POTENTIAL HEALTH EFFECT OF NEEM

INTRODUCTION:

Neem is a known as “wonder tree” and its scientific names is Azadirachta indica and is known for its health promoting properties and offer a wide range of health benfits for several diseases and also act as a natural source of insecticides, pesticides and agrochemicals also [Girish, K., & Shankara, B. S. (2008)]. Neem tree grown mainly in a well-drained deep and sandy loam soil and has more 300 bioactive compounds [Hao, F et-al 2014]. Numerous substances, including limonoids like nimbin, nimbidin, nimbinin , 6-desacetylnimbinene with a variety of pharmacological effects, azadirachtin, and quercetin, are available in numerous parts of this tree .[ Rahmani, et-al 2018]. During researches, its componenets were discovered to have higher anti-oxidant, antibacterial, antifungal, antiviral, hepatoprotective, anti-microbial, and anti-cancerous effects. Neem has been extensively used in Ayurveda, Unani and Homeopathic medicine [Tiwari R et-al ,2014]. Additionally, it exhibits therapeutic implications in the modification of cell signalling pathways implicated in the control of cancer. Neem and its component may also present a potential contender because to its wider pharmacological activity in tumour prevention and treatment. The earliest Sanskrit medical writings refer to the benefits of Neem’s fruits, seeds, oil, leaves, roots and bark.

The word Azadirachta indica comes from a persian word “Azad dirakhat-I-Hind” meaning “noble or free tree of India”.Neem has two closely related species of neem, are referred to as Indian neem (margosa tree) and Persian lilac, respectively. The neem is known as Sarbaroganibarini because its Sanskrit name, Arishtha, means “reliever of disease.” In India, the tree has always been recognized to as the “village dispensary”[Agrawal and D. P. (2001)].This article provides a summary of the potential health-promoting effects of neem and its components through controlling biological processes.

The Neem tree’s botanical name is Azadirachta indica. Neem is mainly a Tracheophytes and it is a member of the Meliacea family and sub-family of Angiosperm Order is Rutales, and is well-known for its vast range of pharmacological actions. The neem tree may be found all throughout India.It flourishes in locations with sub-arid to sub-humid environments, with annual rainfall ranging from 400 to 1200 mm. It can grow in areas with annual rainfall of less than 400 mm, however it is heavily reliant on ground water levels in such instances. Since ancient times, neem tree extracts has a variety of health-promoting properties that have been widely used in health management.It’s offers possible health benefits, including being an antimalarial, insecticidal, anti-filarial ,abortifacient, antibacterial, antifungal, antiviral, antitumor, anti-pyretic, anti-spermatogenic, anti-yeast, and immunomodulator according to National Research Council (1992).

It the is known to be a plant that is widely distributed in several tropical and semi-tropical nations, including Bangladesh, Pakistan, and India[Hao, F et-al 2014]. It can acquire resistance ranging from hot to extremely hot. It can not survive temperatures below 4⁰C. Neem may grow in a wide range of soils, although it grows best in well-drained deep and sandy loam (pH 6.2-7.0).

From various parts of the plant, phytochemicals such as quercetin and azadirachtin, as well as liminoids such as nimbin, nimbinin, and nimbidin, have been isolated. Furthermore, the leaves contain nimbanene, 6-desacetylnimbinene, nimbandiol, nimbolide, ascorbic acid, n-hexacosanol, nimbiol, various amino acids, and other compounds.[ Rahmani, et-al 2018] .From the ancient time neem is used to treat a range of illnesses in Indian Ayurvedic medicine, Homoeopathic medicine, and Unani medicine[Tiwari R et-al ,2014;]

An incredible natural resource, neem has a broad range of chemically diversified and structurally complex metabolites with special biological properties. Neem has been obtained from a variety of ecological niches, and it’s noteworthy to notice that out 400 bioactive compounds of various types have already been discovered. This undoubtedly confirms its historical usage and potential health benefits in traditional medicine [Kharwar et-al,2020]

