• Clinical data 90%
  • Efficacy 80%
  • Security 60%
  • Toxicity 40%

Azadirachta indica
Folium Azadirachti

Synonyms

Melia azadirachta L., M. indica (A. Juss.) Brand., M. indica Brand.

General appearance

Compound leaves up to 40 cm long composed of 8–18 short-petiolate narrow-ovate, pointed, curved toothed leafl ets, 3–10 cm long and 1–4 cm wide arranged in alternate pairs. Glabrous dark green upper surface, paler underside.

Major chemical constituents

The major characteristic constituents are oxidized tetranortriterpenes including azadirachtin (azadirachtin A), 3 tigloylazadirachtol (azadirachtin B), 1-tigloyl-3-acetyl-11-hydroxy-meliacarpin (azadirachtin D), 11 demethoxycarbonyl azadirachtin (azadirachtin H), 1-tigloyl-3-acetyl-11-hydroxy-11-demethoxycarbonyl meliacarpin (azadirachtin I), azadiriadione, azadirachtanin, epoxyazadiradione, nimbin, deacetylnimbin, salannin, azadirachtolide, isoazadirolide, margosinolide, nimbandiol, nimbinene, nimbolin A, nimbocinone, nimbocinolide, nimbolide, nimocin, nimocinol and related derivatives.

Medicinal uses of Azadirachta indica

Uses supported by clinical data
External applications for treatment of ringworm. However, data from controlled clinical trials are lacking.
Uses described in pharmacopoeias and well established documents
Azadirachta indica: Treatment of worm and lice infections, jaundice, external ulcers, cardiovascular disease, diabetes, gingivitis, malaria, rheumatism and skin disorders. External applications for treatment of septic wounds and boils.
Uses described in traditional medicine
Treatment of allergic skin reactions, asthma, bruises, colic, conjunctivitis, dysentery, dysmenorrhoea, delirium in fever, gout, headache, itching due to varicella, jaundice, kidney stones, leprosy, leukorrhoea, psoriasis, scabies, smallpox, sprains and muscular pain, syphilis, yellow fever, warts and wounds. Also used as an antivenin, contraceptive, emmenagogue, tonic, stomatic and vermicide.

Pharmacology

Experimental pharmacology

Anxiolytic and analgesic activities

Intragastric administration of 10.0–200.0 mg/kg body weight (bw) of an aqueous extract of Folium Azadirachti produced anxiolytic effects similar to those of 1.0 mg/kg bw of diazepam in rats in the elevated-plus-maze and open-fi eld behaviour tests. The analgesic effect of an extract of the leaves was assessed in mice using the acetic acid writhing test and the tail fl ick test. Intragastric administration of 10.0–100.0 mg/kg bw of the extract reduced the incidence of writhing and enhanced tail-withdrawal latencies.

Antiandrogenic activity

Intragastric administration of 20.0 mg, 40.0 mg or 60.0 mg of powdered leaves per day to rats for 24 days resulted in a decrease in the weight of the seminal vesicles and ventral prostate, and a reduction in epithelial height, nuclear diameter and secretory material in the lumen of these organs. Decreases in total protein and acid phosphatase activities were also observed.
These regressive histological and biochemical changes suggest that the leaves have an antiandrogenic property. Histological and biochemical changes were also observed in the caput and cauda epididymis of rats treated orally with similar doses of the powdered leaves given daily for 24 days. The height of the epithelium and the diameter of the nucleus in both regions were reduced. Serum testosterone concentrations were also reduced in animals receiving the highest dose. Intragastric administration of an aqueous extract of the leaves (dose not specifi ed) to male mice daily for 10 weeks resulted in a signifi cant (P < 0.01) reduction in total serum testosterone and bilirubin.

Antihepatotoxic activity

The effect of an aqueous extract of the leaves was evaluated in paracetamolinduced hepatotoxicity in rats. Intragastric administration of 500.0 mg/kg bw of the extract signifi cantly (P < 0.01) reduced elevated levels of serum aspartate aminotransferase, alanine aminotransferase and γ-glutamyl transpeptidase.

Anti-inflammatory activity

Intragastric administration of 200.0 mg/kg bw of an aqueous extract of the leaves to rats decreased infl ammation and swelling in the cotton pellet granuloma assay. Intraperitoneal injection of 200.0–400.0 mg/kg bw of an aqueous extract of the leaves to rats reduced carrageenan-induced footpad oedema.

