Neem (Azadirachta indica)
Introduction

 

Neem (Azadirachta indica) is an omnipotent and sacred gift of nature to humankind. The wisdom of use of Neem as a medicinal plant dates back to the ancient Harappa and Mohenjo-Daro civilizations in India. The medical practitioners of that period studied the therapeutic value of Neem tree. The earliest indication of Neem tree being employed for its medicinal properties as a household remedy began nearly 5000 years ago. On the Indian sub-continent the earliest documentation of use of the seeds, oil, bark, leaves and fruit of Neem (Azadirachta indica) for their medicinal properties dates back to more than 4500 years. In the first millennium BC the Neem tree was called “Sarwa-Roga-Niwaaranee” (= one that could cure all ailments). The ‘Upawanawinoda’ an ancient Sanskrit treaty dealing with forestry and agriculture, describes Neem as a ‘cure’ for ailing soils, plants and livestock. Neem has been widely used in Ayurveda and is also extolled in earliest Indian scriptures of medicine- the Charaka Samhita (second century AD) and Sushruta Samhita (fourth century AD).

[1], [2], [3], [4], [5] 


The tree derives its name from the Sanskrit word ‘Nimba’ meaning a sprinkler, a short term for sprinkler of nectar (Ambrosia). However the etymology of its generic name Azadirachta is nebulous. It is said to be derived from the Persian words: azad meaning free, drakhat meaning a tree. When the specific word indica is added the meaning of the botanical term becomes ‘A free tree from India’ which does not convey any significance of the name. According to some scholars the epithet Azadarach itself means a poisonous plant. This explains the meaning of generic name in a better way than the Persian version. Unani scholars named it as ‘Shajar-e-Munarak’ (=the blesses tree) [6], [7], [8] 

In Sanskrit Neem (Azadirachta indica) is also called ‘Arishta’ (=perfect, complete, imperishable), Nimba (= to impart good health), Pichumada (= destroyer of leprosy, healer of skin infections). [9], [10]

Synonyms in Sanskrit – Arishta, Pichumarda, Pichumanda, sarvatibhadra, Hinguniryasa, yavaneshta, Shukaprya, Neta, Subhadra, Prabhadra, Sutikta [11]
 The name Bead Tree comes from the use of the hard nuts to make rosary beads. In the southern United States it was once believed that if a horse ate the fruit of Neem, it would be protected against attacks of 'bots' (also botts = the larva of a botfly) [12]
In India Neem is used in households for giving bath to newly born infants to protect them from skin diseases and people from insect bites. It is also used to ‘cure’ many skin ailments. [13]

From teeth decay to mouth ulcers, from pyrexias of unknown origin to malaria and from simple skin rashes to fungal skin infections Neem ‘cures’ many ailments. Not only bed bugs or agricultural insects, but Neem also kills many other pests. Hence the rural Indians call Neem as their “Village Pharmacy”, “Village Drugstore”, “Village Dispensary”, “Living Pharmacy” etc. [14], [15], [16],[17]

The Neem tree has much to offer people in Africa’s drylands including food, medicine, timber and shade.

In Kiswahiti language of eastern Africa, Neem is known as ‘Mwarunaini’ meaning reliever of 40 human disorders. [18], [19]

The Neem tree being an incredible plant has been declared by the United Nations as the “Tree of the 21st century” [20]

In admiration of this ‘plant wonder’ the US National Academy of Science published a report in 1992 titled “Neem: A tree for solving global problems”[21] 

Since 1920, the pioneering work on the possible commercial use of neem oil had been done by the Indian Institute of Science, Bangalore, India. Researchers also began investigating the active chemical ingredients responsible for the insecticide and pesticide activity of Neem. Till now more than 140 active principles have been isolated [22]

 

Neem is said to be non-toxic, though not really so, (see below) to humans and each part of the tree is used as an active ingredient in different industries. For long Neem had been used in households for giving bath to infants, to protect people from insect bites, to cure skin ailments and also to protect a number of plants as it contains a number of pesticides.


A number of researches have begun to unfold the powers and potential of this revered tree. Their findings on international level vindicate the benefits of Neem described in Ayurveda. Neem is being used on a commercial basis and now, it finds immense use in a number of products in industries ranging from cosmetics to agriculture and pharmaceuticals. 

 

The tree is now being cultivated and grown in a number of countries to fully tap its potential and used on a commercial basis.

Other Names

 

Latin/Botanical/ Taxonomical:  Azadirachta indica A. Juss, Melia azadirachta

Sanskrit: Nimba and many more

English: Neem, Indian Lilac, Margosa Tree, Crackjack, Paradise Tree, White Cedar, Chinaberry

Assamese: Neem

Bengali: Nim, Neem, Neemgachh

Gujarati: Limba, Limbado, Leemgo, Danu-jhada, Nimuri

Hindi: Nim, Neem, Bal-nimb, Nind

Kannada: Bevinamara bevu, Hebbevu, Kiri-bevu, Nimb

Konkani: Nim

Malayalam: Aryaveppu, Veppu, Aryaveshnu, Rajavedhu, Vepe

Marathi: Kadu Nimba, Kadukhajur, Limba, Balanti-limb, Bal-nimb

Oriya: Kakopholo, Limbo, Nimbu, Nimo

Punjabi: Bakam Bukhain Drekh, Nim, Neem, Mahaneem

Rajasthani: Neem, Neemro

Tamil: Aruhundi, Kaduppagi, Kaingi, Vembu, Veppam, Nimbamu, Nim-Banu

Telugu: Nimbanuv, Vepa, Yeppa, Yapa, Vemu [23], [24]


 Taxonomic Classification

 Kingdom: Plantae
(Unranked): Angiosperms
(Unranked): Eudicots
(Unranked): Rosids
Division: Magnoliophyta
Order: Sapindales
Family: N.O. Meliaceae [25], [26]

Geographical Distribution

Neem (Azadirachta indica) is native to India and the Indian subcontinent including Nepal, Pakistan, Bangladesh and Sri Lanka. It is grown in tropical and semi-tropical regions. Now it is grown in islands located in southern part of Iran. [27] 
Neem has ‘poly-climax’ distribution in nature. In other words it can grow in more than one habitat i. e. sandy plains habitat, gravel formations, hilly habitat and aquatic habitat. [28] 
Neem is a hardy tree which is resistant to draught. It can tolerate saline, alkaline as well as slightly acidic soils. It does not grow in naturally forested areas but grows in areas where there is man-nature interaction. It is now found globally.
It is one of the very few shade giving evergreen trees that thrive in drought prone areas. It can grow in regions with an annual rainfall below 400 mm, but in such cases it depends largely on the ground water levels. Neem can grow in many different types of soil but it thrives best on well drained deep and sandy soils.
The oak like deciduous tree from 30 to 50 feet in height is widely distributed throughout the subtropics. It is believed to be native to China, but most definitely native to southwest Asia. It is also found growing in southern France and Spain in avenues. It is widely cultivated and naturalized in the West Indies and southern United States as a crop tree. In parts of Africa it is grown in hedges for easier harvesting. [29], [30], [31]

Plant Morphology

                 

            

                                              
  
 [These images show “poly-climax” distribution of Neem (Azadirachta indica). Hence it is regarded as sacred gift of nature to humankind]

Neem is a fast-growing tree that can reach a height of 15-20 meters (49-66 feet), rarely 35-40 meters (115-131 feet). It is evergreen but in severe draught may shed nearly all of its leaves. Its dense crown is roundish and may reach a diameter of 15-20 meters (49-66 feet). The Neem tree is very similar in appearance to its relative, the Chinaberry (Melia azedarach)   


                                              




[Roots of Neem ((Azadirachta indica) show that the plant can thrive in any habitat]
The Root is a strong taproot with well developed lateral roots having bitter taste and an unpleasant odor.  
Root bark is available as quilled or curved pieces of varying sizes with a thickness of 0.25 to 0.50 cm; outer surface irregular, rough, scaly, fissured, reddish brown or grayish brown; inner surface, yellowish brown with parallel striations; fracture, splintery and fibrous; odor like that of saw dust; taste, bitter 


   
[Trunk, Bark and Branches of Neem (Azadirachta indica)]

The Trunk is short, straight and may reach a diameter of 1. 2m with spreading branches.

The Bark has a rusty grey color. Inside it is yellow, foliated, coarsely fibrous, hard, fissured. Inside it is yellow, foliated and coarsely fibrous.

The Branches are covered with furrowed bark, rusty-gray in appearance, wide and spreading. 

   
[Very young and mature leaves of Neem ((Azadirachta indica)]
 The Leaves alternate, opposite, pinnate from 15 to 25 cm long with 20-30 medium to dark green, pointed, sharply serrate or lobed leaflets about 7 to 8.5 cm  long, ranging in shape from ovate and elliptic to lanceolate. The terminal leaflet is often missing. The  petioles are short. Very young leaves are reddish to purplish in color.
       


[Flowers of white and lilac variety of Neem (Azadirachtaindica]                
 The Flowers white, fragrant, lilac-colored arranged in more or less axillary panicles. The Inflorescence which branch up to the third degree, bear 150-250 flowers. An individual flower is about 5-6 mm long and 8-11 mm wide. Protandrous  bisexual flowers i. e. male flowers come to maturity before female flowers and bloom in early spring; calyx has 5 parts, corolla has 5 petals, stamens are a deep violet in color, the anthers yellow. 
More information:
Dried flowers are brown to deep brown, individual flower 5to 6 mm long and 6 to 11 mm wide, pentamarous, bisexual, regular and hypogynous; Calyx 5, short, united at base; Corolla 5, free, spatulate, spreading, 4.5 to 5.5 mm long, and 2 mm wide; Stamens 10, monoadelphous, staminal tube inserted at base of corolla, Gynoecium tricarpellary, syncarpous, superior, trilocular, two ovules in each locule, Style one, Stigma 3 lobed; taste mildly bitter, odour indistinct 
     

   [Raw, Ripe fruits of white and lilac variety of Neem ((Azadirachta indica)]


           
                         
           [Raw and Ripe Nimbuli of Neem ((Azadirachta indica)]

The Fruit is a glabrous olive-like drupe ( having bony nut) varying in shape from elongate oval to roundish, 1/2 to 3/4 inch by 0.3-0.5 inch with 5 cells, indehiscent, deeply wrinkled, enclosing a single seed in a brownish leathery pulp, odour strong and somewhat sweet or bitter-sweet to taste. The exocarp (the fruit skin) is thin; the mesocarp (pulp) yellowish white and very fibrous, 0.12-0.20 inch thick; the endocarp (inner shell) white, hard, encloses the seed.   

                   