2] PLANT DESCRIPTION AND CLASSIFICATION:

Neem is a fast-growing tree that has a straight trunk with long spreading branches that has 5-15 leaflets per leaf and are compound and imparipinnate in nature and is a tropical evergreen related to mahogany. They are reportedly said to live up to 200 years.The bark is rough dark brown with extensive longitudinal cracks divided by flat ridges and varies in different size according to the age of the plant is taken [Alzohairy and M. A. (2016)]. It contains several blooming panicles, most of which are in the leaf axils and its flower has pentamerous, little, white or pale yellow in colour that are mildly sweet and bisexual when bloom. Neem trees have one or two ellipsoidal, 1-2 cm long seeded drupes. When ripe, they become greenish, and their seeds are ovoid or spherical in shape. When young, the fruits are green, becoming yellow as they develop, and have a garlic-like scent. With a diameter of up to 1.2cm, the trunk is relatively short and straight, and the bark is rough, hard, scaly, and pale grey to reddish brown in colour[Upadhayay et-al ,2014]. The leaves are bitter in taste and new leaves appear to bloom in March and April. The oil found in the seed has potent medicinal and pharmacological properties. Juicing the kernels yields the oil readily. Depending on where you reside, fruits mature between April and August. [Hashmat, I.,et-al 2012].

It can grow on practically any sort of soil, including clayey, saline, and alkaline soil, but it flourishes in deep, well-drained soil with good subsoil water and black cotton soil. Because of their special potential to extract calcium, neem trees can neutralise acidic soils.[ Girish, K., & Shankara, B. S. (2008)]

Scientific Classification table for Neem Tree:
KINGDOM	PLANTEA
FAMILY	MELIACEAE
SUBFAMILY	MELIOIDEAE
CLASS	MAGNOLIOPSIDA
ORDER	RUTALES
SUBORDER	RUTINAE
GENUS	AZADIRACHTA
SPECIES	INDICA

TABLE 1: SCIENTIFIC CLASSIFICATION OF NEEM TREE [Eid et-al,2017]

3] NEEM AS A MIRACLE TREE OF INDIA:

As we all know the scientific name of neem is Azadirachta indica. The word Azadirachta indica comes from a persian word “Azad dirakhat-I-Hind” meaning “noble or free tree of India”.Neem has two closely related species of neem, are referred to as Indian neem (margosa tree) and Persian lilac, respectively. The neem is known as Sarbaroganibarini because its Sanskrit name, Arishtha, means “reliever of disease.” In India, the tree has always been recognized to as the “village dispensary”[Agrawal and D. P. (2001)].According to some study,neem extract was used in toothpaste, soap, cosmetics, and insect repellents. Additionally, according to tradition different parts of neem from the ancient time till date are used to treat disease such as GI disorders, rheumatism, respiratory issues, leprosy, jaundice, fever, headaches, and chicken pox [Eid, Jaradat, & Elmarzugi, 2017; Heyman et al., 2017; Joshi, Bhat,et-al, 2010; Saleem, et-al, 2018; Islas,et-al,2020]

4]CHEMICAL CONSTITUENT AND STRUCTURE OF NEEM :

Neem is well known for its health promoting substances. Recent studies have founded that neem contain about 400 bioactive compounds which are chemically and structurally diversified from each other [Kharwar et-al,2020]. Several research that were published, identified a bunch of biological substances and their effects for insects, as well as other antagonistic effects such as antitrypanosomally and antiprotozoal, antiarthritic, anti-inflammatory, antipyretic, hypoglycemic, ulcerative, fungal, bacterial, and anticancer effects of neem [Bandyopadhyay U, et-al,2004; Sultana B et-al,2007; Ebong PE et-al ,2008; Girish, K., & Shankara, B. S. (2008) ; Trivedi, A.,et-al,2019]. In Ayurveda,neem leaves, seeds, fruits, and roots are widely known and used for its potential health effect and has wide variety of phytochemicals present in it .

