Neem, Azadirachta indica, has similar properties to its close relative, Melia azederach. It is one of the most important detoxicants in Ayurvedic medicine. The young shoots of neem, known as datoon, are used to clean teeth in the villages. It is used as an insecticide, for fumigation and as an air purifier. The word Azadirachta is derived from the Persian azaddhirakt, meaning 'noble tree'.
It is indigenous to the warmer parts of India and south-east Asia and found commonly in the forests of Andhra Pradesh, Tamil Nadu and Karnataka. It is also widespread in West Africa, the Caribbean and South and Central America.
It is a hardy, fast-growing evergreen tree with a straight trunk, long spreading branches and moderately thick, rough, longitudinally fissured bark (Plate 10). Mature trees attain a height of 7-20 m with a spread of 5-10 m. The tree starts producing the yellowish ellipsoidal drupes (fruits) in about 4 years, becomes fully productive in 10 years and may live for more than 200 years. The leaves are compound, imparipinnate, comprising up to 15 leaflets arranged in alternate pairs with terminal leaflets. The leaflets are narrow, lanceolate, up to 6 cm long. The flowers are abundant, sweet-smelling white panicles in the leafaxils.
Seeds, seed kernel, leaves, flowers, stem and stem bark.
All parts of the plant are highly regarded in medicine. The stem bark is an astringent and antiperiodic and the root bark and young fruits are used in a similar way and as a bitter tonic. The flowers are used for dyspepsia and the berries are purgative, emollient and anthelmintic. Fresh twigs are often used for cleaning the teeth in pyorrhoea. The seed is stimulant and applied externally in rheumatism and skin diseases. The oil extracted from the leaf and seed is important as an antiseptic, insecticide and applied to boils, ulcers and eczema. It is also applied externally in rheumatism, leprosy and sprams.
In poultry, the bark is used to treat wounds, diarrhoea, ticks and lice. The leaves are used to treat abscesses and applied after castration. They are also effective against bleeding, udder infections, fever, foot rot and lice in ruminants. The seeds are used for ticks in ruminants and the bark, seeds, leaves and roots are used as an insect repellent. All parts of the plant, as well as the gum and oil, are effective against worms, wounds in the mouth, glossitis, E. coli bacillosis, swelling of the liver, jaundice, bloody dysentery and intestinal wounds. They are also used for constipation, indigestion, respiratory and throat disorders, asthma, pleuropneumonia and swelling of the mucous membranes in the respiratory tract and lungs. They are also used in skin disorders including ringworm, alopecia, eczema, urticaria, scabies, ticks and lice. Other minor indications include metritis, orchitis, tetanus, stoppage of urination, swelling of the kidney, mastitis, otitis, abscess in the ear, rinder pest and rheumatism.
The major active components are the limonoids azadirachtin, 3-deacetyl-3- cinnamoylazadirachtin, I-tigloyl-3-acetyl-II-methoxyazadirachtin, 22,23-dihydro-23?-methoxyazadirachtin, nimbanal, 3-tigloylazadirachtol, 3-acetyl-salannoV nimbidioV margocin, margocinin, margocilin and others.s Terpenoids such as isoazadirolide,6 nimbocinolide,' nimbonone, nibonolone, methylgrevillate! margosinone, margosinolone, nimosone, nimbosone, methyl nimbiol, methyl nimbionone, 13-acetyl-12-methoxy-S, 11, 13-podocarpatriene, sugiol,12,13-dimethoxy-S,II,13-podocarpatriene-3,7-dione1O and gedunin have been isolated. The oil contains salannin, 1 ,3-diacetyl salannin, deacetyl salannin and salannol nimbidin, nimbidinin and nimbinin. Meliacin cinnamates 13 have been isolated from root bark of the plant. Isonimolide, isolimbolide and isonimocinolide14 have been reported from twigs.
The fruit pulp contains arabinogalatans and numerous other polysaccharides, referred to as G-IIa, G-IIIa, G-IIIb, GIIIDO/IIa and GIIIDO/IIb, etc.1s Others, called eSP-II, -III, eSSP-I, -II and -III, are present in the stem bark.
