Azadirachta indica: A Plant With Versatile Potential

Review Article

Azadirachta indica: A Plant With Versatile Potential Sonal Dubey and Pankaj Kashyap Krupanidhi College of Pharmacy, Carmelaram Post, Chikkabellandur, Bangalore 560035, India

ABSTRACT Purpose: The purpose of this article is to present a recent update on the various uses of the indigenous plant Azadirachta indica, and to highlight its importance in various therapeutic fields in traditional as well as modern system of medicine. Design/methodology/approach: The literature review of the plant has been presented covering all the fields of research where this plant has been exploited so far. Findings: The plant possesses powerful antidermatonic and anthelmintic, insect repellent, anti-bacterial, anti-fungal, anti-viral, anti-septic, anti-inflammatory, anti-ulcer and strengthens the body’s overall immune responses. It is widely used in treating chronic malaria, bed bugs ulcer, bad teeth, syphilis, leprosy, spermicidal in preventing pregnancies and other diseases. Externally it’s the oil applied as an antiseptic for urticaria and chronic skin diseases like eczema, scabies, ring worm and maggot infested wounds. It is also used for killing lice, fleas, ticks insecticide and bacterial growth in mouth. Research limitations/implications: This tree’s beneficial values have been known for 4000 years is described by the native as the village pharmacy due to its wide spectrum of medicinal qualities. Practical implications: Over 65 patents have been derived from its various uses, which clearly indicates its practical utility in our daily lives. Social Implications: It has been traditionally used by families for curing household ailments, spermicidal in preventing pregnancies. Originality/value: The paper is an overview of various researches being carried out on the Neem. Keywords: Neem, Azadirachta indica, traditional uses, antimicrobial, anti-inflammatory, liver protectant, anti allergic

INTRODUCTION Azadirachta indica, commonly known as Neem, belongs to Family Meliaceae, is one of the most versatile medicinal plants that has gained worldwide importance due to medicinal and insecticide properties. There are several studies showing the effects of Azadirachta indica in experimental and clinical models.1 Among the natural products, one of the most promising natural compounds is Azadirachtin, an active compound extracted from the Azadirachta indica tree whose antiviral, antifungal, antibacterial and insecticidal properties have been known for several years.2 The International Scientific Community has included Azadirachta indica tree into the top ten lists of plants to be studied and used for the sustainable development of the planet and the health of living beings. Azadirachta indica, identified by WHO/UNEP1989 as an environmentally powerful natural pesticide, is RGUHS J Pharm Sci | Vol 4 | Issue 2 | Apr–June, 2014

considered to be one of the most promising trees of the 21st century for its great potential in pest management, environment protection and medicine. There are about 14 million Azadirachta indica trees growing only in India and the plant is adapted to subarid and subhumid areas of tropical and subtropical areas. Indian trees have the potential to produce 3.5 million tonnes of seed/year, corresponding to a production of 700,000 tonnes of oil/year. Neem is well known and used for its medicinal properties from the ancient period (4000 BC); mainly on the indications of Ayurveda medicine, being very popular, even revered in the Indian subcontinent. In practice, all parts are traditionally used for a variety of indications, Azadirachta indica is indigenous medicine as a bitter tonic, antimalarial, antipyretic, anti-inflammatory, antihelmintic, and for antimicrobial and antiviral effects. Fruits are collected when the drupes turn yellowish-

Received Date : 30-04-2014 Revised Date : 31-05-2014 Accepted Date : 02-06-2014

DOI: 10.5530/rjps.2014.2.2 Address for correspondence Dr. Sonal Dubey Krupanidhi College of Pharmacy, #12/1, Chikkabellandur, Carmelaram Post, Bangalore 560035 E-mail: drsonaldubey@gmail. com

www.rjps.in

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green by hands or machines and are processed as soon as possible. The fleshy part of the fruit is removed and the stones washed in clean water and dried for 5–10 days. The oil is obtained usually by large mechanical expellers or by solvent extraction, only small-scale producers still use traditional pressing methods.3 Azadiracta indica has been used as a potential medicinal agent like anti-inflammatory, anti-neoplastic activity, melanogenesis inhibitory, immunostimulatory agent, larvae of filarial, tumor cell killing, chemotactic activity, larvae of Boophilus decolotatus, acaricidal activity, lar-