Some of the phytochemical that are presents in neem are shown below in table 2.

PARTS OF NEEM	CHEMICAL CONSTITUENTS
FRUITS	5-hydroxy-methyl furfural; nomolin ; Nimolicin; 17-hydroxy-azadiradione; 17β-hydroxy-azadiradione, 17-epi-azadiradione
LEAVES	glucoside of quercetin glucoside of kaemferol quercetin quercetin-3-galactoside(Hperin) rutin isorhamnetin rhamnoside of quercetin quercitin nimbolide vilasinin nimbinene 6-deacetyl nimbinene nimbolide nimocinol(6α-hydroxy-azadirone) β-sitosterol β-sitosterol-β-D-glucoside neem leaf glycoprotein
BARK	sugiol nimbiol nimbin nimbinin deacetylnimbin nimbinene 6-deacetyl nimbinene
OIL	nimbin nimbinin nimbidic acid(salannic acid) salannin meliantriol azadirone
FLOWER	Kaemferol quercetin myricetin melicitrin kaemferol-3-glucoside(astragalin) β-sitosterol-β-D-glucoside β-sitosterol
TRUNK	sugiol ; nimbiol; nimbin; nimbinin; nimbolin a ; nimbolin b.
SAP/TODDY	glucose, sucrose, gums and colouring matter.

TABLE 2: CHEMICAL CONSTITUENTS OF NEEM :[ Kausik B,et-al,2002; Alzohairy and M. A. (2016); Atawodi S. and Atawodi J. (2009); Trivedi, A.,et-al,2019, Reddy et-al,2022]

5] POTENTIAL HEALTH BENEFITS OF NEEM:

[5.1] Anti-bacterial activity: Neem is widely known for its antibacterial property. Neem Oil from the leaves, pods, and bark has a broad spectrum of antimicrobial properties against Mycobacterium TB strains and other streptomycin-resistant gram-positive and gram-negative bacteria. According to In-vitro research by Elekwa et-al ,2017, it prevents the growth of Mycobacterium TB, Klebsiella pneumonia, Vibrio cholera, and M. pyogenes. Streptococcus mutans and Streptococcus faecalis and act as a resistant to neem extract’s antibacterial effects.In another studies by Okemo et-al,2001; Mohammed et-al,2017 , Neem plant crude extract proven extremely efficient against E. coli and Staphylococcus aureus. They observed that an extract concentration of 0.5 mg/ml had significantly reduced the amount of Staphylococcus aureus inoculum after 24 hours, whereas extracts with greater concentrations quickly eradicated all living germs. In few studies it was reported, A. indica leaf has ethanolic extract shown strong antibacterial activity against several gram-negative, gram-positive, and control strains. Beta-d-Mannofuranoside, O-geranyl was shown to be the most effective chemical on control strains and other bacterial important proteins, according to in vitro and in silico tests. In his GC-MS analysis of neem extract indicated the presence of numerous bioactive components, with fatty acids, hydrocarbons, pyridine derivatives and aldehydes being the most prevalent. These components not only have nutritional benefits but also different biochemical activities [Joshi M.et-al,2010; Jogaiah S,et-al,2016; Ralte L et-al,2022; Altayb,et-al,2022]

[5.2] Anti-microbial activity: Neem extracts are abundant in antimicrobial compounds since studies has conclusively demonstrated that they may be beneficial in controlling some foodborne pathogens and other spoilage organisms[Mahfuzul Hoque MD,et-al,2007] The antiviral effectiveness of neem bark extract demonstrated that, at doses of 50 to 100 g/ml, HSV-1 entry into cells was successfully stopped. The results of the another study, which also looked at the antifungal effectiveness of seed extracts on Candida spp., suggest that neem seed extract may be a potential anticandidal agent. [Lloyd CA,et-al,2005, Rahmani, et-al 2018, Tiwari V,et-al 2010].