Antihyperglycaemic activity

A hypoglycaemic effect was observed in normal and alloxan-induced diabetic rabbits after administration of 50.0 mg/kg bw of an ethanol extract of the leaves. The effect was more pronounced in diabetic animals, and reduced blood glucose levels. The hypoglycaemic effect was comparable to that of glibenclamide. Pretreatment with the extract 2 weeks prior to alloxan treatment partially prevented the rise in blood glucose levels as compared with control diabetic animals. Intragastric administration of 50.0–400.0 mg/kg bw of a 70% ethanol extract of the leaves signifi -cantly (P < 0.001) reduced elevated blood glucose levels in normal and streptozocin-induced diabetic rats. A 70% ethanol extract of the leaves signifi cantly (P < 0.05) blocked the inhibitory effect of serotonin on insulin secretion mediated by glucose in isolated rat pancreas .

Antimalarial activity

An aqueous or ethanol extract of the leaves inhibited the growth of Plasmodium falciparum in vitro, with median inhibitory concentrations of 115.0 μg/ml and 5.0 μg/ml, respectively. Nimbolide, a constituent of the extract, inhibited the growth of P. falciparum in vitro with a median effective concentration of 2.0 μg/ml. However, intragastric administration of 746.0 mg/kg bw of the aqueous extract, 62.5 mg/kg bw of the ethanol extract or 12.5 mg/kg bw of nimbolide had no such effect in Plasmodiuminfected mice. P. berghei-infected mice showed parasite suppression after intragastric administration of 125.0–500.0 mg/kg bw of a dried methanol extract of the leaves per day for 4 days, but all the animals died after 5 days. A 95% ethanol extract of the leaves at concentrations of up to 500.0 mg/ml did not inhibit the growth of P. falciparum in vitro.

Antimicrobial and antiviral activity

A methanol extract of the leaves, 1.0 mg/ml, inhibited plaque formation in six antigenic types of coxsackievirus B at 96 hours in vitro. The minimal inhibitory concentrations were not toxic to Vero African green mon-key kidney cells. The subtoxic concentration was 8.0 mg/ml and the cytotoxic concentration was 10.0 mg/ml.
An aqueous extract of the leaves, at various concentrations depending on the organism, inhibited the growth of Bacteroides gingivalis, B. intermedius, Streptococcus salivarius and S. viridans in vitro. A petroleum ether extract of the leaves, at various concentrations depending on the organism, inhibited the growth of Epidermophyton floccosum, Microsporum canis, M. gypseum, Trichophyton concentricum, T. violaceum and T. rubrum.

Antioxidant activity

The effect of the leaves on hepatic lipid peroxidation and antioxidant status during gastric carcinogenesis induced by N-methyl-N’-nitro-N-nitrosoguanidine was assessed in rats. Intragastric administration of 100.0 mg/kg bw of an aqueous extract of the leaves decreased lipid peroxidation in the liver of tumour-bearing animals, which was accompanied by a decrease in the activities of glutathione peroxidase, glutathione-Stransferase and γ-glutamyl transpeptidase, and a reduction in glutathione level. Administration of 100.0 mg/kg bw of an extract of the leaves suppressed lipid peroxidation and increased hepatic levels of glutathione and glutathione-dependent enzymes. Intragastric administration of 100.0 mg/kg bw of an aqueous extract of the leaves three times per week to hamsters with buccal pouch carcinogenesis induced by 7,12-dimethylbenz[α]anthracene reduced lipid peroxidation and increased the glutathione concentration in the oral mucosa of tumour-bearing animals.

Antiulcer activity

The antiulcer effects of an aqueous extract of the leaves were investigated in rats exposed to 2-hour cold-restraint stress or given ethanol for 1 hour.
The extract, administered orally in doses of 10.0 mg/kg bw, 40.0 mg/kg bw or 160.0 mg/kg bw as single- or fi vedose pretreatments produced a dose-dependent reduction in the severity of gastric ulcers induced by stress and a decrease in gastric mucosal damage provoked by ethanol. The extract prevented mast cell degranulation and increased the amount of adherent gastric mucus in stressed animals. Intragastric administration of 40.0 mg/kg bw of an aqueous extract of the leaves per day for 5 days to rats inhibited stress-induced depletion of gastric wall adherent cells and mucus production.

