutic intervention in various pain and inflammatory disorders.^49-50

1.5: Antimalarial activity:

The acetone extract of Alstonia scholaris, Moringa oleifera and Tinospora cordifolia has strong schizonticidal activity. IC₅₀ value of acetone extracts of all three plants against Plasmodium falciparum pose a claim for the new antimalarial compounds.  A. scholaris show higher schizont reduction compared to other two plants at the same concentration. Further purification and screening of acetone extract of A. scholaris would be developed as new antimalarial drug. Traditionally A.scholaris is also known for its malarial fever treatment. IC50 value of acetone extract of A.scholaris indicates the strong schizonticidal activity. A. scholaris shows presence of glycoside saponins, tannins, terpenoids, and flavanoids. These compounds are also well known for their antimicrobial activity .^{51, 54}

1.6: Antioxidant activity:

Antioxidants are the agents that have gained significance in modern time due to their capability to counterbalance free radicals ⁵⁵. Antioxidants are the compounds which stops the chain reactions of oxidations. Antioxidants have been reported to avert oxidative harm caused by free radicals. They can interfere with the oxidation process by reacting with the free radicals, chelating catalytic metals and also acting as oxygen scavengers ⁵⁶. Presently there has been an upsurge of curiosity in the therapeutic potentials of plants, as antioxidants in plummeting free radical induced tissue injury.

Natural and synthetic antioxidants are of two groups. Although numerous man-made antioxidants, such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), are commercially available, they are somewhat risky and their toxicity is a trouble of worry, and are carcinogenic. Hence, sturdy margins have been positioned on their appliance and there is a fashion to surrogate them with naturally available antioxidants. Dichloromethane and ethyl acetate fraction of drug possess powerful in vitro antioxidant activity. The encouraging results of dichloromethane and Ethyl acetate with the various in vitro antioxidant tests proved the plant as a reducing agent, metal chelator, its hydrogen donating ability and effectiveness as scavengers of hydrogen peroxide, superoxide, and free radicals. Drug was also found to decrease the malondialdehyde level and prevent lipid peroxidation in vivo. ^57-59

1.7: Antihelminthic activity:

The dita bark contains substances that might prove as potent antihelminthic as evidence. Dita bark has a stronger and more potent antihelminthic activity as compared to the tamarind seeds and even the standard drug mebendazole.⁶⁰

1.8: Wound Healing activity:

The various ointments prepared with the selected plant materials exhibited a good wound healing effect comparable to that of nitrofurazone irrespective of the type of the base used. For effective evaluation of the formulated ointment variants, we used excision and incision wound healing models and studied suitable and relevant parameters such as wound contraction  hydroxyproline  content (collagen content) and skin  breaking strength which generally  indicate the rate  of tissue cell regeneration, amount of  collagen or rate of collagenation and tensile strength of the skin.⁶¹

1.9: Ameliorative activity:

The cultures were treated either alone with Alstonia scholaris aqueous bark extract (ASE) as well as in combination with radiomimetic drug Bleomycin.  Positive implications about radioprotective effects by Alstonia scholaris aqueous bark extract on Bleomycin induced cytogenetic alteration in the form of chromosomal aberrations in in vitro human lymphocyte culture was recorded.⁶²

2.0: Anti irritant activity:

 Alstonia scholaris contained echitamine and loganin as its major compounds and could potentially be used as an anti-irritation agent to counter unwanted skin symptoms such as those induced by retinoid treatment. The drug not only markedly decreased several components of retinoid-induced dermatitis, it but also boosted the ability of retinoids to inhibit MMP-1 protein expression, suggesting that it could enhance the antiwrinkle effect of retinoids.⁶³

2.1: Antistress and Cognition activity:

The methanolic extract of bark posses the antistress activity.  Pretreatment of mice with A. scholaris 100, 250 mg/kg significantly decreased stress induced elevation in plasma corticosterone, glucose, cholesterol and total protein levels compared to stress control group. This is due to the active constituent present in bark.⁶⁴

2.2: Parathenium management activity:

The aqueous leaf extract of A. scholaris contain potent herbicidal constituents for the management of parthenium weed which is an aggressive weed of the family Asteraceae cause allergic reactions in people.⁶⁵

2.3:Molluscidal and Anti-cholinesterase activity:

The aqueous extract of stem barked leaf of drug has molluscidal as well as in vivo and in-vitro anticholinesterase activity against the snail Lymnaea acuminate. The aqueous stem bark extract shows strong molluscidal activity in comparison to leaf at all exposure periods in time as well as dose dependent manner (LC₅₀ value decreases from 665.82mgL^-1 to 138.32mgL^-1. The anticholinesterase activity also dose dependent.⁶⁶

2.4: Anti-tussive, Anti-asthmatic and Expectorant activities:

Alstonia scholaris (Apocynaceae) was documented as an effective herb for the treatment of chronic respiratory diseases in “dai” ethnopharmacy historically since 100 years in Yunaan. ⁶⁷ Its leaf crude extract, used for releasing tracheitis and cold symptom, was approved to be a commercial formulation by State Food and Drugs Administration of China (SFDA).

Recently, Jian-Hua Shang et al. in 2010 reported the anti-tussive activity was evaluated using three different models including ammonia or sulfur dioxide induced mice coughing, and citric acid induced guinea pigs coughing. The anti-asthmatic activity was investigated on guinea pigs bronchoconstraction induced by histamine. The expectorant activity was evaluated by volume of phenol red in mice's tracheas. ^68-69

2.5: Anti-adenovirus and anti-HSV Activity:

Li Zhang et al. in 2014 reported the anti- HSW and anti adenovirus activity of indole alkaloids from leaves of Alstonia scholaris. The results showed significant inhibitory activity against herpes simplex virus (HSV) and adenovirus ⁷⁰.

Future aspects:

Revived interest among the researchers all around the world in the structural modification and synthesis of novel analogues of the privileged molecule is attributed to the wide array of biological activities it possesses. As it is very well evident from the literature that Alstonia  has got tremendous potential, thus appropriate modification on the alstonine molecule and synthesis of its analogues can be of great benefit particularly in cancer treatment/therapy.

CONCLUSION: From the present review, it can be concluded that a very exhaustive work had been done on the plant but there is still need for the research work on the pharmacological aspects. The overall conclusion of the review is that privileged phytoconstituent is attributed to the wide array of biological activities it possesses. Moreover, update compilation of the literature on the phytoconstitutents will make it convenient for the researchers to further explore the potential of the molecule by synthesizing various analogues taking Alstonine as a lead. The plant has long being investigated for its phytochemicals and pharmacological activities Traditional use of this plant has been validated by several pharmacological Investigations.

The plant has been reported extensively as Anti-neoplastic, antidiabetic, antimicrobial, anxiolytic and antipsychotic, anti-inflammatory, anti-tussive, antioxidant and antimalarial agents. However, many of the diseases treated indigenously using the plant have not been confirmed in the laboratory. This leaves an opportunity to explore the species both phytochemically and pharmacologically. Therefore ethnopharmacology can bridge between the folklore use and actual medicinal attributes of this plant. In this way it may be used in novel drug discovery programs in the future.

ACKNOWLEDGMENTS: Authors are grateful to Er. S.K. Punj, Honorab’le Chancellor, Sri Sai University, Palampur (H.P.) and Chairman, SSGI Manawala. Respected, Smt. Tripta Punj, Pro- Chancellor, Sri Sai University, Palampur (H.P.) and M.D. of SSGI Manawala, Amritsar for their valuable suggestions and constant support.

CONFLICT OF INTEREST: The authors confirm that this article content has no conflict of interest.

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    How to cite this article:

    Sharma P, Sharma R, Rao HS and Kumar D: Phytochemistry and Medicinal Attributes of A.Scholaris: A Review. Int J Pharm Sci Res 2015; 6(12): 505-13.doi: 10.13040/IJPSR.0975-8232.6(12).505-13.

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