                      Chennai                            Theni, Tamilnadu       
                                                 Florida                 
Seeds of Neem (Azadirachta indica)
 The Seed usually one but rarely two or three, convex dorsally, up to 1.5 cm long and 0.6 cm wide; brownish, seed-coat thin, brownish, shell like, cracks to touch, inside of cracked pieces golden yellow; seed kernel light brown, oily; odour strong, taste bitter [32], [33], [34]
Microscopic Structure
Root:
Root bark shows cork, cortex and phloem; cork generally 6-7 layers of polygonal and thin-walled cells with reddish-brown contents; outer cortex of tangentially elongated large rectangular cells with tangentially elongated sclereids; singly or in groups in isolated patches; sclereids vary in size and wall thickness, distinctly striated, pitted and often associated with cells containing crystal; inner cortex of polygonal parenchymatous cells with bundles of sclerenchymatous fibres, thick walled with irregular lumen; secondary phloem composed of alternating tangential bands of bast fibers and parenchymatous tissues intercepted by uni or biseriate phloem rays; abundant starch grains present in parenchymatous cells of cortex and phloem; starch grains simple, or more usually, compound with 2 or 3 components; hilum cleft or radiate, each grain 5 to 20µ in diameter; abundant prismatic calcium oxalate crystals in cortex of 10 to 15 µ in diameter also associated with phloem fibres; idioblasts with reddish brown contents seen in cortex cells with fat droplets seen in inner cortex and phloem [35]
Powder of Root bark:
Reddish-brown, shows cork cells; numerous prismatic crystals of calcium oxalate both isolated and in association with phloem fibres; individual fibres with narrow lumen and elongated tapering ends; pitted macrosclereids with wide lumen and distinct striations; simple and compound starch grains with 2 or 3 components of 5 to 20 µ in diameter in size; parenchymatous cells large and occasionally filled with brown contents. [36]
Stem Bark:
Stem bark shows outer exfoliating pieces hard, woody considerably thick in older trunks; almost entirely dead elements of secondary phloem, alternating with discontinuous tangential bands of compressed cork tissue, former composed of several layers of stone cells occurring in regularly arranged groups together with collapsed phloem elements filled with brown contents; in between the successive zones of cork tissue 3-5 layers of fiber groups with intervening thin-walled and often collapsed phloem elements present; each zone of cork tissue consists of several layers of regular thin-walled cells occasionally with a few compressed rows of thick-walled cells towards outer surface; within exfoliating portion a number of layers of newly formed cork composed of thin-walled rectangular cells and one or two layers of cork cambium, below which a wide zone of secondary phloem present; secondary cortex absent in most cases; secondary phloem commonly composed of well-developed fibre bundles traversed by 2-4 seriate phloem rays and transversely separated by bands of parenchymatous tissue of phloem; phloem element of outer bark mostly collapsed; a few fairly large secretory cavities also occur in phloem; most of phloem parenchyma contain starch grains and prismatic crystals of calcium oxalate; starch grains simple, round with central hilum, measuring 2.75-5µ; structure of bark varies considerably according to gradual formation of cork bands.
Powder of Stem Bark: Reddish-brown; shows numerous prismatic calcium oxalate crystals, phloem fibres with narrow lumen and pointed ends; cork cells, stone cells mostly in groups, lignified rectangular to polygonal having wide lumen and distinct striations, simple starch grains, measuring 2.75-5µ in diameter. [37]
Leaf:
Midrib- leaflet through midrib shows a biconvex outline; epidermis on either side present; stele composed of one crescent-shaped vascular bundle towards lower and two to three smaller bundles towards upper surface; rest of tissues composed of thin-walled, parenchymatous cells having secretory cells and rosette crystals of calcium oxalate; phloem surrounded by non-lignified fibre strand; crystals also present in phloem region.
Lamina- shows dorsi-ventral structure; epidermis on either surface, composed of thin-walled, tangentially elongated cells, covered externally with thick cuticle; anomocytic stomata present on lower surface only; palisade single layered; spongy parenchyma composed of 5-6 layered, thin-walled cells, traversed by a number of veins; rosette of calcium oxalate crystals present in a few cells; palisade ratio 3.0-4.5; stomal index13.0-14.5 on lower surface and 8.0-11.5 on upper surface
Powder of leaf: green; shows vessels, fibres, rosette crystals of calcium oxalate, fragments of spongy and palisade parenchyma. [38]
Flower:
Calyx: Sepal shows thin-walled polygonal papillose epidermis; elongated thin-walled unicellular conical trichomes of varying lengths; rosette crystals in cells of epidermis
Petals: Petals shows epidermis of rectangular cells papillose at margin, non-glandular unicellular trichomes, over 150µ long, tubular and hyaline; glandular trichomes of about 20µ numerous rosette crystals in epidermal cells
Androecium: Epidermis of stamina tube composed of thick-walled rectangular parenchymatous cells and the endothecium of the anther walls
Gynoecium: Stigma sticky, parenchymatous epidermal cells, elongated into extensive papillae, style thin-walled, rectangular, ovary superior, trilocular
Pollen Grain: Porous, 4-colporate, spherical 105 to 161 µ in diameter with a smooth exine 
Powder of Flower: Yellowish brown, fragments of parenchymatous papillose epidermal cells, trichomes, numerous vessels, rosette calcium oxalate crystals, and yellowish brown pollen grains
Fruit:
Pericarp well-differentiated into epicarp, mesocarp and endocarp; epidermis more than one layered; squarish to rectangular cells containing yellowish brown contents and oil droplets; mesocarp many layered of loosely packed cells with large elongated sclereids scattered in outer layers; endocarp of 2 distinct layers, outer of closely packed lignified stone-cells, inner fibrous, loosely packed, lignified
Seed:
Seed kernel shows a thin brown testa of isodiametric stone cells overlying integument of loosely packed parenchymatous cells; cotyledon consisting of parenchymatos cells containing abundant oil droplets

Powder of Neem Seeds:

Dark brown; shows abundant brachysclereids, columnar sclereids and pitted stone cells with wide lumen and distinct wall striations; groups of lignified fibres, thin-walled, arranged in network of loose strands; parenchymatous cells of cotyledon containing aleurone grains and oil globules; fragments of testa showing distinctly striated isodiametric stone cells; a few scattered rosette crystals of calcium oxalate [39]
 Parts Used
All parts of the tree (seeds, leaves, flowers and bark) are used for preparing many different medical preparations.  
Phytochemistry       

Till today more than 140 compounds have been isolated from different parts of Neem. Detailed discussion of each one is out of scope of this work. Only important ones will be discussed here. [40]

Chemical constituents 

Moisture
59.4%
Proteins
7.1%
Fats
1.0%
Carbohydrates
22.9%
Fiber
6.2%
Calcium
510mg/100g
Phosphorus
80mg/100g
Iron
17mg/100g
Thiamine
0.04mg/100g
Niacin
1.40mg/100g
Vitamin C
218mg/100g
Carotene
1998microgram/100g   
Glutamic acid
73mg/100g
Tyrosine
31.50mg/100g
Aspartic acid
15.50mg/100g
Alanine
6.40mg/100g
Proline
4.00mg/100g
Glutamine
1.00mg/100g

[41] 
Classification of chemical constituents

Terpenoids
A. Protolimonnoids
B. Limonoids
Subgroup:
(1) Azadirachtin (2) Salannin (3) Nimbin (4) Nimbolinin
(5) Gedunin (6) Azadirone (7) Amoorastatin (8) Vepinin
(9) Vilasinin
C. Pentatriterpenoids
D. Hexatriterpenoids
Neem oil fatty acids
Omega-3: Alpha-linoleinic acid?
Omega- 6: Linoleic acid 6-16%
Omega-9: Oleic acid 25-54%
Palmitic acid: Hexadecanoic acid 16-33%
Stearic acid: Octadecanoic acid 9-24%
Palmitoleic acid: 9-Hexadecenoic acid ?
Sterols
Campesterol
β-sitosterol
Stigmasterol
Fucosterol
Bitter principles
                                 
Tannins

Flavonoids

Sesquiterpene


[42], [43], [44]
Chemical Constituents of various parts of the plant
(Based on zero moisture per 100 grams)  

Seed
Protein 28.7g, fat 44.0g (oleic acid, palmitic acid, linoleic acid, stearic acid and margosa) and two new triterpenoids: azadiractin H and azadirachtin I, nimbin, nimbidin, nimbolide, gedunin, mahmoodin, sodium nimbidate
Leaves/Leaf extract
Paraisine, isomeldenin, nimbin, nimbinene, 6-desacetylnimbene,
nimbandiol, nimocinol, quercetin, beta-sitosterol, tannin and two tetracyclic triterpenoids
Fruits
Azadirine, azadirachtin and resin
Bark
Margosine, margolone, margolonone, isimargolonone, gallic acid, catechin, epicatechin, polysaccharides G1 A- G1B, polysaccharides G2A, G2 B, NB-2-peptidoglucan  
Cortex
Vanillic acid and dl-catrchol
Pericarp
Bakayanin and bakayanic acid
Fruit oil
Glycerides of palmitic-oleic-linoleic and stearic acid.
Does NOT contain linolenic-chaulmoogric or hydnocarpic acids
Tree (all parts)
Azadirachtin

[45], [46], [47], [48], [49], [50]


Properties of the chemicals

Azadirachtin
Insect repellant, anti-fedent, anti-hormonal, antimalarial
Nimbin
Anti-inflammatory, anti-histaminic, anti-pyretic, anti-bacterial and antifungal,  spermicidal
Nimbidin
Anti-inflammatory, analgesic, anti-bacterial, anti-fungal, anti-arthritic, anti-arrhythmic, anti-ulcer, hypoglycemic, spermicidal
Nimbolide
Anti-pyretic, antibacterial, anti-tubercular, antimalarial, anti-protozoal
Sodium nimbinate
Anti-inflammatory, Anti-arthritic, diuretic and spermicidal
Gedunin
Anti-fungal, anti-malarial and vasodilator
Salannin
Insect repellant
Quercetin
Anti-inflammatory, anti-oxidant, anti-bacterial and anti-
Protozoal
Mahmoodin
Antibacterial
Gallic acid, Catechin and Epicatechin
Anti-inflammatory, immunomodulatory
Margolone, Margolonone and Isomargolonone
Anti-bacterial
Cyclic trisulphide and Cyclic tetrasulphide
Anti-fungal
Polysaccharides
Anti-inflammatory
Polysaccharides G1A, G1B
Anti-tumor
Plysaccharides G2 A
G3 A
Anti-inflammatory
NB-2 peptidoglucan
Immunomodulatory
Nimbidol
Anti-pyretic, anti-tubercular, anti-protozoan
[51], [52], [53], [54], [55], [56]

Identity, Purity and Strength (of root-bark extract):

Foreign matter:                            Not more than 2%
Total Ash:                                       Not more than 15%
Acid-insoluble ash:                     Not more than 3%
Alcohol soluble extractive:      Not less than  6%
Water-soluble extractive:        Not less than 7%  [57]

T. L. C. of Root-bark
TLC of the alcoholic extract on pre-coated silica gel ‘G’ plate (0.2 thick) using hexane: ethylacetate (1:1) shows spots at Rf 0.08, 0.12, 0.19 (all violet), 0.25 (mustard yellow), 0.33, 0.39, 0.46 (all light violet) and 0.82 (purple) on spraying with 1 % Vanillin-sulphuric acid reagent followed by heating the plate at 1050 C for about ten minutes.

Identity, Purity and Strength (of stem-bark extract):

Foreign matter                                Not more than 2%
Total Ash                                           Not more than 7%
Acid-insoluble ash                         Not more than 1.5%
Alcohlo-soluble extractive          Not less than   6%
Water-soluble extractive             Not less than 5%

T. L. C. of Stem Bark

T. L. C. of the alcoholic extract of the drug on Silica gel ‘G’ using Chloroform: Ethyl acetate; Formic acid (5:4: I:) shows UV (366nm) three fluorescent zones at Rf. 0.72 (blue), 0.86 (blue) and 0.90 (green). On spraying with 5% Methanolic phosphomolybdic acid reagent and heating the plate for about 10 minutes at 1050 C four spots appear at Rf. 0.20, 0.45, 0.63 and 0.90 9all blue)  [58] 

Identity, Purity and Strength (of leaf extract):

Foreign matter:                                   Not more than 2%
Total Ash:                                              Not more than 10%
Acid-insoluble Ash:                           Not more than 1%
Alcohol-soluble extractive:            Not less than   13%
Water-soluble extractive:              Not less than 19 %   [59]

Identity, Purity and Strength (of flower extract):

Foreign matter:                                 Not more than 2%
Total Ash:                                            Not more than 14%
Acid-insoluble Ash:                          Not more than 5%
Alcohol-soluble extractive:            Not less than   5%
Water-soluble extractive:              Not less than 12 % [60]
T. L. C.
TLC of the alcoholic extract on pre-coated silica gel ‘G’ plate (0.2 mm thick) using chloroform: octane (20: 1) shows spots at Rf 0.12 (violet), 0.17 (light pink), 0.33 (violet), 0.5 (purple), 0.64 (dark purple) 0.80 (light purple), 0.85 (light purple), 0.92 (purple) on spraying with 1 % Vanillin-Suphuric acid reagent followed by heating the plate at 105 C for about fifteen minutes [61]

Identity, Purity and Strength (of fruit extract):

Foreign matter:                          Not more than 2%
Total Ash:                                     Not more than 8 %
Acid-insoluble Ash:                   Not more than 20 %
Alcohol-soluble extractive:     Not less than  16 %
Water-soluble extractive:       Not less than 19 % [62]

T. L. C.
T. L. C. of the alcoholic extract on pre-coated silica gel ‘G’ plate (0.2 mm thick) using chloroform: acetone (18. 5: 1.5) shows spots at Rf 0.11 (grayish violet), 0.16  (yellow), 0.19 (green), 0.24 (violet), 0.29 (grey), 0.33 (mustard yellow), 0.42 (pink), 0. 49 (grayish black), 0.57 (violet) and 0.76 (light purple) on spraying with 1% Vanillin-Sylphuric acid reagent and heating the plate at 1050 C for about ten minutes [63]
Cytological Identity:
13 chromosome count in Azadirachta indica A. Juss [64]
Genetic Study:

Genus Azadirachta belongs to family Meliaceae which includes 600 species. To avoid confusion regarding identification and prevent adulteration when used for medicinal purpose, scientists have established DNA fingerprinting of the plant. [65]
By using RAPD molecular markers R. S. Dhillon et al established the accurate genetic identity of Neem (Azadirachta indica) [66]  
Safety Tests

No safety data for each specific species of herb is available. Here are general guidelines: 

Heavy Metals:
Arsenic:             Not more than 5.0 mg/kg
Mercury:           Not more than 0. 5mg/kg
Lead:                  Not more than 10.0 mg/kg
Chromium:      Not more than 0.3 mg/kg 

Microbial Limits:
Total bacterial count:                                           Not more than  10cfu/g    
Total yeast and mould count:                            Not more than  10cfu/g                  
Bile tolerant gram negative bacteria:             Not more than 10cfu/g                
Specific Pathogens:
Salmonella spp:                                Absent in 25 g
Escherichia coli:                              Absent in 1 g   
Staphylococcus aureus:                Absent in 1 g          
Pseudomonas aeruginosa:          Absent in 1 g [67]

Properties and Pharmacology

Ayurvedic Properties

Ganas (Classical categories)
Charaka Samhita:

Kandughna: Antipruritic group
Tiktaskandha: Bitters

Sushrut Samhita: 
Aaragwadhaadi, Guduchyaadi and Laakshaadi group

Energetics:
Rasa (Taste): Tikta (Bitter), Kashaya (Astringent)
Weerya (Potency): Sheeta (Cold in nature)
Wipaaka: Katu
Gunas: (Qualities and properties)
Sheeta: Has cooling effect
Laghu: Easy to digest
Graahee: Herbs that help solidify the stool, increase the appetite and improve the digestion and improve the absorption of fluids.
Katu: Acrid, pungent
Tikta: Bitter
Agnikrut: Appetizer, improves digestion
Waatakrut: Increases waat-flatulence
Ahrudya:  Not benevolent for heart
Shramapranut (Shramhara) : Relieves fatigue
Trut-nut (Trusha-hara): Quenches thirst
Kaasa-nut (Kaasahara): Antitussive, relieves cough
Jwara-nut (Jwarahara): Antipyretic (? Diaphoretic)
Aruchi-nut (Aruchihara): Relieves dyspepsia, loss of appetite
Krumi-prnut (Krumihara): Anthelmintic
Wrnahara: Heals wound quickly
Pittahara: Relieves hyperacidity, allergies
Kaphahara: Reduces phlegm, reduces expectoration
Chhardi-hrullasa-nut (Chhardi-hrullasa-hara): Anti-emetic, relieves retching, relieves gastro-esophageal-reflux
Mehanut (Mehahara): Useful in diabetes and increased frequency of urination
Kushthahara: Antileprotic and useful in skin diseases [68], [69], [70]

Properties of Neem root:

While most of the properties of root are similar to those mentioned above, only those showing some special and different Properties are mentioned here—

Kanduhara: Antipruritic
Graahee: see above
Sheeta: Has cooling effect
Ahrudya: see above
Kaphahara: Relieves phlegm, expectotation
Pittahara: Anti-histaminic, relieves hyperacidity
Ruchya: see above
Deepana: Appetizer
Wishghna: Antidotes poisons
Wranashodhana: Relieves wound infections, reduces wound discharges etc. [71]

Properties of Neem stem-bark: 

While most of the properties of stem-bark are similar to those mentioned above, only those showing some special and different properties are mentioned here—

Kandughna: Antipruritic
Kaphahara: See above
Pittahara: See above
Wishghna: See above
Wranashodhanakara: See above
Hrudaya-widaaha-shantikara: Relieves heart-burn [72]

Properties of Neem leaf:

While most of the properties of leaf are similar to those mentioned above, only those showing some special and different properties are mentioned here—

Nertya: Beneficial to eyes
Krumi-nut (Krumihara): Anthelmintic
Pittanut (Pittahara): Relieves hyperacidity, allergies
Wishnut (Wishahara): Antidotes poisons
Waatala: Increases waata, induces flatulence
Arochakanut: Relieves dyspepsia, improves appetite
Kushthnut (Kushthahara)): Antileprotic, useful in skin diseases [73], [74], [75]

Properties of Neem flower:   

While most of the properties of neem flower are similar to those mentioned above, only those showing some special and different properties are mentioned here—

Chakshushya: Useful in ophthalmic disorders
Krumighna: Anthelmintic
Kaphahara: See above
Pittahara: See above
Waatakara: May be harmful to nervous system
Wishghna: See above
Kushthghna: See above
Graahee: See above [76]

Properties of Neem fruit: 

While most of the properties of neem fruit are similar to those mentioned above, only those showing some special and different properties are mentioned here—

Tikta Rasa: Bitter in taste
Bhedana: Relieves constipation, laxative, softens stool
Snigdh: Unctous (Oily, greasy)
Laghu: Easy to digest, light to digest
Ushna: Hot in potency
Kushthghna: Anti-leprotic, useful for skin diseases
Gulmanut: Exhibits anti-tumor properties
Arshnut (Arsha-hara, Arshaari): Relieves fissures and piles (hemorrhoids)
Kruminut (Krumihara, Kruminaashaka): Anthelmintic
Mehanut (Mehahara): Anti-diabetic, relieves increased frequency of micturition
[77], [78], [79]

Sushrut Samhitaa:

Raktapittanut: Relieves bleeding disorders
Shothahara: Anti-inflammatory, relieves edema
Netrya: Twigs and flowers are useful in ophthalmic disorders
Effects on Doshas: Kapha and Pitta
Effects on Dhatus: Predominantly Rakta (Blood and hematopoetic system)
Effects on Srotas: Rasawaha (Lymphatic), Raktawaha (Blood), Praanawaha (Respiratory system), Annawaha (Digestive system) [80]

Modern view:

Azadirachtin
Molecular formula: C35H44O16 
Structural formula: 


Azadirachtin belongs to the limonoid group of chemical compounds. It is a secondary metabolite present in the seeds, bark and leaves of Neem tree.
Azadirachtin fulfils many of the criteria of a good insecticide. In addition it has anti-bacterial, anti-viral and anti-fungal properties. [81]

Nimbolide  

Molecular formula: C27H37O7
Structural formula:      

      [82], [83], [84]

Nimbolide is a terpenoid lactone derived from leaves and flowers of Neem tree.  It displays a vatiety of biological activities. Of these proapoptotic and anticancer activities have attracted the attention of research scholars


Nimbolide exhibits anticancer activity via selective modulation of multiple cell signaling pathways linked to inflammation, survival, growth, invasion, angiogenesis and metastasis.

In cancer cells Nimbolide induces apoptosis through reactive oxygen species, down regulation of cell survival proteins and up regulation of pro-apoptotic proteins. [85], [86], [87]

Nimbolide, a natural triterpenoid isolated from the leaves and flowers of Neem inhibits the cell proliferation and development of metastasis of cancer cells by inducing apoptosis and cell cycle arrest. [88]
Salannin
Molecular formula: C34H44O9
Structural formula:

Azadirachta, salannin, nimbin and 6-desacetylninbin inhibit E-20-M activity in insects. Thus they exhibit insecticidal activity [91]

Nimbin 
Molecular formula: C30H36O9
Structural formula:


Nimbin is a triterpenoid isolated from Neem. It is responsible for much of the biological activities of neem oil. It is anti-inflammatory, anti-pyretic, anti-histaminic, antiseptic and fungicidal. [92]
Nimbin in a dose dependent manner arrests the growth of mosquito larve thus preventing the spread of vector borne diseases. [93]

Nimbolinin                
Molecular formula:   C35H46O10
Structural formula:

                                           
                                            Nimbolinin A                                   Nimbolinin B         

                                       
                                            Nimbolinin C                                    Nimbolinin D

Nimbolinin compounds are anti-inflammatory. They also prevent neurodegenerative disorders such as Parkinsonism and Alzheimer’s disease. [98]

Gedunin 
Molecular formula: C28H34O7
Structural formula:  



Hps90 (heat shock protein 90) stabilizes a number of proteins required for tumor growth. That is why Hsp90 inhibitors are investigated as anti-cancer drugs. [99]
Gedunin is a naturally occurring Hsp90 inhibitor found in neem  [100], [101], [102], [103]

Recently gedunin was investigated for its anticancer potential against ovarian cancer. Its effect was evaluated on SKOV3, OVCAR4 and OVCAR8 ovarian cancer cell lines proliferation, alone and in presence of cisplatin. The study showed that gedunin alone produced up to 80% decrease in cell proliferation and combining gedunin with cisplatin up to 47% decrease in cell proliferation compared with treatment by cisplatin alone. The molecular mechanism of anticancer activity of gedunin is complex and may involve modulation of cell survival and apoptosis pathways. [104]
P23 is simple protein having complex function. It is a part of Hps90.
Gedunin directly binds to p23, inhibits its activity, blocks its cellular interaction with Hsp90 and interferes with p23 mediated gene regulation. That is how gedunin leads to the death of cancer cells. [105], [106]

Azadirone 
Molecular formula: C28H36
Structural formula:

       [107]

Azadirone, a limonoid tetranortriterpene, sensitizes human cancer cells to tumor necrosis factor-related apoptosis-inducing ligand through a p53 protein independent mechanism and inhibits tumor growth [108]

Amoorastatin 
Molecular formula: C28H36O10
Structural formula: 

     [109]

Amoorastatin has anti-neoplastic properties [110]

Vepinin 
Molecular formula: C28H36O5
Structural formula:


As of today there is no authentic information about pharmacology of Vepinin [111]

Vilasinin    
Molecular formula:  C39H46O9
Structural formula: 


   

[112]
Vilasinin is found in the seed extract of Neem. It has antifeedant activity towards Epilachna varivastis (Mexican bean beetle).
(Antifeedant = a chemical agent that causes a pest to stop eating) [113]

Pharmacology at a glance

Anti-inflammatory
Nimbidin, sodium ninbidate, gallic acid, catechin, polysachharides
Anti-oxidant
Extract of Neem seed
Immunomodulatory
NB-II peptoglycan, gallic acid, epicatechin and catechin
Anti-pyretic, Anti-arthritic
Nimbidin
Antimicrobial
Nimbidin, nimbolide, mahmoodin, margolone, isomargolonone
Antifungal
Nimbidin, gedunin, cyclic trisulfide
Anthelmintic
Vanellic acid
Anti-malarial

Nimbolidfe, gedunin, azadirachtin, bakayanin and bakayanic acid.

Larvicidal on malarial vector

Neem oil formulations

 

Anti-peptic ulcer

Nimbidin

Regenerative effect on the mucosa of the stomach and the ileum

Aqueous extract of the plant

Hepatoprotective

Aequeous extract of Neem leaf

Hypoglycemic

Nimbidin

Diuretic

Nimbidin

Spermicidal

Nimbin, nimbidin

Anti-cancer

Polysaccharides


[114]

Some testimonials from modern research
Anti-inflammatiry activity:
Neem was in vogue for the treatment of rheumatoid arthritis and osteoarthritis.
There are several chemical compounds of Neem having a proven anti-inflammatory activity that antagonize histamine and other mediators of inflammation in the body. The important chemicals that contribute to this effect are nimbidin, limonoids, and  catechin. Warmed Neem oil is also recommended for external use to reduce pain and inflammation in affected joints.

The chloroform extract of stem bark of Neem is effective against carrageenin-induced paw edema in rats. The bark extract of Neem cures inflammatory stomatitis in children. [115], [116], [117]

Neem oil has been reported to exhibit anti-inflammatory and antipyretic activity. [118]

The methanol extract of Neem leaves exerts anti-inflammatory and antipyretic action in rabbits [119]
Neem exhibits analgesic activity. It is mediated through opiod receptors in laboratory animals [120]
The major active principle of Neem seed oil is nimbidin. It is a mixture of tetranortriterpenes. It possesses a potent anti-inflammatory activity. In an experimental study on rats, oral administration of 5 to 25 mg/kg body weight of nimbidin for 3 consecutive days inhibited inflammatory activity. Nimbidin inhibited nitric oxide (NO) and prostaglandin E2 production in lipopolysaccharide stimulated macrophages, where as interleukin-1 was weakly inhibited. Investigating the mechanism of NO inhibition revealed that nimbidin ameliorated the induction of inducible NO synthase without inhibition in its catalytic activity. Nimbidin also attenuated degranulation in neutrophils. Thus nimbidin can be valuable in treating inflammatory diseases. [121]

Antioxidant activity
On the basis of free radical scavenging activity the extracts of leaf and bark of Neem were shown by Ghimeray et al in 2009 to possess anti-oxidant activity. [122], [123]
In an experimental study the antioxidant activity of neem seed has been demonstrated. An antioxidant principle, a potent inhibitor of plant lipooxigenase has also been isolated [124] 

Immunomodulatory activity
The aqueous extract of Neem bark possesses immunostimulant effect.
The aqueous extract of Neem stem bark enhances the immune response of Balb-c mice to sheep red blood cells in vivo.
Humoral and cell mediated response shows that the aqueous extract of Neem leaf has potent immunostimulatory activity.
Via cell mediated mechanism Neem oil shows potent immunostimulatory activity. [125]

Antibacterial activity 
Neem stick extract even at concentration as low as 5% shows antibacterial activity against Streptococcus mutan, Streptococcus salivavius, Streptococcus mitis, and    Streptococcus sanguis [126]
Neem leaf extract is effective against E. faecalis, Staphylococcus aureus, Streptococcus mutans and Candida albicans [127], [128]
Extracts of various parts of neem exert bactericidal effect on Staphylococcus aureus, Escherichia coli, Pseudomonas aerugenosa and fungicidal effect on Candida albicans [129]
A wide range of antibacterial agents present in neem leaves, bark and seed show antibacterial actions against Gram-positive, Gram-negative microorganisms including streptomycin resistant strains of Micobacterium tuberculosis. In vitro studies show that neem inhibits Vibrio cholera, Klebsiella pneumonia, Micobacterium tuberculosis. [130]