The extracts of the leaves and seeds were tested against several pathogens to determine their minimum inhibitory concentration (MIC) and minimum fungicidal concentration. The outcome showed that the MIC of seed extracts for all the pathogens tested was 31 g/mL. Additionally, it was discovered that a seed extract concentration of 15 g/mL was adequate to alter the studied organisms’ development patterns[Natarajan V,et al,2003 and Rahmani, et-al 2018]. Malaria, which typically results in a fever, is caused by a parasite. Fresh neem leaf alcohol extract is said to include liminoids such nimbandiol, nimocinol, isomeldenin and meldenin that are helpful against malaria caused by Plasmodium falciparum [Vasanth et al., 1990]

[5.3] Anti-viral activity: Neem seed extracts demonstrated a protective effect against the virus that causes duck plague (Xu et al., 2012). Another investigation on the antiviral properties of neem revealed that the polysaccharides in neem were responsible for inhibiting the polio virus[Faccin-Galhardi et al., 2012]. Azadiracta indica bark extract shown a protective effect against herpes simplex type- 1 virus infection [Tiwari et al., 2010]. Neem leaves were used to extract polysaccharides that had a protective effect against the type-1 bovine herpes virus (BoHV-1) [Saha et al., 2010 and Asghar et-al 2022].

In one recent study have shown that Neem acetone-water extract is used to remove SARS-CoV-2 from the vascular endothelium because to its broad-spectrum action. If this mechanism is successful, endothelial impairment and the resulting implied uncontrolled inflammatory response, which might defeat COVID-19, can be avoided. The research suggested that careful clinical studies should be conducted on the acetone-water Neem extract to establish the ideal dose for effectiveness. Further research on the extract should clarify the bioactive phytochemical principles in order to create pure compound anti-COVID-19 therapies which might include preventing cancer cells from adhering to and metastasizing, preventing HIV from attaching to and infecting target T lymphocytes, and also removing parasitized erythrocytes from the vascular endothelium [Eze et-al,2022].

[5.4] Anti-cancerous activity: Neem is a medicinal plants and widely known for its anti-cancerous activity.The uncontrolled and abnormal cell development that interfere with the body’s regular processes causes cancer which can be treated by using neem extract.In research study ,one has evidence that, Methylnitronitrosoguanidine(MNNG) was used to cause stomach and mouth cancer in rats. Tumor cells’ ability to proliferate after being given neem leaf extract was seen to decreased.[Arivazhagan et al., 1999; Asghar et-al,2022].In another study done by Mahapatra et al., 2011 ,it was found that prostate tumour cell proliferation was inhibited after consuming Azadirachta indica.

Malignant cells exhibited death of the live cell and p53-independent apoptosis after receiving liminoids from neem oil [Srivastava et al., 2012]. The results of another study shown that the compound nimbolide, which is present in neem leaves, induces apoptosis in human breast cancer cell lines [Elumalai et al., 2012; Asghar et-al,2022]

According to Dkhil et al.,2013and Asghar et-al.,2022, a hepatic stress research has made use of a methanolic extract of Azadirachta indica leaf.A 500 mg/kg body weight methanolic extract of neem leaves was administered to mice daily for five days. Real-time PCR was used to estimate the hepatic stress measures, such as tissue changes, antioxidant levels in the tissues, and mortality indicators, as a result of neem leaf therapy. Antioxidant enzyme levels, including those of SOD, CAT, GPx, GST, and glutathione level was seen to elevated in that research.

[5.5] Antioxidant activity: Free radicals, also known as reactive oxygen species (ROS), are a primary cause of inflammation because they damage numerous biological components by removing electrons to achieve a stable state, causing oxidative stress in the cell [Alzohairy and M. A. (2016); Kiranmai, Mahender Kumar, & Ibrahim, 2011].another study was done where it was found that Because the Neem bark’s aqueous portion had more phenolic compounds than the leaf extract, it demonstrated better antioxidant activity[Ghimeray,et-al,2009]

In an in-vitro study in the literature done by Biswas,et-al,2002 and Shareef, M., & Akhtar, M. S. (2018) proved antioxidant activity that a variety of unprocessed neem (Azadirachta indica) leaf extracts had and the various crude extracts had such as chloroform ,Hexane and methanol extracts come after the butanol ethyl acetate extract.