Cardiovascular effects

Intragastric administration of 200.0 mg/kg bw of an alcohol extract of the leaves to anaesthetized rabbits decreased the heart rate from 280 to 150 beats per minute, and had a weak antiarrhythmic effect against ouabain- induced dysrhythmia. Intravenous administration of 100.0 mg/kg bw, 300.0 mg/kg bw or 1000.0 mg/kg bw of an ethanol extract of the leaves to rats resulted in initial bradycardia followed by cardiac arrhythmias.
The treatment produced a dose-related fall in blood pressure that was immediate, sharp and persistent. Pretreatment with atropine or mepyramine failed to prevent the hypotensive effect of the extract.

Immune effects

The effect of an aqueous extract of the leaves on humoral and cell-mediated immune responses was assessed in mice treated with ovalbumin. At doses of 10.0 mg/kg bw, 30.0 mg/kg bw or 100.0 mg/kg bw, the extract produced no appreciable effects on organ/body weight indices for liver, spleen and thymus compared with controls. In tests for humoral immune responses, IgM and IgG levels, and antiovalbumin antibody titres were higher in mice receiving the highest dose of extract than in animals in the control group. In tests for cell-mediated immune responses, mice receiving the highest dose of extract showed enhancement of macrophage migration inhibition and footpad thickness. Intragastric administration of 100.0 mg/kg bw of an aqueous extract of the leaves to normal and stressed rats lowered blood glucose and triglyceride levels, attenuated stress-induced elevations of cholesterol and urea, and suppressed humoral responses.
The effect of powdered leaves on humoral and cell-mediated immune responses was assessed in chickens infected with infectious bursal disease. A dose of 2.0 g/kg bw per day given in the diet increased antibody titres against Newcastle disease virus antigen and enhanced infl ammatory reactions to chloro-2,4-dinitrobenzene in the skin contact test.

Toxicology

Chickens fed diets containing the powdered leaves, 2% or 5%, from the 7th to the 35th day of age, and then a control diet for 2 weeks, showed a reduction in body weight gain and effi ciency of feed use compared with controls. The main pathological changes observed included an increase in lactic dehydrogenase, glutamic-oxaloacetic transaminase and alkaline phosphatase activities, an increase in uric acid and bilirubin concentrations, and a decrease in total serum protein levels. There were marked reductions in the values of erythrocyte count, haemoglobin concentration, packed cell volume, mean corpuscular volume and mean corpuscular haemoglobin, which were associated with yellow discoloration on the legs and hepatonephropathy.
Intragastric administration of 50.0 mg/kg bw or 200.0 mg/kg bw of aqueous suspensions of the leaves per day to goats and guinea-pigs over a period of up to 8 weeks produced a progressive decrease in body weight, weakness, inappetence, loss of condition and decreases in the pulse and respiratory rates. In goats, the higher dose produced tremors and ataxia during the last few days of treatment. No statistically signifi cant haematological changes were observed, although there was a tendency towards lowered erythrocyte counts, packed cell volume and haemoglobin levels. The treatment increased aspartate transferase and sorbitol dehydrogenase activities, and concentrations of cholesterol, urea, creatinine and potassium in the plasma. No signifi cant changes in the plasma concentrations of sodium, chloride or bilirubin were detected. Autopsy of treated goats revealed areas of haemorrhagic erosion. The hearts appeared fl appy and in some animals there was hydropericardium. Histopathologically, there was evidence of various degrees of haemorrhage, congestion, and degeneration in the liver, kidney, lung, duodenum, brain and seminiferous tubules. The effect of intragastric administration of 40.0 mg/kg bw and 100.0 mg/kg bw of an aqueous extract of the leaves per day for 20 days on thyroid function was assessed in male mice. The higher dose decreased serum tri-iodothyronine and increased serum thyroxine concentrations.
There was a concomitant increase in hepatic lipid peroxidation and a decrease in glucose-6-phosphatase activity.
The lower dose produced no signifi cant changes.
The median lethal dose of a 50% ethanol extract of the leaves in mice was 681.0 mg/kg bw when administered by intraperitoneal injection.

Clinical pharmacology

A 70% ethanol extract of the leaves was used for the treatment of ringworm in seven patients. External applications of a 40% solution of the extract twice per day to the affected areas for 5–10 days were reported to be effective (no further details available).

Adverse reactions

A case of ventricular fi brillation and cardiac arrest due to neem leaf poisoning has been reported. Contact dermatitis has also been reported.

Contraindications

Owing to potential genotoxic effects, the leaves should not be administered during pregnancy or nursing, or to children under the age of 12 years.

Warnings

No information available.

News and Journals

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