Antiviral activity

The extract of neem seed kernel was found to be effective against duck plaque virus (DPV) infecting ducks. The extract increased the cell viability by reducing cytopathic effects caused by DPV and the amount of protein expressed in virus-infected cells. [131]
In another study neem bark extract significantly blocked Herpes simplex virus type-1 from entering cells at concentrations ranging from 50 to 100µg/ml. When the extract was directly incubated with virus, the activity of virus was blocked. This suggests that neem extract has anti-HSV-1 property. Further virions treated with neem bark extract failed to bind the cells. This highlights the cell-attachment-blocking activity of neem bark extract. Cells treated with neem bark extract also inhibited HSV-1 glycoprotein mediated cell to cell fusion and polykaryocytes formation. This suggests that neem bark extract blocks viral fusion. These findings are important for the development of anti-herpetic microbicide from neem. [132]
Methanolic extract of leaves of neem was found to be useful against Coxsackie B group of viruses. It exhibits virucidal activity at concentration 1000µg/ml. The virucidal action is complete in 96 hours. The antiviral activity of neem is attributed to flavonoids, triterpenoids and Neuronal ceroid lipofuscinoses (NCL) present in the plant. 
Recently an in vitro study shows that aqueous extract of neem leaves exhibits antiviral activity against Vaccinia, Chikungunia and measles viruses. [135], [136]
Norterpenoid compounds isolated from the seeds of Neem inhibit the Epstein-Baar virus antigen activation induced by Tissue Plasminogen Activator (TPA) [137]
Antifungal activity 
Various studies were conducted with water extract/methanol extract/ethanol extract/ethyl acetate extract of neem leaf, neem seeds and neem seed oil. The extracts were found to exhibit antifungal/ fungicidal activity against Tricophyton rubrum, Tricophyton mentagragrophytes, Tricophyton violaceaum, Microsporum nanum, Epidermophyton floccosum, Aspergillus flavus, Aspergillus fumigantus, Aspergillus niger, Aspergillus terreus, Candida albicans, Microsporum gypseum, Microsporum nanum and Microsporum canis. The main component responsible for this activity was said to be nimonol. [138], [139], [140], [141], [142]
Antiparasitic activity 
The alcoholic extract of neem leaf and seed is effective against both chloroquin resistant and sensitive strains of malarial parasites. Neem seed extract and its purified fractions inhibit the growth and development of asexual and sexual stages of Plasmodium falciparum. [143]

Chloroform, diethyl ether, methanol and ethanol extracts of neem leaves show antifilarial and anthelmintic activity. All the solvents show significant anthelmintic activity at the concentration of 200 µg/ ml after 135 minutes of incubation. Highest mortality rate of microfilariae was observed in methanol and ethanol extracts. [144]
To evaluate the utility of Neem leaves as anthelmintic, experimental studies were arranged in the Department of Animal Nutrition, Madras Veterinery College, Tamilnadu, India during 2006. The studies revealed that Neem leaves are anthelmintic. The anthelmintic activity was attributed to azadirachtin [145]

Actions on the Skin

Neem leaves have antiseptic, anti-bacterial, anti-viral, anti-fungal and anti- head lice properties. These properties are useful for the treatment of pimples, non- specific skin inflammations, fungal skin infections, dandruff, lice infestation and hair fall. Neem sooths the oily skin without drying the skin. [146]
These activities of Neem are attributed to various anti-oxidants present in it. Neem imparts the skin a youthful glow. [147]
Herbalists and naturalists recommend Neem leaf tea orally and application of Neem oil locally for the treatment of eczema and psoriasis.
Anti-inflammatory, antiseptic and anti-oxidant properties of Neem are said to be useful in this regard.
However there is no internationally accepted research data. [148]
Of thirty one norterpenoid complounds found in Neem seeds six newly isolated limonoids, (1)7-benzoyl-17-epinimbocinol, (2) 3-acetyl-7-tigloylnimbidin, (3)1-isovaleroyl-1-detigloylsalanninolide, (4) 2,3-dihydro-3α-methoxylimbonide, (5) deacetyl-20, 21,-epoxy-20, 22-dihydro-21-deoxyisonimbinolide, (6) deacetyl-20,21,22,23-tetrehydro-20,22-dihydroxy-21,23-dimethoxynimbin inhibit the effect of melanogenesis and melanin in the B16 melanoma cells. Furthermore, azadirachtin B inhibits carcinogenesis of mouse skin induced by peroxynitrite. [149], [150], [151]

Wound healing
To study the effect of Neem oil on wound healing, patients with chronic non healing wounds of more than six weeks duration were selected. The wounds were biopsied before initiating the local application of the oil. The dressings were changed daily. Every two weeks the wound area, formation of granulation, microscopic angiogenesis were assessed. The results showed that Neem oil dressings were useful for wound healing. [152]
Neem oil directly accelerates the process of wound healing. According to R. L. Bhardwaj, an associate professor of veterinary Anatomy and Histology, COVAS, CSKHPKV, Palampur, India; a high content of essential fatty acids in Neem oil adds moisture and softness to the skin during wound healing. This supported by anti-inflammatory, anti-bacterial, ani-viral and anti-fungal properties of Neem oil. [153]
Neem oil processed from seeds of the plant is used in veterinary practice in Nigeria for the management of surgical wounds, both clean and infected wounds. There Neem oil is used in veterinary practice for dressing of wounds after drainage of abscesses. [154]

Actions on Hematopoetic System
Nimbolide is cytotoxic to human B-lymphocyte cancer. Its anticancer activity is is mediated through mitochondrial apoptosis. Nimbolide is also effective in killing B-lymhocyte cancer cells resistant to some chemotherapeutic drugs. [155]
Norterpenoid compounds present in Neem seeds show cytotoxic activity against leukemia (HL 60) cells. [156]

Actions on Nervous System
The leaf extract of Neem shows varying degrees of CNS depressant activities in mice. Leaf extract up to a dose of 200mg/kg body weight produces significant anxiolytic activity in rats. [157], [158]
In a number of animal models investigated nimbidin a bitter principle isolated from seed oil of Neem exhibited sedative activity. Further, in vitro studies showed that nimbidin has a pronounced anticholinergic, antihistaminic, antiserotonin and antinicotinic activities. But in vivo studies did not show any anticholinergic or antihistaminic activities. Nimbidin did not show any local anaesthetic activity in rodents. [159]
In a study on rats, leaf extract of Neem 500mg/kg body weight and seed oil 2ml/kg body weight exhibited antinociceptive effect. Leaf extract was more potent than the seed oil. [160]

Actions on the eye 
In diabetic rats with diabetic retinopathy aqueous extract of Neem leaves at a dose of 250mg/kg body weight 16 weeks reversed retinopathy. [161]
By causing cell cycle arrest nimbolide found in Neem directly inhibits retinoblastoma and suppresses the growth of glioblastoma [162]

Actions on Endocrine System
Oral administration of Neem leaf extract up to 100mg/kg body weight for 20 days to male rats did show adverse effects on thyroid function. But administration of higher doses increased thyroxine levels in the blood. [163]

Actions on CVS 

The ethanol extract of stem bark and root bark of Neem showed hypotensive effect. The anti-histaminic nimbidin present in Neem leaves is a potent vasodilator. It reduces elevated blood pressure. Neem leaf extract, tincture or capsules when taken for a month lower cholesterol levels. [164], [165]
In an experimental study on rats, intravenous administration of alcoholic extract of neem leaf at doses of 100, 300, 1000mg/kg resulted in bradycardia and fall in blood pressure. Bradycardia was later followed by cardiac arrhythmia. All these effects were dependent on the dose administered. Pretreatment with either atropine or mepyramine failed to prevent the hypotensive effect of the extract. [166]

Actions on RS
Asprgillosis an opportunistic fungal infection can be acute or chronic. It is often found in immuno-compromised patients, in patients on prolonged antibiotic or steroid therapies. It is characterized by invasion of blood vessels which can result in dissemination to other organs. Aspergilloma is a fungal ball that develops in previous cavitary lesions in the lungs. Inhalation of essential oil of Neem kills the fungi attached to the inner lining of the respiratory tract. [167]

Actions on GI System
The antioxidant, antibacterial and antifungal activities of Neem make it vary suitable for periodontal and endodontic diseases. The bitter taste can be masked by sweeteners and agreeable flavors. [168], [169], [170]
Antioxidant activity of limonoids from Neem leaf show inhibitory effect on 7, 12-dimethylbenzanthracin-induced hamster buccal pouch carcinogenesis. On a comparative basis, nimbolide was found to be a potent antiproliferative and apoptosis inducing agent. [171], [172]
Nimbidin a bitter principle found in Neem exhibited significant antisecretory activity in pylorus-ligated rats and cats. On intra venous administration of 40mg/kg body weight, nimbidin suppressed basal as well as histamine and carbachol stimulated gastric secretion. However nimbidin had no effect on aspirin induced gastric secretion. The anti secretory activity of nimbidin was found to be similar to H-2 receptor antagonists. [173] 
At 500 mg/kg body weight aqueous extract of Neem leaf extract showed gastric ulcer healing effects in diabetic as well as non diabetic rats. This effect was studied on various parameters of offensive acid-pepsin secretion in 4 hour pylorus ligation, pentagastrin (Dose: 5µg/kg/hr) stimulated acid secretion and gastric mucosal proton pump activity. Pretreatment with aqueous extract of Neem significantly decreased gastric secretion. Further the extract inhibited the rat-gastric mucosal proton pump activity. This effect was comparable to omeprazole. This shows that the gastroprotective activity of the extract was due to proton pump inhibition. No toxicity was observed up to the dose of 1g/kg for 28 days in this study.
In another study by Dorababu and his co-researchers on rats, at 500 mg/kg body weight aqueous extract of Neem showed significant anti-gastric ulcer and ulcer healing activity in non-diabetic and non-insulin-dependent diabetic rats. [174], [175] 
Cold-restraint stress is a method used to produce experimental stomach ulcers. In this process by exposing gastric mucosa to 40C for 2 hours gastric ulceration is produced. Hypothermia, ischemia of gastric mucosa following extreme cold and possibly some other factors are responsible for the ulceration and depressed gastric motility. 
To evaluate antisecretory and anti-ulcer effect of aqueous extract of Neem bark, in experiments on rats, Bandopadhyay U et al used pyloric ligation, cold-restraint stress method, and indomethacin to produce gastric ulceration. The bark extract showed very potent antisecretory and ulcer healing activity. The researchers found that the extract was equipotent to ranitidine but more potent than omeprazole in inhibiting pylorus ligation-induced acid secretion. In the model of stress ulcer, the extract was more effective than ranitidine but equipotent to omeprazole. The researchers think that the pharmacological effects of the bark extract are due to a phenolic glycoside. [176], [178], [179], [180], [181]
To evaluate the anticancer effects of Neem, N-methyl-N’-nitro-N-nitrosoguanidine (MNNG) was used to induce gastric cancer in Wistar rats. By intragastric intubation 200mg/kg body weight, ethanolic extract of neem leaf was administered three times per week. To assess the results all the animals were killed after 26 weeks. The results of the study suggest that ehtanolic extract of Neem leaf exerts chemoprotective effect on gastric carcinoma by modulating lipid peroxidation and antioxidant status in the stomach, liver and erythrocytes  [182]
Proinflammatory microenvironment plays an important role in the development of colorectal cancer. Nimbolide can suppress the growth of human colorectal cancer by suppressing the proinflammatory microenvironment. [183] 
·        Development of cancer implies dysregulation of multiple cell signaling pathways.
·        Chemoprevention can block, retard or reverse carcinogenesis
·        Nimbolide exhibits anticancer activity by inducing apoptosis and inhibiting tumor cell proliferation in vitro and in vivo.
For more details of mechanisms of suppression of colorectal cancer by nimbolide see above. [184] 

Actions on the Pancreas
Nimbolide inhibits pancreatic cancer growth and cancer metastasis. It inhibits the generation of Reactive Oxygen Species (ROS) thereby regulating the apoptosis in pancreatic cancer cells. Inhibition of generation of ROS inhibits proliferation and development of metastasis of pancreatic cancer via mitochondrial-mediated apoptosis.  [185], [186]

Actions on the Liver
In a study Bhanwara et al induced hepatotoxicity in rats by administering a single dose of paracetamol 2 g/kg. The liver damage was evidenced by elevated levels of serum aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transpeptidase and by histological studies. Administration of aqueous extract of Neem leaves at the dose of 500mg/kg reduced the elevated levels of enzymes. The liver necrosis also reduced as observed macroscopically and microscopically. [187] 

Chattopadhyay RR and Bandopadhyay M. also observed hepatoprotective effects of Neem leaf extract on paracetamol-induced liver damage.
They attribute hepatoprotection by Neem to antoxidants present in the plant. [188], [189]
To investigate hepatoprotective activity of fresh juice of young stem bark of Neem, carbontetrachloride was administered to albino rats to induce hepatic damage. Administration of fresh juice (200 and 500mg/kg) of tender Neem stem bark showed reversal of hepatic damage. The best results were observed at the dose of 500mg/kg body weight. The effect was comparable to silymarin. The effect was attributed to antioxidant phytochemicals present in the plant. [190]

N. S. Baligar et al used higher doses (500 to 2000 µg/kg bodyweight) of the phytochemical Azadirachtin A present in Neem to counteract the hepatotoxicity produced by carbontetrachloride. They confirmed the usefulness of Azadirachtin A by increased levels of decreased levels of liver enzymes, improvement in ultrastructure as evidenced on sonography and improvement of the liver architecture as noted by liver histology. This study reveals that Azadirachtin A in pure form, when used at higher doses, posseses a very potent hepatoprotective activity. But the effective concentration and the dose needs to be determined.[191]

To probe the utility and mechanism of action of Neem leaf-powder in the treatment of alcoholic liver damage, alcoholic liver damage was induced in Wistar rats. After treatment with Neem leaf-powder the liver damage was reversed. The effects were comparable to those of silymarin. The leaf powder normalized the decreased levels of glutathione, superoxide dismutase and catalase caused by alcoholic liver damage. [192] 