vicidal activity, anti-tumor activity, leukocyte adopsis, propylactic activity, anthelmintic activity, hepatotoxicity, anti-cancer effects, transmission blocking activity, insecticidal activity, anti-oxidant activity, anti-trypanosomal, anti-hypertensive activity, immunological function, nutritional activity, free radical scavenging activity, antiviral activity, antibacterial activity, antimalarial activity, anti-diabetic and anti-bovine activity. Some potential medicinal compounds had been isolated from A. indica like anti-plasmodial triterpenoids and snake venom phospholipage A.4

TAXONOMY:5

Botanical name: Family: Synonym: Common names Sanskrit: Bengali, Hindi, Panjabi: Gujarati: Tamil: English: German: French:

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Azadirachta indica, A.Juss. Meliaceae. MeliaAzadirachtalinn. Ravipriya; Vembaka, Nimba, Arishta. Nim or Nimb, Nimgachh. Limba. Vembu. Neem or Margosa tree; Indian Lilac. Indischer Zedrach. Azadiraed’Inde.

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Chemical Composition: 6,7,8

A. Neem Fruit (fresh): Greenish Brown Kernels – 30% Other Shell, Pulp etc., – 70% B. Neem Seed: Shell – 55.3% Kernel – 44.7% C. Neem Kernel Oil Content: – 46-48% D. Other Ingredients: TOP APPLICATIONS OF Azadirachta indica:9

Here in we present a short review of various uses of Azadiracta indica established so far: All parts of plant Azadiacta indica have been widely useful in the life of humankind. The current update of use of this plant is presented below. Against microorganisms

a. Use as antibacterial and antimicrobial agent: Azadirachta indica A. Juss leaves extract exhibit power of antibacterial activity. It has shown to possess significant effects on both gram-positive and gram-negative organisms and other bacteria that cause a wide array of human and animal diseases including E. coli, Streptococcus and Salmonella.10 RGUHS J Pharm Sci | Vol 4 | Issue 2 | Apr–June, 2014

b. Use as antifungal agent: The leaf extracts of Azadirachta indica has great potential to strongly inhibit the members of the Trichophyton and Microsporum species causing superficial infection of the skin. Antifungal study conducted by Maragathavalli S, Brindha S, Kaviyarasi NS et al. on Azadirachta indica showed significant value and confirm the therapeutic potency of such plant used in traditional medicine.11–15 c. Antiviral compounds in Azadirachta indica: Neem inhibits the growth of dengue virus, a hemorrhagic fever related to Ebola, and interferes with the reproduction of the B virus, one of a group of “enteroviruses” that are second only to the common cold as the most infectious viral agents in human beings.11 d. Anti-plasmodial: Malaria is a major public health problem in the world in general and developing countries in particular, It is becoming more difficult to manage malaria particularly in areas of multi-drug resistance. Azadirachta indica leaf and stem bark extracts are able to reduced 68% plasmodia in malaria.16 e. Anti parasitic: Giardia lamblia is both the most common intestinal parasite in the United States and a frequent cause of diarrheal illness throughout the world. In spite of its recognition as an important human pathogen, there have been relatively few agents used in therapy. Azadirachta 41

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indica plant was found to reduce Giardiasis and decrease the anorexia. As reported by Akpek EK, Vittow J et al.17 f. Azadirachta indica in chicken pox: Azadirachta indica leaves are used to soothe the patient and prevent further spreading of the virus during the course of the infection. The patient is given a bath with water in which Neem leaves are soaked as a post-treatment care.11 Antioxidant and anti-inflammatory