Antifungal, antibacterial and antiviral activity: A leaf extract of neem showed significant inhibition of aflatoxin synthesis and fungal spore infection of Aspergillus flavus growing on the seeds of developing cotton bolls. The oil extracted from the seeds exhibited significant antibacterial efficacy against Bacillus subtilis, Salmonella typhosa and S. paratyphi. NIM-76, a spermicidal fraction prepared from neem oil, was investigated for its antimicrobial action against various bacteria, fungi and the polio virus. NIM-76 showed a stronger activity than whole neem oil and inhibited the growth of pathogens including Escherichia coli and Klebsiella pneumoniae, which were not affected by the whole oil. It also inhibited the growth of Candida albicans and replication of the polio virus. NIM-76 protected mice from systemic candidiasis, measured as an enhanced survival rate, and reduced colony formation in various tissues, demonstrating a potent, broad-spectrum, antimicrobial activity.19 Neem leaf extract at a concentration of 3-4 mg/ml inhibited plaque formation of the chickungunya and measles viruses, together with a reduction in virus titre.
Antiatherosclerotic activity: Administration of the mature leaf extract (IP) decreased serum cholesterol significantly without changing serum protein, blood urea and uric acid levels in rats.
Antidiabetic activity: A significant reduction of insulin dosage (30-50%), without a significant effect on the blood glucose levels, was observed with the administration of 5 g of aqueous leaf extract or an equivalent amount of dried leaf. The same doses of insulin alone did not produce the effect when given without leaf preparation. Oral administration of 10% w/v aqueous leaf extract to normoglycaemic animals at a dose 200 mg/kg resulted in marked hypoglycaemia. Intravenous administration of 0.15 mg/kg of a 50% w/v aqueous leaf extract in dogs resulted in a significantdecrease in blood glucose levels in both normoglycaemic animals and adrenaline-induced hyperglycaemic animals.
Antimalarial activity: The leaf extract containing the limonoid gedunin was examined for antimalarial activity using in vitro tests with two types of Plasmodium falciparum, one sensitive to chloroquine rNJ and one chloroquine resistant (DJ The extract was found to be more effective against the W2 than the D6 clone, suggesting there is no cross-resistance to chloroquine. Isolated gedunin was more potent than chloroquine against W2.
Antinociceptive activity: The analgesic potency of an aqueous extract was tested using experimental pain models in mice. In the glacial acetic acid (GAA)-induced writhing test, the extract (at 10,30 and 100 mg/kg) dose-dependently reduced both the incidence and the number of writhes. ft also enhanced tail withdrawal latencies in the tail flick test for nociception, at similar dose levels.
Antipyretic activity: A 75% methanolic extract of leaf and bark showed antipyretic; effects in rabbits when administered at a dose J of 400 mg/kg. Similar effects were observed with the hexane, chloroform, 90% ethanol and water-soluble fractions at a dose of 150 mg/kg.
Antiulcer activity: An aq ueous extract of the leaf, at doses of 10,40 or 160 mg leaf/kg boor weight, in rats exposed to 2 hours of cold-restrained stress or given ethanol orally, caused a reduction in gastric ulcer severity and decreased ethanol-induced gastric mucosal damage. It prevented mast cell degranulation, which increased the amount of gastric mucus, in stressed animals.
Anxiolytic activity: A single dose of freshly prepared leaf extract, given 45 minutes before behavioural testing in rats, showed that low doses (10,20,50,100 and 200 mg/kg) of the extract produced a significant anxiolytic effect in both maze and open field tests. The effect induced by lower doses was comparable to that induced by diazepam(1 mg/kg), but was absent with higher doses.
Cardiovascular activity: Administration of the leaf extract of Azadirachta indica was found to induce a potent and dose-dependent hypotension in rabbits (5-200 mg/kg, IP) and guinea pigs (5-40 mg/kg). The extract also exhibited antiarrhythmic activity (40 mg/kg IV) against ouabain-induced dysrhythmia in rabbits. The mechanism of action may be due to an effect on vascular smooth muscle, giving rise to vasodilation.
CNS depressant adivity: CNS depressant activity, evidenced by a reduction in locomotor activity and potentiation of pentobarbitone-induced hypnosis, was observed with the oral administration of an acetone extract of the leaf.
Hepatoprotective activity: The leaf extract provided a hepatoprotective effect against paracetamol-induced hepatic cell damage in rats, findings supported by histopathological studies.
Hypoglycaemic adivity: Both the leaf extract and seed oil produced a hypoglycaemic effect in normal as well as diabetic rabbits, comparable to that of glibenclamide. The effect was more pronounced in the diabetic animals. Pretreatment with indica leaf extract or seed oil, given 2 weeks prior to alloxan, partially prevented the rise in blood glucose levels as compared to control diabetic animals.