Actions on metabolism
Experiments conducted on rats by R.R. Chattopadhyay and M. Bandyopadhyay showed that fresh extract of mature leaves of Neem normalized the lipid profile in non diabetic and diabetic rats. [193]

Antidiabetic activity 

There are many research papers showing antidiabetic activity of various parts of Neem plant. Here are some important references:
Aqueous extract of leaves of Neem significantly decreases elevated blood blood sugar in non diabetic and diabetic rats. [194]
Epinephrine increases hepatic glucose production by stimulating glycogenolysis and gluconeogenesis. Glycogenolysis wanes rapidly but gluconeogenesis and glucose disposal persist longer. Hence epinephrine-induced hyperglycemia continues for a long time. Thus epinephrine is an important contributory factor to stress-induced hyperglycemia and susceptibility of diabetics to complications of metabolic ill effects of stress. Neem does not show any action on peripheral utilization of glucose and on hepatic glycogen. Neem acts as an antidiabetic agent by blocking the action of epinephrine [195]
Administration of 500mg of Neem seed kernel powder for 30 days to alloxan induced diabetic rabbits, reduced elevated blood sugar serum lipids. [196]
To evaluate antidiabetic effect of Neem root bark, alcoholic extract of Neem root bark was administered orally at 200, 400 and 800 mg/ kg body weight for 15 days to alloxan-induced diabetic Wister rats. The hypoglycemic activity was significant only at doses of 800mg/kg body weight. The activity was not as significant as that of glibenclamide. [197]
Dixit V. P. et al demonstrated hypoglycemic activity of Neem seed oil in nondiabetic and diabetic rats. [198]

Actions on Urinary System 

Nimbidin a bitterprinciple on Neem shows moderate diuretic activity [199]

Actions on Male Reproductive System
Neem oil exhibits spermicidal activity. The mechanisms involved are:
1. Neem oil decreases the motility of sperms. The motility of sperms depends on mitochondrial activity present in mid-piece of sperms. The researchers found that neem oil significantly decreases the mitochondrial activity. As the duration of contact between the oil and sperm increases the mitochondrial activity decreases significantly. Thus Neem oil applied to vagina before coitus kills sperms.

NIM-76 is the odorus and volatile fraction of Neem oil. Its antifertility activity was investigated in animal models. The fraction applied to vagina of rats, rabbits and rhesus monkeys before coitus killed sperms. There was no alteration in the valuse of estradiol (E2) and progesterone (P) suggesting that the action of the drug was local and independent of female hormones.
It is suggested that active compounds present in Neem oil are absorbe through the vaginal mucosa and exert antifertility effect. [200], [201], [202]
Oral administration of aqueous extract of Neem leaf, purified extract of Neem seed exhibited antifertility effect in various experimental animal models [203]
The effect of antifertility activity of Neem can be produced in the male by interference at the following steps:
1. Secretion and release of Follicle Stimulating Hormone Releasing Factor (FSHRF) and Leuteinizing Hormone Releasing Factor (LHRF) from the hypothalamus
2. Secretion and release of Follicle Stimulating Hormone (FSH) and Leutinizing Hormone (LH) from the pituitary
3. Production of spermatozoa and androgenic hormone 
4. Transport of sperms into the epididymis with simultaneous maturation of spermatozoa.
5. Passage of spermatozoa through through vas deferens to ampula
6. Suspension of sperms in seminal plasma during ejaculation
7. Passage of ejaculate through cervix.
8. Ascent of sperms through the uterus and oviducts.
9. Penetration of ovum by spermatozoa.
This preliminary report on the antifertility activity of Neem in male mice shows that the antifertility activity of Neem is not due to inhibition of spermatogenesis. The mechanism may be much complex than thought of. [204], [205], [206]
The antifertility effect of Neem is possibly due to activation of cell-mediated immune reaction. The mechanism of action of neem oil appears to be non-hormonal, probably mediated through its spermicidal effect and may have fewer side effects than steroidal contraceptives.  [207]
More likely mechanisms for abortive effects involve the activation of macrophages by neem and subsequent secretion of cytokines that may alter immune and non-immune cells. In rats, CD4 and CD8 cells (particularly CD8 cells) increased in the spleen 96 hours after treatment onset and tumor necrosis factor alpha and gamma-interferon increased in serum, mesenteric lymph nodes, and fetoplacental tissue. [208]
The ethanol extract of Neem leaves showed anticancer activity against prostate cancer. The phytochemicals 2’ 3-dehydrosalannol, 6-desacetyl nimbinene and nimolinone exhibit this activity. [209], [210], [211]
Actions on Female Reproductive System
Local application of Neem to vagina before coitus and instillation of a single dose of Neem oil in the uterus blocks the fertilization of ovum. [212]
Antioxidant and antiproliferative activity of limonoids found in Neem suppress the growth of cancer of the cervix of the uterus. [213]
Antitumor activity

Prophylactic treatment on Swiss albino mice with Neem leaf preparation once a week for four weeks restricted the growth of Ehrlich’s carcinoma. [214]
Nimbolide, a natural triterpenoid present in Neem inhibits the growth of carcinoma of the colon by cell cycle arrestin the G2/M phase. [215]
Nimbolide induces apoptosis by both intrinsic and extrinsic pathways in breast cancers. The studies by Arumugam A et al suggeast that Neem leaf extract inhibits human breast cancer by altering cell proliferation, apoptosis and angiogenesis. [216], [217]

Culinary uses
Neem gum is a rich source of protein. It is used as a bulking agent and for the preparation of special purpose foods for diabetics.
The tender shoots and flowers are eaten as a vegetable in India. Neem flowers are popular for their use for soup-like pickle in South India.
Neem is also used as a culinary item in parts of mainland Southeast Asia, particularly in Cambodia.

The taste of Neem is quite bitter and thus the food is not enjoyed by all inhabitants of these nations, though it is consumed since it is said to be good for one's health. 

Toxicity
The epithet Azadarach itself means a poisonous plant.
Neem indeed is Nature’s drug house but injudicious, unscrupulous use of the drug can take its toll.
Nimbidin produces sub-acute toxicity in adult rats after daily administration of 25, to 100 mg/kg for six weeks. A significant hypoglycaemic effect was observed by feeding nimbidin. It has spermicidal activity.

Nimbolide and nimbic acid were found to be toxic to mice when given intravenously or intraperitoneally. At a lethal dose they cause death in most animals by hepato-renal failure as well as by marked and sudden drop of arterial blood pressure. 
Due to lack of sufficient data regarding the clinical trials and possible toxicity, it is inadvisable for children and pregnant or lactating mothers to use Neem.
Those who have impaired liver or kidney function should also use great caution. Large doses of seed or seed components may be toxic.
Even the hardcore traditional Ayurvedic practitioners advise against the use of Neem if the patient suffers from consumption (old term for tuberculosis), wasting and acute or chronic fatigue. Excess of neem causes diarrhea, vomiting, and symptoms of narcotic poisoning.
Ripe fruits more poisonous than green ones and sometimes cause human fatalities. 
NOT TO BE GIVEN TO WEAK, OLD, OR VERY YOUNG [218]
Some Case Reports:
Report 1:
AR Suresh et al, reported a rare case of toxic optic neuropathy secondary to consumption of neem oil in Indian J ophthalmol. 2014, Mar; 62(3): 337-339

Report 2:
Neem oil was considered as a 'cure all' medicine in many countries. It has been considered to be 'safe' to use. But not really. In fact the oil is poisonous.In rats oral LD 50 of Neem oil is 14ml/kg and in rabbits 24ml/kg. The features of poisoning are: stupor, convulsions, diarrhea, respiratory depression and death.
Report 3

Margosa oil (Neem oil) causes toxic encephalopathy particularly in infants and children. The usual features are vomiting, drowsiness, tachycardia, recurrent convulsions, metabolic acidosis and leucocytosis. The management is aimed at controlling convulsions and treatment of encephalopathy. If infants and children survive neurological deficits have been reported. [223], [224]
Report 4

Both neem seed oil and azadirachtin impair intrauterine development and alter antioxidant/oxidative status during pregnancy. [225]

Report 5

In experimental studies on animal models, Adult Wistar rats who received ethanolic extract of neem root bark orally at doses of 500, 1000 and 2000 mg/kg body weight for three weeks developed nephrotoxicity. The results were confirmed by histological study. [226]

Medicinal Actions and Uses

Traditional Uses
Neem has been used internally for intermittent fevers, malaria, tuberculosis, rheumatism, arthritis, jaundice, and skin diseases, intestinal worms and candidiasis. For its internal use usually combined with Glycyrrhiza glabra to reduce toxicity.
It has been used externally for ringworm, eczema, lice-fungal infections.
Juice of the leaf is anthelmintic, antilithic, emmenagogue; decocotion of the leaf is astringent, stomachic.
Flower has been used for nervous headache, neuralgia, prickly heat.
Stembark is anthelmintic and has been used for dyspepsia, and gastralgia. Can it be used for H. pylori infection?
Fruit has been used for abdominal pain, urethritis, cystitis, delirium, ringworm, endometritis, weeping eczema; pulp of fruit has been used to make ointment to destroy lice and other skin diseases.
Root bark has been used against ringworm, scabies and for ascariasis. 
Root bark has been used externally for vaginal infections.
Oil from the bark has been used medicinally as an anthelmintic and emetic.
Bark of the tree is bitter and astringent and has been used in India as a tonic.
Oil from the nuts and seeds has been used for cramps, obstinate ulcers, and elimination of intestinal worms; also applied externally for rheumatism. 
Decoction has been used as a cathartic and in large doses slightly narcotic; possible febrifuge; has also been used for hysteria; either the decoction or the powdered root bark has been taken for worms (dose is followed by a purgative).
Decoction has been used in the southern United States to expel intestinal worms. A drink was prepared using 100 grams of the bark boiled in 1 litre of water until it was reduced to half (500ml). Dose = 15ml every 3 hours being accompanied by a purgative such as castor oil or Cascara sagrada).
The tender twigs are used as crude form of tooth brush to scrub teeth and the powder as dentifrice (Marathi: Dantamanjan). Probably the Ayurvedic scientists were not conversant with the chemical constituents of the plant but their wisdom of using the plant for medicinal purpose is commendable 
In modern era the liquid extract is used in toothpastes.  [227], [228], [229], [230]
Here are medicinal uses of Neem plant from myths to medicine:
Used by the folk: 
Fresh leaf tea = Malaria
Decoction, infusion of all parts of tree, root and bark = Malaria, viral fevers, viral hepatitis, bronchitis, coughs, and helminthiasis.
Edible pulp of the fruit = Hemorrhoids.
Externally poultice of leaves= Acute and chronic lymphadenitis, contusions, sprains, abscesses. 
It is said, that it treats 40 different diseases.

Uses in Ayurvedic medicine:
Leaf- Leprosy, helminthiasis, ophthalmic problems, skin wounds, contusions, ulcers, hematomas, anorexia, biliary dyspepsia.
Bark  – Analgesic and PUO.
Flower – Viral hepatitis, helminthiasis, bronchitis
Fruit - Hemorrhoids, helminthiasis, UTI, (?)Urinary calculi, urinary disorder, epistaxis, bronchitis, ophalmic disorders, diabetes, wounds and leprosy.
Twig – Scrubbing teeth, dentifrice, cough, asthma, hemorrhoids, intestinal worms, spermatorrhea, urinary disorders, diabetes. 
Gum - Ringworms, scabies, wounds and ulcers.
Seed pulp and oil- Leprosy and intestinal worms.
Leaf's oil is used as local antiseptic and insecticide.

Neem oil may be useful for gingivitis, stomatitis, aphthous ulcers.
In the rural areas, burning of leaves and seeds is used as mosquito repellant. The extract is used as larvicidal spray for prophylaxis of malaria.

Some studies show that even chloroquine-resistant strains of malaria are sensitive to Neem, particularly a component called Irodin A. The recommended preventative measure is to chew and consume the leaves on a daily basis. [231], [232], [233], [234]

Preparations and Dosages 
There are many forms and routes of use for Neem.
Neem oil: Used as hair oil for dandruff and head lice.
For topical use Neem oil and leaf extracts are incorporated into soaps, lotions, creams, ointments etc. These act to relieve inflammation and kill bacteria, fungi, insects and skin parasites.
It is applied externally for pain relief in RA and OA.