a. Anti-inflammatory: Nimbidin, a component of Azadirachta indica, has been shown to possess potent anti-inflammatory and antiarthritic activity. Nimbiden suppresses the functions of macrophages and neutrophils involved in inflammation. Nimbidin, a compound isolated from the oil of seeds of Azadirachta indica, has been screened in comparison with two standard anti-inflammatory agents, phenylbutazone, a non-steriod and prednisolone, a steroid; against various experimental models of inflammation. It was found to significantly reduce acute paw oedema in rats induced by phlogistic agents, carrageenan and kaolin. The test drug significantly suppressed the formalin-induced arthritis of ankle joint and the fluid exudation in croton oilinduced granuloma in rats.18,19 b. Antioxidant: The process, through which free radicals are created, is a normal function of the body but the resulting molecules are unstable and can damage other cells. A series of disorders, including cardiovascular disease, eye health, cataracts and macular degeneration, age related neurodegeneration (decline of the brain cells and nervous system) and even cancer occurs due to high levels of free radicals. Azadirachtaindica protects against chemically induced carcinogens and liver damage by boosting antioxidant levels.18 c. Neuroprotective: Antioxidant compounds in Azadirachta indica help to prevent brain damages, who had suffered a stroke by enhancing lipid peroxidation and increasing ascorbic acid (Vitamin C) concentration in the brain.20 d. Inhibition of nitric oxide production: Leukocytes play an important role in defense of the mammary gland; similarly they are also involved in the pathophysiology of many inflammatory diseases by releasing cytotoxic molecules such as reactive nitrogen intermediates and reactive oxygen species into the extra cellular space and damage surrounding tissues. Nitric oxide is one of the important secretory reactive molecules of 42

milk cells. It plays a complex role in inflammatory response, apart from several other physiological functions. Nitric oxide is produced by inducible and non-inducible nitric oxide synthase. The extract of A. Indica has shown to inhibit the enzyme nitric oxide synthase thereby inhibiting the nitric oxide production by milk leukocytes.21 Immune stimulatory:

Immune stimulating properties of Azadirachta indica are most important benefit. It boosts both the lymphocytic and cell-mediated systems, including “Killer T” cells which are able to destroy microbes, viruses and cancer cells by injecting toxic chemicals into the invaders. Stimulation and sedation both depend on dose. Chewing of 8-10 Azadirachta indica leaves early in the morning for twenty four days protect the body from diseases like diabetics and hypertension. The body also becomes immune to skin problems.22 Effect on ANS:

Nimbidin the major bitter principle from oil of seeds of Azadirachta indica was investigated for various pharmacological actions in number animal models. On central nervous system it exhibited moderate sedative effect but it did not show any significant cardiovascular effects in experimental animals. Autonomic pharmacological studies (in vitro) revealed pronounced anticholinergic antihistaminic (H1-receptor), anti 5 HT and antinicotinic activities. But in-vivo tests did not show any anticholinergic or anti-histaminic activity. Nimbidin possessed moderate diuretic activity and was found to be devoid of local anaesthetic and antiandrogenic effects in rodents.23 a. Anti-anxiety: Low doses of Azadirachta indica leaf extracts have sedative effects. The effect disappears at high doses, approximately 400 or 800 milligrams per kilograms of body weight. It also reduces anxiety and stress.23 Liver protectant:

It helps to protect the liver from damage, which in turn helps to cleanse the blood. Azadirachta indica leaf minimize, chemically induced liver damage by stabilizing levels of serum marker enzymes and boosting levels of antioxidants, like those found in vitamin C and E and carotenoids, which neutralize free radicals and prevent damage.24 a. Azadirachta indica use in biliousness: Biliousness is a medical condition that is caused by a disorder of the gall bladder or liver. This is a gastric distress which results from an excess secretion of bile. Biliousness is characterized by RGUHS J Pharm Sci | Vol 4 | Issue 2 | Apr–June, 2014

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abdominal pain, constipation, nausea and headache. Neem has been found to be very useful in curing this condition.24 b. Azadirachta indica in jaundice: Azadirachta indica plant is very useful in liver problem, particularly it is very helpful in curing jaundice disease. Juice of Azadirachta indica leaves and half the quantity of honey is taken on an empty stomach for seven days helps in jaundice.24 Anti- allergic

a. Azadirachta indica in urticaria: Urticaria commonly referred to as hives, is a kind of skin rash notable for pale red, raised, itchy bumps. Hives might also cause a burning or stinging sensation. Hives are frequently caused by allergic reactions; however, there are many nonallergic causes. Most cases of hives lasting less than six weeks (acute urticaria) are the result of an allergic trigger. Chronic urticaria (hives lasting longer than six weeks) is rarely due to an allergy. A decoction of Azadirachta indica bark, sandal and guduchi is taken internally.25 b. Cures Asthma: Traditionally it is believed that 3 drops of Neem oil should be placed at the center of the thong and swallowed to cure asthma. The dose can be increased by a drop each week up to one tea spoon.25 Antipyretic properties:

Azadirachta indica juice is wildly used as antipyretic agent. It reduces the body temperature and usually acts as antipyretic agent.26 Potential Contraceptive Properties:

Azadirachta indica is either a pre or post coital contraceptive, noting that it prevented proliferation of sperm cells in concentrations as low as 0.05 to 1%. Purified extracts contain immunomodulators that stimulate the cells and macrophages that terminate pregnancies. Fertility was regained after one or two cycles with no apparent impact to future pregnancies..It posses spermicidal activity also.26–28 In dysmenorrhea:

Azadirachta indica helps in curing painful menstruation. Juice of Neem leaves and ginger juice mixed well and taken internally cure painful menstruation27 In post-delivery care:

Azadirachta indica is beneficial in post-delivery care as well as in pregnancy. To bring back structure and function of uterus after delivery, one ounce of juice of RGUHS J Pharm Sci | Vol 4 | Issue 2 | Apr–June, 2014

Azadirachta indica leaves should be taken for 27 days in the morning on an empty stomach. Extractives of the Azadirachta indica plant such as Azadirachta indica oil have also been proposed as spermicides based on laboratory studies. Animal studies of creams and pessaries derived from Azadirachta indica have shown they have contraceptive effects; however trials in humans to determine its effectiveness in preventing pregnancy have not yet been conducted.26 Antigastric ulcer properties of Azadirachta indica:

Properties of nimbidine, the bitter amorphous, neutral powder isolated from the oil expressed from the seed kernels of Azadirachta indica in animals as well as in humans with duodenal ulcer. It reduced the incidence and severity of histamine induced duodenal ulcers in guinea pigs and accelerated the healing of gastric ulcers induced by acetic acid in rats and dogs.29 Enhances Blood Circulation and Regulates Hormonal Levels:

Azadirachta indica is known since the ancient times for cleansing the blood and the body. Regular consumption of Azadirachta indica leaves helps in enhancing blood circulation as well as preventing hormonal imbalance that are a major reason behind some skin and hair problems. Consumption of 2–3 Azadirachta indica leaves mixed with some honey on empty stomach every day has been reported that to bring change in people stem and overall health. The concoction that should not be made in boiling water as the leaves tend to leave behind a pungent smell after they are boiled which would make it difficult for you to consume the liquid.30 Azadirachta indica in eye problems:

Neem is very useful in eye diseases. Application of Neem leaves to the eyes every night is traditionally believed to be helpful in curing night blindness. The juice of Neem leaves is useful in pain in eyes caused by conjunctivitis. Dried Neem leaves for urinary stones:

Kshara or ash is prepared by burning the dry Azadirachta indica leaves in an earthen pot. The ash is mixed well with water and allowed to stand still for 24 hours. The sediment is used as kshara after filtering the water out. The kshara of Neem leaves taken with warm water every day in morning removes urinary stone.31 Wound healing:

Wound in skin heals in multiple processes. Azadirachta indica oil contains active ingredients that directly deal with wound healing process. It has a high content of essential fatty acids. This plays an important in adding moisture role and a soft texture to the skin during the 43

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healing process. The leaf extracts and seed oil of the tree has a proven anti-microbial effect. This keeps any wound or lesion free from infection by bacteria, viruses, parasites and fungi. Clinical studies have also shown that Azadirachta indica plays another important role in wound healing by inhibiting inflammation as effectively as cortisone acetate.31 Anti-cancer:

Azadirachta indica has shown efficacy in killing cancer cells or boosting the body’s immune system to protect it from damage. Azadirachta indica or its isolated compounds have shown impressive action against a wide variety of human cancer cell that include colon, stomach, lung, liver, skin, oral, prostate and breast. Ethanolic Azadirachta indica leaf extract was found to induce apoptosis in 4T1 breast cancer cells in Human and as well as Animals.32,33 Anti-diabetics:

With its extremely bitter properties, Azadirachta indica has been a corner stone of Ayurvedic therapy for pitas, or disorders caused by overeating sweets. As the tale is told, when an Indian manufacturer applied to the government for an Azadirachta indica capsule to treat diabetes, it was approved in 24 hours. After almost 4,500 years of almost continuous uses, even the Indian equivalent of the US FDA apparently believes that “anything from Azadirachta indica has to be good.”34 Azadirachta indica in HIV AIDS:

Each part of Azadirachta indica plant reportedly has various medicinal properties and has been in use in many continents for centuries. Recently, a fractionated Azadirachta indicia leaf extract known as IRAB with reported activities against Malaria, HIV/AIDS and cancer has been developed into a drug and currently marketed in Nigeria.35 Azadirachta indica as corrosion resistant:

The corrosion of mild steel in H2SO4 was studied using gravimetric, gasometric and IR methods. The results indicate that the rate of corrosion of mild steel in H2SO4 increases with increase in the concentration of the acid and that ethanol extracts of the seeds and leaves of Azadirachta indica inhibit the corrosion of mild steel in H2SO4.36 Use in dental care:

Another traditional use of Azadirachta indica has been to chew the Azadirachta indica sticks. It is still used to clean teeth in rural parts of India. Antimicrobial properties that help to reduce plaque and gingivitis. People used Azadirachta indica twigs as tooth brushes for centuries. 44

Azadirachta indica twigs contain antiseptic ingredients necessary for dental hygiene and prevents tooth decay, periodontal diseases, infections, tooth decay, bleeding gums and sore gums.37 Anthelmintic for small ruminants:

Azadirachta indica products such as fresh leaves, seeds and bark act as anthelmintic for eco small ruminants which rear primarily on the grazing land and tree leaves, These cause a high occurrence of helminthic diseases and protozoan diseases along with this thing are also mend to manage pediculosis and tick infestations.38 Pesticide:

Neem oil is a naturally occurring pesticide found in seeds from the neem tree. It is yellow to brown, has a bitter taste, and a garlic/sulfur smell. It has been used for hundreds of years to control pests and diseases. The biologically active compound azadirachtin (extract of Azadirachta indica seed), act as repellent for a broad spectrum of agricultural and household insects. This plant is traditionally used as pesticidal agent in India.39 Azadirachtin reduces insect feeding and acts as a repellent. It also interferes with insect hormone systems, making it harder for insects to grow and lay eggs. Neem oil kills or control the following pests: Garden Snails and Slugs, Cockroaches, Bed Bugs, Scabies Mites, Dust Mites, Ants, Fleas, Ticks, Fruit Fly, Whiteflies, Japanese Beetles, Cherry slug, Pear slug.40 Apart from these uses Neem products are being marketed world over by many companies, such as neem soaps, shampoo, toothpaste, hand and body lotions, face wash, food supplements, agricultural products and veterinary products. Agroneem® is a formulation containing azadirachtin (0.15%) as the active ingredient. It also contains 15% neem biomass (neem lipids), thus utilizing the complete spectrum of neem’s potential as a pest management tool. It attacks insects at different stages of growth as anti-feedant, insect repellant, growth regulator and insecticide. It is non - toxic and does not harm the workers. It is bio-degradable and protects the environment. It is compatible with most commonly used fertilizers, fungicides and insecticides. It is registered with the US EPA.41 Neem Patents :

Sixty-five patents for products derived from the Neem tree have been filed with the EPO till 2013 of which 22 have been granted, 28 are “dead” for various reasons, and 15 are currently being examined. These include claims for insecticides, fungicidal effects, methods of extraction, and storage stable formulations of one of the active ingredients, azadirachtin, contraceptives, and RGUHS J Pharm Sci | Vol 4 | Issue 2 | Apr–June, 2014

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medical uses. Although some Indian companies have claimed patents on the Neem, they are outnumbered 2 to 1 by multinational corporations, such as the U.S. pharmaceutical company Rohm and Haas and the agrochemical giant W.R. Grace. It is important to note that the Neem patents do not involve a genetically engineered product; neither has the tree itself been patented, nor any of its parts.42 During the past five decades intensive investigations on the diverse properties of Neem have been carried out. As a result large numbers of research publications and books have been published. Many conferences have been conducted at national and international level.