Antiinflammatory activity: Oral administration of 800 mg/kg of a 75% methanolic extract of bark and leaf produced inhibition of carrageenan-induced oedema in rats.33 Sodium nimbate, administered IP at a dose of 40 mg/kg, also reduced carrageenan-induced oedema in rats, with an EDso of 44.1 mg/kg. Formaldehyde-induced arthritis in rats was also inhibited by 20 mg/kg sodium nimbate.34 Polysaccharides coded as G-IIa, G-IIIa, G-IIIb, GIIIDO/lla and GIIIDO/IIb, isolated from stem bark, exhibited significant antiinflammatory activity at doses of25, 0.40, 50,10 and 10 mg/kg respectively.3s Nimbidin, the crude bitter principle from the seed oil consisting of a mixture of limo no ids, exhibited a dose-dependent inhibition of carageenan-induced oedema (EDso = 79.4 mg/kg). Doses of 40 and 80 mg/kg also produced a significant inhibition of both kaolin-induced oedema and formaldehyde-induced arthritis. Inhibition of croton oil-induced granuloma formation was also observed (at 80 mg/kg).
Antitumour adivity: Antitumour effects were seen against Sarcoma-180 ascites tumour cells in mice following the IP administration of polysaccharides Gia and Gib, isolated from the stem bark of Azadirachta indica.
Antifertility adivity: Oral administration of a 50% ethanol extract of neem flower caused a marked decrease in the weight of testes and epididymis of male rats, by arresting spermatogenesis. Sperm motility and density were significantly reduced.3s Depletion in the levels of androgen and spermatogenesis were also observed due to reduced testicular weight and protein, sialic acid and glycogen content. The seed extract caused degenerative changes in the ovarian follicles and led to a degeneration of endometrial epithelium, disorganisation of uterine glands, breakage and deterioration of luminal epithelium and a decrease in protein and glycogen contents.39 No change in hormonal parameters was observed. An active fraction of the hexane extract of the seed (containing mono- and diunsaturated free fatty acids and their methyl esters) resulted in long-term, reversible, antifertility effect after a single intrauterine administration in female rats of proven fertility. The mechanism appeared to involve intervention of local cell-mediated immunity in the reproductive system.
Insecticidal and growth regulatory activity: Aqueous and ethanol extracts of the seed, flower and leaves of Azadirachta indica were found to disrupt the growth and development of larvae of tobacco caterpillar and Sodoptera litura (E) at 0.25%, 0.5% and 1.0% concentrations. Various types of abnormality as well as a reduction in size and weight were observed. The seed kernel extract was found to have the highest activity, followed by that of the leaf, seed coat and flower. Oral administration was more effective than topical application. Azadirachtin has been identified as the active compound against a range of insects. The seed kernel extract induced histological and histochemical alterations in the ovaries of Caryedon gangara (Caleoptera: Bruchidae), evaluated by comparing oogenesis in normal-maturing females reared on tamarind seed with those treated with neem kernel extract. Where oocytes were already developed, degenerative changes involving yolk deposition in oocytes of the treated females, and disturbance in the post-vitellogenic follicles, were observed. The effects of azadirachtin, salannin, nimbin and 6-desacetylnimbin, isolated from seed kernels, have been studied on ecdysone 20-monooxygenase (E-20-M) activity using various preparations of Drosophila melanogaster, Aedes aegypti or Manduca sexta. They were incubated with radio labelled ecdysone and increasing concentrations of the compounds. All were found to inhibit,in a dose-dependent fashion, the E-20-M activity in all three insect species. The concentration of compounds required to produce 50% inhibition ranged from 2 x W to 1 X 10-3 M.
Antiulcer activity: Nimbidin exhibited a strong protective effect in tests against acetylsalicylic acid-, stress-, serotonin- or indomethacin-induced gastric lesions in rats, as well as histamine or cysteamine-induced duodenal lesions in guinea pigs and rats respectively. In ulcer-healing tests, the healing process was enhanced in acetic acid-induced chronic gastric lesions using rats and dogs, after oral doses of nimbidin.
Immunomodulatory activity: An aqueous extract of the bark, leaf and seed showed an increase in phagocytic activity and induced expression ofMHC-II antigens on macrophages, indicating enhancement of antigenic potency, stimulated lymphocyte proliferative response of splenocytes to mitogens and selectively activated TH1-type of T-cell response. A significant inhibition of intracellular multiplication of Chlamydia ana cytopathic effect of Herpes was observed when mouse spleen cells were treated with neem extracts, indicating that these effects of neem are probably mediated by the immune system.
No toxicity has been observed in moderate use, although toxic effects have been observed in the liver and kidneys of laboratory animals after the administration of concentrated aqueous suspensions of fresh and dried leaves. The LD50 of a 50% ethanolic extract of the stem bark was found to be > 1000 mg/kg body weight when given IP to adult albino rats. Occasionally toxic effects have been reported, especially with the oil and seeds, but these may be due to infestation with mycotoxins.
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