The oil from the nuts is useful for cramps, burns, wounds and refractory, obstinate indolent ulcers, etc.  
Neem oil is spermicidal. Its intravaginal application exerts anti fertility action and also prevents embryo-implantation.
Neem oil is used for preparing soap, shampoo, balms and creams. It is useful for skin care such as acne, keeping skin elasticity.
Neem oil can be mixed with olive oil and gently massaged into the hair serves to treat dandruff and dispose of headlice if left without washing for one hour. Following the hour, hair should be rinsed normally with shampoo. Dandruff and headlice will usually subside within three weeks of a once-weekly treatment course.
Pure Neem oil can also be applied to the nose like nasal drops in order to clear sinustis. 
Lepa (Paste for topical skin application): Neem powder is mixed with water or honey to make paste. It is used to dress wounds, ulcersThe paste prepared with Neem and Turmeric is effective in the treatment of scabies.
Ointment is used to destroy lice is made from the pulp. It is also used for bald head and other skin diseases.
Aahaar (Diet): Neem is used as vegetable. 
Snaana (Bath): Some 5-6 leaves are placed in a bucketful of water. This helps reduce skin irritation, skin eruptions (especially measles) [235], [236], [237], [238] 
Neem tea made of boiled neem leaves, sometimes combined with other herbs such as ginger, can be ingested to fight intestinal parasites. 
Lotion derived from Neem leaf, when locally applied, can cure ringworm, eczema and scabies within 3-4 days in acute stage or a fortnight in chronic stage. 
Kwath (Decoction):  The decoction of the bark is used externally for hemorrhoids. Bark extracts are also bactericidal.
The decoction of Neem is cathartic and in large doses slightly narcotic. It also has febrifuge properties. It is used as a remedy for hysteria.
To prepare an infusion ten clean Neem leaves are boiled in a litre of water for precisely ten minutes and left to cool. It can be used as eyewash, gargle for stomatitis, aphthous ulcers, pharyngitis, laryngitis etc. 
The decoction is made from 50 grams of bark to 400ml of water boiled down to 200ml. One tablespoonful of this taken every two or three hours followed by a purgative is an effective dose for intestinal parasites. 
Neem leaf extract has been prescribed for oral use for the treatment of malaria. 
Other many preparations: Neem Kwath, Nimbaarishta, Nimbaharidrakhanda, Brihatpanchanimbachoorna, Neem Malahara, Nimbawaarunee and many more commonly used in Ayurvedic practice is available in Ayurvedic textbooks.

Dosages:
Neem Churna: 1 to 3 gms.
Leaf Juice: 10 t0 20 ml.
Oil: 5 to 10 drops.   [239], [240], [241], [242]



References:

1. http://ssnaneem.weebly.com/neem-history.html

2. http://www.natureneem.com/index_fichiers/Neem_history_Neem_and_India.htm
3. http://www.neem-products.com/neem-history.html
4. www.boloji.com/ayurveda
5. http://www.gigers.com/matthias/engmala/neemtree.htm
6. http://ssnaneem.weebly.com/neem-history.html
7. http://www.gardenguides.com/90131-history-neem-tree.html
8. http://www.natureneem.com/index_fichiers/Neem_history_Neem_and_India.htm
9. The Student’s New Sanskrit Dictionary by Dr. G. V. Dewasthalee, Y. B. Joshi and G. R. Kulkarni, 3rd edition, 1984
10. http://www.natureneem.com/index_fichiers/Neem_history_Neem_and_India.htm
11. http://easyayurveda.com/2012/11/28/neem-in-ayurveda-benefits-usage-side-effects-full-reference/
12. Cepeda-Palacious R et al, In vitro and in vivo effects of neem tree (Azadirachta indica A. Juss) products on larvae of the sheep nose bot fly (Oestrus ovis L. Diptera: Oestridae), Vet Parasitol, 2014 Feb 24; 200(1-2): 225-8 

13. http://www.neem-products.com/neem-history.html

14. Azadirachta indica: Neem tree, the “village pharmacy” Eleonora Mugnai ele.mugnai@fastwebnet.it ASAT - Associazione Scienze Agrarie Tropicali ASAT Sci-Tec - Vol. 1, 2009
15.http://www.banyanbotanicals.com/info/ayurvedic-living/living-ayurveda/herbs/neem/#
16. Xin Tinghui, Malcolm Wegener, Michael O’Shea, Ma Deling, World Distribution and Trade in Neem Products with Reference to their Potential in China,  http://ageconsearch.umn.edu/bitstream/126066/2/Xin.pdf
17. Sunday E. Atawodi, Joy C. Atawodi, Azadirachta indica (neem): A plant of multiple biological and pharmacological activities, Phytochemistry Reviews, October 2009, Volume 8, Issue 3, pp 601-620
18. Azadirachta indica : Neem tree, the “village pharmacy” Eleonora Mugnai ele.mugnai@fastwebnet.it ASAT - Associazione Scienze Agrarie Tropicali ASAT Sci-Tec - Vol. 1, 2009
19. http://www.natureneem.com/index_fichiers/Neem_history_Neem_and_India.htm
20. United Nations Environment Programme Neem: The UN’s tree of the 21st Century. Nairobi: United Nations Environment Programme; 2012; Available on line: http://www.unep.org/wed/tree-a-day/neep.asp.
21. National Academy of Science. Washington, DC: NAS; 1992. Neem, a tree for solving global problems [R] 
22. http://www.gigers.com/matthias/engmala/neemtree.htm
23. http://www.goodhealthnyou.com/library/reading/neem/apendix4.asp
24. https://en.wikipedia.org/wiki/Azadirachta_indica
25. http://www.goodhealthnyou.com/library/reading/neem/apendix4.asp
26. https://en.wikipedia.org/wiki/Azadirachta_indica
27. https://en.wikipedia.org/wiki/Azadirachta_indica
28. Dr. Ramkishore Sharma, Dr. Mukesh Kumar Sharma, Phytogeographical Distribution of Azadirachta indica in Churu District, Rajasthan, International Journal of Geogology, Agriculture and Environmental Sciences, Volume 2, Issue 1, February 2014, Website: www.woarjournals.org/IJGAES
29.Anjana Chowdhary and Vinod Singh, Geographical Distribution, Ethnobotany and Indigenous Uses of Neem
https://books.google.co.in/books?hl=en&lr=&id=PyYRUCoIDk4C&oi=fnd&pg=PA20&dq=geographical+distribution+of+neem&ots=yVt8OnMMfZ&sig=UlmSbIqXdxgkHCR2b8ymHlIDSqc#v=onepage&q=geographical%20distribution%20of%20neem&f=false
30. http://www.gigers.com/matthias/engmala/neemtree.htm
31. www.boloji.com/ayurveda
32. https://en.wikipedia.org/wiki/Azadirachta_indica
33. The Ayurvedic Pharmacopoeia of India, Part I, Volume V
34. google images
35. The Ayurvedic Pharmacopoeia of India, Part I, Volume V
36. The Ayurvedic Pharmacopoeia of India, Part I, Volume V
37. The Ayurvedic Pharmacopoeia of India, Part I, Volume II
38. The Ayurvedic Pharmacopoeia of India, Part I, Volume II
39. The Ayurvedic Pharmacopoeia of India, Part I, Volume II
40. emedtv.com, healthjockey.com, indianscience.org
41. http://helloindya.com/neem/chemical_composition.html
42. https://neemtree.wordpress.com/5-chemical-constituents/
43. https://en.wikipedia.org/wiki/Neem_oil
44. http://www.essentialoils.co.za/neem-oil.htm
45. www.neemfoundation.org
46. http://www.sigmaaldrich.com/life-science/nutrition-research/learning-
center/plant-profiler/azadirachta-indica.html
47. Tomar Lokeshwar et al, Review on Neem (Azadirachta indica): Thousand problems one solution, IRJP, 2011, 2 (12): 97-102
48. www.vedamsbooks.com
49.www.springerlink.com
50.www.ncbi.nlm.nih.gov/pubmed
51. http://www.organeem.com/activeconstituentsofneem.html
52. www.neemfoundation.org
53. Tomar Lokeshwar et al, Review on Neem (Azadirachta indica): Thousand problems one solution, IRJP, 2011, 2 (12): 97-102
54.http://mason.gmu.edu/~vandrade/projects/plant/plant.htm
55. Neem: The Village Pharmacy, 2007, from http://netowne.com/alt-healing/ayurveda
56. P. Sudhir Kumar, Debasis Mishra, Gautam Ghosh, Chandra S. Panda, Biological action and medicinal properties of various constituent of Azadirachta indica (Meliaceae) an  Overview, Scholars Research Library, Annals of Biological Research, 2010, 1 (3): 24-34, Available online at www.scholarsresearchlibrary.com
57. The Ayurvedic Pharmacopoeia of India, Part I, Vovume V
58. The Ayurvedic Pharmacopoeia of India, Part I, Volume II
59. The Ayurvedic Pharmacopoeia of India, Part I, Volume II
60. The Indian Pharmacopoeia of India Part I, Volume V 
61. The Indian Pharmacopoeia of India Part I, Volume V
62. The Indian Pharmacopoeia of India Part I, Volume V
63. The Indian Pharmacopoeia of India Part I, Volume V
64. Chromosome Count Data Base, http://ccdb.tau.ac.il/Azadirachta    
65. Seham S. El-Hawary et al, DNA fingerprinting and botanical study of Azadirachta indica A, Juss. (neem) family Meliaceae, Beni-Suef University Journal of Basic and Applied Sciences, Volume 2, Issue 1, March 2013, pages 1-13
66. R. S. Dhillon et al, Assessment of genetic diversity in Azadirachta indica based on DNA fingerprinting, Indian Journal of Biotechnology, Volume 6, October 2007, pp 519-524
67. www.globinmed.com
68. Bhaawaprakaash
69. http://easyayurveda.com/2012/11/28/neem-in-ayurveda-benefits-usage-side-effects-full-reference/
70. www.ayurvedaacademy.com/academy/media/ppt/KAA106PPT.pdf
71. The Ayurvedic Pharmacopoeia of India Part I, Volume V
72. The Ayurvedic Pharmacopoeia of India Part I, Volume II
73. Bhaawaprakaash
74. The Ayurvedic Pharmacopoeia of India Part I, Volume II
75. http://easyayurveda.com/2012/11/28/neem-in-ayurveda-benefits-usage-side-effects-full-reference/
76. The Ayurvedic Pharmacopoeia of India Part I, Volume V
77. Bhaawaprakaash
78. The Ayurvedic Pharmacopoeia of India Part I, Volume V
79. http://easyayurveda.com/2012/11/28/neem-in-ayurveda-benefits-usage-side-effects-full-reference/
80. http://www.banyanbotanicals.com/info/ayurvedic-living/living-ayurveda/herbs/neem/#
81. https://en.wikipedia.org/wiki/Azadirachtin
82. http://www.biovision.com/nimbolide-4818.html
83.  http://www.scbt.com/datasheet-397039-casnumber-25990-37-8.html
85. www.biovision.com/nimbolide-4818.html
86. Laxmi Narendra Bodduluru et al, Chemopreventive and therapeutic effects of nimbolide in cancer: The underlying Mechanisms, Toxicology in Vitro, Volume 28, Issue 5, August 2014, Pages 1026-1035
http://www.sciencedirect.com/science/article/pii/S0887233314000745
87. Takashi Kikuchi et al, Cytotoxic and Apoptosis-Inducing activities of Limonoids from the seeds of Azadirachta indica (Neem), Journal of Natural Products, 2011, 74 (4), pp 866-870
88. Elumalai P, Arunakaran J, Review on molecular and chemoprotective potential of nimbolide in cancer, Genomics Inform 2014, Dec; 12(4): 156-64
89. http://www.ebi.ac.uk/chebi/searchId.do?chebiId=67309
90. http://pubchem.ncbi.nlm.nih.gov/compound/6437066
91.Mitchell MJ, Smith SL, Johnson S, Morgan ED, Effects of the neem tree compounds Azadirachta, salannin, nimbin and 6-desacetylninbin on ecdysone 20-monooxygenase activity, Arch Insect Biochem Physiol. 1997; 35 (1-2): 199-209
94. http://www.chemspider.com/Chemical-Structure.9016869.html
95. http://www.chemspider.com/Chemical-Structure.8755461.html
96. http://www.chemspider.com/Chemical-Structure.8969582.html
97. https://www.google.co.in/search?q=Nimbolinin&biw=1366&bih=673&noj=1&tbm=isch&imgil=FS1jHWXdEIICbM%253A%253B7OOC-
98. Tao L et al, 1-O-tigloyl-1-O-deacetyl- nimbolinin B inhibits LPS-stimulated inflammatory responses by suppressing NF-κB and JNK activation in microglia cells, Pharmacol Sci 2014; 125 (4): 364-74 Epub 2014 Jul 11
99. https://en.wikipedia.org/wiki/Hsp90
100. https://nl.wikipedia.org/wiki/Gedunine
101. http://www.tocris.com/dispprod.php?ItemId=220954#.Vr7XobR97VQ
102. http://www.scbt.com/datasheet-203967-gedunin.html
103. https://pubchem.ncbi.nlm.nih.gov/compound/12004512#section=Top
104. Kamath SG et al, Gedunin, a novel natural substance, inhibits ovarian cancer cell proliferation, Int J Gynecol Cancer 2009 Dec; 19(9): 1564-9
105. Sara J, Felts, David O. Toft,  p23, a simple protein with complex activities, Cell Stress Chaperones. 2003, Apr; 8(2): 108-113 
106. Patwardhan et al, Gedunin inactivates the co-chaperone p23 protein causing cancer cell death by apoptosis; J Biol Chem. 2013 Mar 8; 288(10):  7313-25
107. http://www.chemspider.com/Chemical-Structure.9081498.html
108. Gupta SC, Francis SK, Nair MS, Mo YY, Aggarwal BB, Azadirone, a limonoid tetranortriterpene, induces death receptors and sensitizes human cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) through a p53 protein-independent mechanism: evidence for the role of the ROS-ERK-CHOP-death receptor pathway, J Biol Chem. 2013 Nov 8; 288(45): 32343- 55
109.http://www.molbase.com/en/71590-47-1-moldata-1498406.html
110.Judith Polonsky et al, Antineoplastic agent. 61. Isolation and structure of amoorastatin, J. Am. Chem. Soc., 1978, 100 (24), pp7731-7733
111. http://chem.sis.nlm.nih.gov/chemidplus/rn/24021-78-1/US National Library of Medicine/Toxinet Toxicology Data Network
112. http://pubchem.ncbi.nlm.nih.gov/compound/102403692#section=Top
113. http://dictionary.reference.com/browse/antifeedant