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Neem Conferences

1. First International Neem Conference, RottachEgern, Germany, 1980. 2. Second International Neem Conference, Rauischholzhausen, Germany, 1983. 3. Third International Neem Conference, Nairobi, Kenya, 1986. 4. First World Neem Conference, Bangalore, India, 1993. 5. Second World Neem Conference, Queensland, Australia, 1996. 6. Third World Neem Conference, Vancouver, Canada, 1999. 7. Fourth World Neem Conference, Mumbai, India, 2002. 8. Fifth World Neem Conference, Maritius, 2006. 9. Sixth World Neem Conference, Nagpur, India, 2012. Neem, correctly stated as “Tree for Solving Global Problems” is one of the most precious gift by nature to us. It is indeed a ‘Green Gold’, which we should nourish and cherish for centuries to come.

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30. B alakrishnan V. Exploring indian medicinal plant for anti ulcer activity. Indian J Pharmacol. 2006; 38(2): 95–9. 31. Kalaivani T, Meignanam E, Premkumar N. Studies on hepato protective properties of leaf extracts of Azadirachta indicaA. Juss (Meliaceae). Ethnobotanical Leaflets. 2009; 13: 165–70. 32. Bhardwaj RL. Medicinal Values of Neem. Available at http://www. hillagric.ac.in/edu/covas/vpharma/winter%20school/lectures/32%20 Neem%20medicinal%20values.pdf 33. Subapriya R, Bhuvaneswari V, Nagini S. Ethanolic Neem (Azadirachta indica) leaf extract induces apoptosis in the hamster buccal pouch carcinogenesis model by modulation of bcl-2, bim, caspase 8 and caspase 3. Asian Pacific Journal of Cancer Prevention. 2005; 6(4): 515–20. 34. Othman F, Motalleb G. Extract of Azadirachta indica(Neem) leaf induces apoptosis in 4T1 breast cancer BALB/c mice. CELL JOURNAL (Yakhteh). Summer. 2011; 13(2): 107–16. 35. Oluwole B, Akinola, Ezekiel A, Martins C. Chronic treatment with ethanolic extract of the leaves of azadirachta indica ameliorates lesions of pancreatic islets in streptozotocin diabetes. Int. J. Morphol. 2010; 28(1): 291–302. 36. Anyaehie UB. Medicinal properties of fractionated acetone/water Neem (Azadirachta indica) leaf extract from nigeria: a review. Nigerian Journal of Physiological Sciences. 2009; 24 (2): 157–9.

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37. E ddy NO, Mamza PAP. Inhibitive and Adsorption Properties of Ethanol Extract of Seeds and Leaves of Azadirachta indica on the Corrosion of Mild Steel in H2SO4. Portugaliae Electrochimica Acta. 2009; 27(4): 443–56. 38. Khan I, Srikakolupu SR, Darsipudi S. Phytochemical studies and screening of leaf extracts of Azadirachta indica for its anti-microbial activity against dental pathogens. Scholars Research Library. 2010; 2 (2): 246–50. 39. Tiwary MK, Pandey A. Feeding Neem (Azadirachta indica) products to small ruminants as anthelmintic. Food Science and Technology BIOINFO publication. 2010; 1(1): 976–82. 40. Schmutterer H. Properties and Potential of Natural Pesticides from the Neem Tree, Azadirachta Indica. Annual Review of Entomology. 1990; 35(1): 271–97. DOI: 10.1146/annurev.en.35.010190.001415. 41. Aggarwal R.S. in ‘Ghar ka Vaidya Neem (in Hindi)’, Manoj Publications. New Delhi; 2000. 42. Tinghui X, Wegener M. World Distribution and Trade in Neem Products with Reference to their Potential in China. Contributed paper to AARES 2001 conference of Australian Agricultural and Resource Economics Society. Adelaide; 2001; 1–15. 43. A list of all the Neem patent applications at the European Patent Office and their current status - compiled by Dr. Ruth Tippe and is available from Kein Patent auf Leben! ([email protected])