114. http://www.infinityfoundation.com/mandala/t_es/t_es_agraw_neem.htm

115. Tidjani, M. A., Dupont, C. and Wepierre, J., Planta Med. Phytother., 1989, 23, 259–266.
116. Prakash Kumar Singh,Bechan Sharma, Certain Traditional Indian Plants and Their Therapeutic Applications: a Review VRI Phytomedicine Volume 1, Issue 1, July 2013.
117. Lorenz, H.K.P.J. Praxis 1976, 8, 231-233
118. Kaushik Biswas et al, Biological activities and medicinal properties of neem (Azadirachta indica), Current Science, Volume 82, No 11, 10 June 2002
119. Okpanvi S. N., Ezeukwu G. C. Anti-inflammatory and Antipyretic activities of Azadiracta indica, Planta Med, 1981, 41, 34-39 
120. Vohra S. B. Dandiya P. C. Phytoterapia, 1992, 63, 195-207
121. Kaur G et al, Nimbidin suppresses functions of macrophages and neutrophils: relevance to its anti-inflammatory mechanisms, Phytother Res. 2004 May; 18(5): 419-24
122. Amal Kumar Ghimeray et al, Antioxidant activity and quantitative estimation of azadirachtin and nimbin in Azadirachta indica A. Juss grown in foothills of Nepal, African Journal of Biotechnology Vol. 8 (13), pp. 3084-3091, 6 July 2009
123. Gayatri Nahak and R. K. Sahu, Antioxidant activity in bark and roots of Neem (Azadirachta indica) and Mahaneem (Melia azedarach) , Continental J. Pharmaceutical Sciences 4:28-34 2010
124. P. Sudhir Kumar, Debasis Mishra, Goutam Ghosh, Chandra S. Panda,   Biological action and medicinal properties of various constituents of Azadirachta indica (Meliaceae), an overview, Annals of Biological  Research, 2010, 1, (3): 24-34; http://scholarsresearchlibrary.com/abr-vol-1-iss3.html
125. Kausik Biswas et al, Biological activities and medicinal properties of neem (Azadirachta indica), Current Science, Vol. 82, No. 11, June 2002; http://repoitory.ias.ac.in/5193/1/305.pdf
126. Prashant GM et al, The effect of mango and neem extracts on four organisms causing dental caries: Streptococcus mutan, Streptococcus salivavius, Streptococcus mitis, and    Streptococcus sanguis: An in vitro study, Indian J Dent Res. 2007, 18: 148-51
127. Bohora A, Hegde V, Kokate S. Comparison of antibacterial efficiency of neem leaf extract and 2% sodium hypochlorite against E. faecalis, C. Albicans and mixed culture. Endodontology. 2010; 22:10–3.
128. Dhanya Kumar NM, Sidhu P. The antimicrobial activity of Azadirachta Indica, Glycyrrhiza glabrat, Cinnamum zeylanicum, Syzygium aromaticum, Acacia nilotica on Streptococcus mutans and Enterococcus faecalis: An in vitro study. Endodontology. 2011; 23:18–25.
129. Okemo P.O. et al, The kill kinetics of Azadirachta indica A. Juss (Meliacae) extracts on Staphylococcus aureus, Escherichia coli, Pseudomonas aerugenosa and Candida albicans  African Journal of Science and Technology (AJST) Science and Engineering Series. 2001; 2(2): 113-118
130. P. Sudhir Kumar, Debasis Mishra, Goutam Ghosh, Chandra S. Panda,   Biological action and medicinal properties of various constituents of Azadirachta indica (Meliaceae), an overview, Annals of Biological  Research, 2010, 1, (3): 24-34; http://scholarsresearchlibrary.com/abr-vol-1-iss3.html
131. Xu J et al, Antiviral activity and mode of action of extracts from neem seed kernel against duck plaque virus, Poult Sci. 2012 Nov; 91 (11): 2802-7
132. Vaibhav Tiwari et al, In vitro antiviral activity of neem (Azadirachta indica L.) bark extract against herpes simplex virus type-1 infection, Phytotherapy Res. 2010 Aug;  24 (8): 1132-1140
133. Badam L, Joshi SP, Bedekar SS, ‘In vitro’ antiviral activity of neem (Azadirachta indica. A. Juss) leaf extract against group B coxsackie viruses, J Commun Dis. 1999; Jun 31 (2): 79-90
134. http://en.wikipedia.org/wiki/Neuronal_ceroid_lipofuscinoses
135. P. Sudhir Kumar, Debasis Mishra, Goutam Ghosh, Chandra S. Panda,   Biological action and medicinal properties of various constituents of Azadirachta indica (Meliaceae), an overview, Annals of Biological  Research, 2010, 1, (3): 24-34; http://scholarsresearchlibrary.com/abr-vol-1-iss3.html
136. Rao, A.R., Kumar, S.S.U., Paramasivam, T.B., Kamalakshi, S., Parashuraman, A.R., and Shantha, M. (1969) Study of antiviral activity of tender leaves of margosa tree (Melia azadirachta) on vaccinia and variola virus - A preliminary report. Indian Journal of Medical Research 57: 495-502.
137. Akihisa T et al, Melanogenesis inhibitory, anti-inflammatory and chemoprotective Sci. 2009; 58(11): 581-94 
138. Bhatnagar et al, The inhibitory effect of of neem (Azadirachta indica) leaf extracts on aflatoxin synthesis in Aspergillus parasiticus. Journal of the American Oil Chemists’ Society. 1998; 65(7): 1166-1168
139. Bohra N. K. , Purohit D. K., Effect of some aqueous plant extracts on toxigenic strain of Aspergillus flavus , Advances in Plant Sciences, 2002;15 (1): 103-106
140. Charmaine Lloyd A. C. et al, Anticandidal activity of Azadirachta indica, Research Paper, 2005; 37(6): 386-389, http:// www.ijp-online.com 
141. Natarajan V et al,  Antidermatophytic activity of Azadirachta indica (neem) by in vitro study, Med Chem Anticancer Agents, 2002; 5(2): 149-156
142. Natarajan V, Venugopal P. V. Menon T., Effect of Azadirachta indica (neem) on the growth pattern of dermatophytes, Indian Journal of Medical Microbiology, 2003, 21(2): 98-101
143. P. Sudhir Kumar, Debasis Mishra, Goutam Ghosh, Chandra S. Panda,   Biological action and medicinal properties of various constituents of Azadirachta indica (Meliaceae), an overview, Annals of Biological  Research, 2010, 1, (3): 24-34; http://scholarsresearchlibrary.com/abr-vol-1-iss3.html
144. Sharba Kausar et al, In vitro evaluation of antifilarial effect of Azadirachta indica leaves extract in different solvents on the microfilariae of Setaria cervi, Journal of parasitic diseases, January 2016
145. L. Radhakrishnan, S. Gomathinayagam,  V. Balakrishnan, Evaluation of Anthelmintic Effect of Neem (Azadirachta indica) Leaves on Haemonchus contours in Goats, Research Article, http://scialert.net/fulltext/?doi=jp. 2007.57.67 
146. http://www.thehealthsite.com/beauty/six-amazing-beauty-benefits-of-neem
147. http://www.stylecraze.com/articles/amazing-benefits-of-neem-for-skin-and-hair
148. http://www.discoverneem.com/neem-oil-eczema.html
149. Akihisa T et al, Melanogenesis inhibitory, anti-inflammatory and chemoprotective Sci. 2009; 58(11): 581-94
150. Manosroi A et al, Limonoids from Azadirachta indica var. siamensis extracts and their cytotoxic and melanogenesis-inhibitory activities, Chem Biodiverse. 2014 Apr; 11 (4): 505-31
151. Takagi M et al, Cytotoxic and melanogenesis-inhibitory activities of limonoids from the leaves of Azadirachta indica (Neem), Chem Biodivers. 2014 Mar; 11 (3): 451-68
152. Anjali Singh et al, Effect of Neem oil and Haridra on non-healing wounds, Ayu, 2014 Oct-Dec; 35 (4): 398-403
153. http://www.hillagric.ac.in/edu/covas/vpharma/winter%20school/lectures/32%20Neem%20medicinal%20values.pdf
154. Bwala DG et al, Management of surgical wounds using crude neem oil in one year old ram: A successful report, National Veterinary Research Institute, Plateau State, Nigeria; Journal of Veterinary Medicine and Animal Health, Volume 36(6) pp75-78, October 2011 
155. K. Chitta et al, Nimbolide targets BCL2 and induces apoptosis in preclinical models of Waldenstroms macroglobulinemia, Citation: Blood Cancer Journal (2014) 4, e260; Published on line 7 November 2014
156. Manosroi A et al, Limonoids from Azadirachta indica var. siamensis extracts and their cytotoxic and melanogenesis-inhibitory activities, Chem Biodiverse. 2014 Apr; 11 (4): 505-31
157. P. Sudhir Kumar, Debasis Mishra, Goutam Ghosh, Chandra S. Panda,   Biological action and medicinal properties of various constituents of Azadirachta indica (Meliaceae), an overview, Annals of Biological  Research, 2010, 1, (3): 24-34; http://scholarsresearchlibrary.com/abr-vol-1-iss3.html
158. Jaiswal AK, Bhattacharya SK, Acharya SB, Anxiolytic activity of Azadirachta indica leaf extract in rats, Indian J Exp Biol 1994; 32(7): 489-491
159. N. R. Pillai, G. Santhakumari, Johannes Laping, Some pharmacological actions of ‘Nimbidin’ – A bitter principle of Azadirachta indica-A Juss  (Neem), Anc Sci Life, 1964 Oct-Dec; 4(2): 88-95
160. P. Khosla et al, Antinociceptive activity of Azadirachta indica (Neem) in rats, Indian Journal of Pharmacology 2000; 32: 372-374
161. Halim Eshrat M, Ali Hussain, Reversal of diabetic retinopathy in streptozotocin induced diabetic rats using traditional Indian anti-diabetic plant Azadirachta indica (L.), Indian Journal of Clinical Biochemistry, July 2002, Volume 17, Issue 2, pp 115-123
162. Karkare S et al, Direct inhibition of retinoblastoma phosphorylation by nimbolide causes cell cycle arrest and suppresses glioblastoma growth, Clin Cancer Res. 2014 Jan 1; 20(1): 199-212
163. Sunanda Pandya, Anandkar, How safe is neem extract with respect to Thyroid function in male mice? Pharmacological Research, Volume 41, Issue 4, April 2000, pages 419-422
164. P. Sudhir Kumar, Debasis Mishra, Goutam Ghosh, Chandra S. Panda,   Biological action and medicinal properties of various constituents of Azadirachta indica (Meliaceae), an overview, Annals of Biological  Research, 2010, 1, (3): 24-34; http://scholarsresearchlibrary.com/abr-vol-1-iss3.html
165. Klaus Ferlow, HMH-10/2007, The Miraculous Neem, http://www.energygrid.com/health/2014/02kf-neem.html
166. Koley KM, Lal J, Pharmacological effects of Azadirachta indica (neem) leaf extract the ECG and blood pressure of rat,Indian J Physiol Pharmacol, 1994 Jul; 38 (3): 223-5
167. Veena Uniyal, R. P. Bhatt, Seema Saxena, Amitabh Talwar, Antifungal activity of essential oils and their volatile constituents against respiratory tract pathogens causing Aspergilloma and Aspergillosis by gaseous contact, Journal of Applied and Natural Science; 4(1): 65-70 (2012)
168. Botelho M, Santos AD, Martin J, Carvalho C, Paz M, Azenha C, et al. Efficacy of a mouthrinse based on leaves of neem in the treatment of patient s with chronic gingivitis. J Med Plant Res. 2008; 2:341–6.
169. Behl M, Sidhu O, Kumar V, Singh D, Saimbi C. Efficacy of neem active metabolites for prevention of dental plaque and gingivitis. Neem Foundation. 2002
170. Botelho M, Santos AD, Martin J, Carvalho C, Paz M, Azenha C, et al. Efficacy of a mouthrinse based on leaves of neem in the treatment of patient s with chronic gingivitis. J Med Plant Res. 2008; 2:341–6.
171. Manikandan P, Letchoumy PV, Gopalkrishnan M, Nagini S, Evaluation of Azadirachta indica leaf fractions for in vitro antioxidant potential and in vivo modulation of biomarkers of chemoprevention in hamster buccal pouch carcinogenesis, Food Chem Toxicol. 2008 Jul; 46(7): 2332-43
172. Harish Kumar G et al, The neem limonoids azadirachtin and nimbolide inhibit cell proliferation and induce apoptosis in an animal model of oral oncogenesis, Invest. New Drugs. 2010 Aug; 28 (4): 392-401
173. Pillai NR, Santhakumari G, Effect of nimbidin on gastric acid secretion, Anc Sci Life 1985, Oct; 5(2): 91-7
174. Dorababu M, Joshi MC, Kumar MM, Chaturvedi A, Goel RK, Effect of aqueous extract of  neem (Azadirachta indica) leaves on offensive and diffensive gastric mucosal factors in rats, Indian J Physiol. Pharmacol, 2006, Jul-Sep; 50(3): 241-9
175. Dorababu M, Prabha T, Priyambada S, Agrawal VK, Aryya NC, Goel RK, Effect of Bacopa monniera and Azadirachta indica on gastric ulceration and healing in experimental NIDDM rats, Indian J Exp Biol. 2004 Apr; 42(4): 389-97
176. Koo MW, Cho CH, Ogle CW, Effect of cold-restraint stress on gastric ulceration and motility in rats, Pharmacol Biochem Behav.  1986 Oct; 25(4): 775-9
178. Bandopadhyay U etal, Gastroprotective effect of Neem (Azadirachta indica) bark extract: possible involvement of H (+)-K(+)-ATPase inhibition and scavenging of hydroxyl radical, Life Sci. 2002, Nov 1; 71(24): 2845-65
179. Chattopadhyay l et al, Mechanism of antiulcer effect of Neem (Azadirachta indica) leaf extract: effect on H+K+ATPase, oxidative damage and apoptosis, Inflammopharmacology, 2004; 12(2): 153-76
180. Maity P et al, The use of neem for controlling gastric hyperacidity and ulcer, Phytother Res. 2009 Jan; 23(6): 747-55
181. Raji Y, Ogunwande IA, Osadebe CA, John G, Effects of Azadirachta indica extract on gastric ulceration and acid secretion in rats, J Ethnopharmacol, 2004 Jan; 90(1): 167-70 
182. R Subapriya, S Nagini, Ethanolic Neem Leaf Extract Protects Against N-methyl -N’-nitro-N-nitrosoguanidine-induced Gastric Carcinogenesis in Wistar Rats,
http://www.apocpcontrol.com/paper_file/issue_abs/Volume4_No3/S%20Nagini.pdf, Neem Leaf Inhibition of MNNG Gastric Carcinogenesis, RESEARCH COMMUNICATION
183. Gupta SC et al, Nimbolide, a limonoid triterpene, inhibits growth of human colorectal cancer xenografts by suppressing the proinflammatory microenvironment, Clin Cancer Res. 2013 Aug 15; 19 (16): 4465-76
184. Laxmi Narendra Bodduluru et al, Chemopreventive and therapeutic effects of nimbolide in cancer: The underlying Mechanisms, Toxicology in Vitro, Volume 28, Issue 5, August 2014, Pages 1026-1035
http://www.sciencedirect.com/science/article/pii/S0887233314000745
185. Ramadevi Subramani et al, Nimbolide inhibits pancreatic cancer growth and metastasis through ROS-mediated apoptosis and inhibition of epithelial-to-mesenchymal transition, Scientific Reports 6, Article number 19819, published 25 January 2016, htto://www.nature.com/articles/srep 19819 
186. Veeraraghavan et al, Impact of Curcumin, Raspberry Extract and Neem Leaf Extract on Rel Protein-Regulated Cell Death / Radiosensitization in pancreatic Cancer Cells, Pancreas: October 2011-Volume 40-Issue7-pp1107-1119   
190. Pravin V Gomase, Vinod D Rangari, R. R. Verma, Phytochemical Evaluation  and Hepatoprotective Activity of Young Stem (Tender) Bark of Azadirachta indica A. Juss, International Journal of Pharmacy and Pharmaceutical Sciences ISSN- 0975-1491 Vol 3, Suppl 2, 2011
191. N. S. Baligar et al, Hepatoprotective activity of the neem-based constituent azadirachtin-A in carbon tetrachloride intoxicated Wistar rats, Canadian Journal of Physiology and Pharmacology, 2014, 92(4) 267-277

192. Hepatoprotective effect of Azadirachta indica (Neem) leaves against alcohol induced liver injury in albino rats, ARTICLE · JANUARY 2009, HTTPS://WWW.RESEARCHGATE.NET/PUBLICATION/40441140_HEPATOPROTECTIVE_EFFECT_OF_AZADIRACHTA_INDICA_NEEM_LEAVES_AGAINST_ALCOHOL_INDUCED_LIVER_INJURY_IN_ALBINO_RATS

193. R.R. Chattopadhyay, M. Bandyopadhyay, Effect of Azadirachta indica leaf extract on serum lipid profile changes in normal and streptozotocin induced diabetic rats, African Journal of Biomedical Research, Vol. 8 (2005); 101 - 104 ISSN 1119 – 5096 © Ibadan Biomedical Communications Group Available online at http://www.bioline.org.br/md
194. Singh, P. P., Junnarkar, A. Y., Thomas, G. P., Tripathi, R. M. and Varma, R. K., ibid, 1980, 61, 164–168, CURRENT SCIENCE, VOL. 82, NO. 11, 10 JUNE 2002, http://repository.ias.ac.in/5193/1/305.pdf
195. Chattopadhyay RR, Possible mechanism of antihyperglycemic effect of Azadirachta indica leaf extract. Part IV, Gen pharmacology: The Vascular System, 1966 Apr; 27 (3): 431-4    
196. KN Bopanna, J Kannan, Gadgil Sushma, R Balaraman, SP Rathod, Antidiabetic and antihyperlipaemic effects of neem seed kernel powder on alloxan diabetic rabbits, Indian Journal of Pharmacology, 1997; 29 (3): 162-167
197. Prabhakar Patil et al, Antidiabetic activity of alcoholic extract of Neem (Azadirachta indica) root bark, National Journal of Physiol Pharm Pharmacol, 2013; 3(2): 142-146
198. V. P. Dixit, Rakesh Sinha, Rita Tank, Effect of neem seed oil on the blood glucose concentration of normal and alloxan diabetic rats, Journal of Ethnopharmacology, Volume 17, Issue 1, July 1986, Pages 95-98
199. N. R. Pillai, G. Santhakumari, Johannes Laping, Some pharmacological actions of ‘Nimbidin’ – A bitter principle of Azadirachta indica-A Juss  (Neem), Anc Sci Life, 1964 Oct-Dec; 4(2): 88-95
200. Prashant Patil et al, Effect of Neem oil on Sperm Mitochondrial Activity, Free Online Journal Published Quarterly: Mangalore, South India: ISSN 0972-5997 Volume 8, Issue 4; Oct - Dec 2009
201. S. S. Riar et al, Antifertility activity of volatile fraction of neem oil, Contraception, Volume 44, Issue 3, September 1991, pages 319-326 
202. Jaya Bardhan et al, A fertility controlling agent in rhesus monkey, Indian Journal of Physiol Pharmacol, 1991; 35(4) 278-280 
203.  Despande, V. Y., Mendulkar, K. N. and Sadre, N. L., Male antifertility activity of Azadirachta indica in mice, J. Postgrad. Med. (Bombay) Year: 1980, Volume: 26, Issue: 3, page: 167-70
204. Jackson, H.: Development of antifertility substances, Progress in Drug Research, 7: 133-192, 1964
205. Despande, V. Y., Mendulkar, K. N. and Sadre, N. L., Male antifertility activity of Azadirachta indica in mice, J. Postgrad. Med. (Bombay), Year: 1980, Volume: 26, Issue: 3, Page: 167-70 
206. Mukharjee S, Garg S, Talwar G. P., Early post implantation contraceptive effects of purified fraction of Neem (Azadirachta indica) seeds, given orally in rats: Possible mechanisms involved, J Ethnopharmacol 11-30-1999; 67 (3): 287-296
207. P. Sudhir Kumar, Debasis Mishra, Goutam Ghosh, Chandra S. Panda,   Biological action and medicinal properties of various constituents of Azadirachta indica (Meliaceae), an overview, Annals of Biological  Research, 2010, 1, (3): 24-34; http://scholarsresearchlibrary.com/abr-vol-1-iss3.html
208.Talwar, G. P., Shah, S., Mukherjee, S., and Chabra, R. Induced termination of pregnancy by purified extracts of Azadirachta Indica (Neem): mechanisms involved. Am J Reprod Immunol 1997; 37(6):485-491. 
209. Mahapatra S et al, Novel molecular targets of Azadirachta indica associated with inhibition of tumor growth in prostate cancer, AAPS J. 2011 Sep; 13 (3): 365-77
210. Wu Q et al, Preclinical evaluation of the supercritical extract of Azadirachta indica (neem) leaves in vitro and in vivo on inhibition of prostate cancer tumor growth, Mol Cancer Ther 2014 May; 13 (5): 1067-77tps://www.researchgate.net/publication/40441140_Hepatoprotective_effect_of_Azadirachta_indica_Neem_leaves_against_alcohol_induced_liver_injury_in_albino_rats 193. R.R. Chattopadhyay, M. Bandyopadhyay, Effect of Azadirachta indica leaf extract on serum lipid profile changes in normal and streptozotocin induced diabetic rats, African Journal of Biomedical Research, Vol. 8 (2005); 101 - 104 ISSN 1119 – 5096 © Ibadan Biomedical Communications Group Available online at http://www.bioline.org.br/md
211. Kumar S et al, Anticancer effects of ethanolic neem leaf extract on prostate cancer cell line (PC-3), J Ethnopharmacol, 2006 Apr 21; 105 (1-2): 246-50
212. Shakti N et al, Antifertility Effects of Neem (Azadirachta indica) Oil by Single Intrauterine Administration: A Novel Method for Contraception, proceedings of the Royal Society B, Biological Sciences, 22 December 1990.
213. Priyadarshini RV, Murugan RS, Sripriya P, Karunagaran D, Nagini S, The neem limonoids azadirachtin and nimbolide induce cell cycle arrest and mitochondria-mediated apoptosis in human cervical cancer HeLa) cells, Free Radic Res. 2010 Jun; 44 (6): 624-34
214. Haque E, Mandal I, Pal S, Barel R, Prophylactic dose of neem (Azadirachta indica) leaf preparation restricting murine tumor growth is nontoxic, hematostimulatory and immunostimulatory, Immunopharmacol Immunotoxicol. 2006; 28(1): 33-50
215. Roy MK, Kobori M, Takenaka M, Nakahara K, Shinmoto H, Tsushida T. Inhibition of colon cancer (HT-29) cell proliferation by a triterpenoid isolated from Azadirachta indica is accompanied by cell cycle arrest and up-regulation of p21. Planta Med 2006; 72: 917–923.
216. Elumalai P et al, Induction of apoptosis in human breast cancer cells by nimbolide through extrinsic and intrinsic pathway, Toxicol Lett. 2012, Nov 30; 215(2): 131-42
217. Arumugam A et al, Neem leaf extract inhibits mammary carcinogenesis by altering cell proliferation, apoptosis and angiogenesis, Cancer Biol. Ther. 2014 Jan; 15 (1): 26-34   

218. http://www.ncbi.nlm.nih.gov/pubmed/24722271

219. AR Suresh, P Rajesh, KS Anil Raj, Radhika Torgal, A rare case of toxic optic neuropathy secondary to consumption neem oil, Indian J Ophthalmol. 2014 Mar; 62(3): 337-339, drsureshaar@yahoo.co.in
220. Gandhi M et al, Acute toxicity study of the oil from Azadirachta indica seed (neem oil) J Ethnopharmacol, 1988; 23 (1): 39-51
221. Brahmachari G, Neem- an omnipotent plant: a retrospection, Chembiochem, 2004; 5(4): 408-421
222. Sinniah D, Margosa oil poisoning as a cause of Reye’s syndrome, Lancet, 1981, Feb 28; 1 (8218): 487-9
223. Lai SM, Lim KW, Cheng HK, Margosa oil poisoning as a cause of toxic encephalopathy, Singapore Med J. 1990 Oct; 31 (5): 463-5
224. Dhongade RK, Kavade SG, Damle RS, Neem oil poisoning, Indian Pediatr. 2008 Jan; 45(1): 56-7
225. Bruna Dallaqua et al, Treatment with Azadirachta indica in diabetic pregnant rats: Negative effects on maternal outcome, Journal of Ethnopharmacology, Volume 143, Issue 3, 11 October 2012, pages 805-811
226. Onimisi BO, Nadabo YA, Musa SA, Musa MA, Nephrotoxic Effects of Methanolic Extract of Azadirachta Indica (Neem) Root Bark on The Adult Wistar Rats, International Journal of Health Sciences and Research (IJHSR) 2015; 5 (4): 116-121        
227. www.neem-products.com
228. http://www.gigers.com/matthias/engmala/neemtree.htm
229. www.boloji.com/ayurveda
230. https:// en.wikipedia.org
231. www.neem-products.com
232. http://www.gigers.com/matthias/engmala/neemtree.htm
233. www.boloji.com/ayurveda
234. https:/en.wikipedia.org
235. www.neem-products.com
236. http://www.gigers.com/matthias/engmala/neemtree.htm ww.bioline.org.br/md
237. www.boloji.com/ayurveda
238. http://en.wikipedia.org
 239. www.neem-products.com
240. http://www.gigers.com/matthias/engmala/neemtree.htm
241. www.boloji.com/ayurveda
242. https://en.wikipedia.org


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