[5.6]Anti-mutagenic activity: Neem is also known for its anti-mutagenic activity .Extracts from neem leaves are used as antimutagenic where Channa punctatus, a model fresh water fish, had substantial antimutagenic activity in response to the ethanolic extract of neem leaves [Farah et-al.,2006].

[5.7]Anti-diabetic activity: A research done on Neem root and leaf aqueous extract which had shown antidiabetic action in rats by lowering blood sugar levels [Halim et-al,2003]. When given at a dose of 30-60 mg twice day for 10 weeks, the bark extract totally cured the duodenal ulcers. Neem bark extract may be able to reduce gastric hypersecretion as well as gastroesophageal, gastroduodenal, and other ulcers [Bandyopadhyay U, et-al,2004].

Several research in induced-diabetic rat models have also shown that neem extract therapy can rescue the G6PD.Basir et al. specifically showed that the antioxidative system recovered and damage to the liver and kidneys was delayed (Basir & Shailey, 2012; Upreti et al., 2013). In people who are genetically predisposed to it, a combination of a sedentary lifestyle and a high caloric intake results in the development of type II diabetes, in which insulin resistance is the main factor influencing the uptake of glucose by fat and muscle cells. In this case, a decrease in glucose-6-phosphate dehydrogenase (G6PD) inhibits the synthesis of NAPDH. Over time, the intracellular loss of NAPDH results in a reduction in the antioxidant system’s efficiency and an upsurge in the production of ROS (Abdel-Moneim, Othman, & Aref, 2014; Basir & Shailey, 2012; Ghatule et al., 2012).

Another study done by Patil P et-al,2013 has shown that Neem root bark extract had lowering blood glucose levels at doses of 200 and 400 mg / kg b. w. taller than the dose of this extract (800 mg / kg body weight) showed a significant reduction of Blood sugar level 54% lower than blood sugar level check.

[5.7]Anti-fungal activity: Nimbidol and gedunin, two pharmacological bioactive chemicals found in neem leaves, have been shown in clinical trials to be effective at inhibiting some pathogenic fungus [Tembe-Fokunang et-al, 2019; Benelli G,et-al,2017]. Ethyl acetate extract of neem leaves is the most powerful antifungal agent. HPLC analysis revealed the presence ofdal nimonolo in the extract. It is effective against Aspergillus flavus, fumigatus, niger, terreus, Candida albicans and Microsporum patch [Mahmoud DA,et-al 2011; Trivedi,et-al,2019]

[5.8] Hepato-protective activity: Hepatoprotective role of azadirachtin-A derived from neem and others well known ingredients are well study where it was shown that, CCl4

was used to induce hepatotoxicity in animal models and it was observed that the complaint control groups displayed dropped total protein position and significantly increased aminotransferase [aspartate aminotransferase( AST) and alanine aminotransferase( ALT)] and alkaline phosphatase situations. Treatment with azadirachtin A significantly bettered the reference range of these proteins and enzymes and also confirmed to reduced necrosis[Baligar NS et-al,2014].

[5.9]Anti-inflammatory activity: Previous study by Govindachari et-al,1998, has demonstrated that extract of neem leaves at a prescription of 200 mg/kg, used as antagonistic-angering project to understand pill granuloma assay in rats. However, dexamethasone is less productive than the neem extract.The information has proved that nimbidin restrain the functions of macrophages and neutrophils having to do with swelling.In another study, inflammation is a pathophysiological condition complicated in a excess of diseases like tumor and diabetes, in addition to in additional states such as intoxicating devouring and cuisine digesting (Eldeen et al.,2016).

[5.10] Dentistry: In one research by Rajaseenivasan T et-al,2016 and Sharma, A., & Paliwal, M. (2021)., neem extract was administered to judge productiveness of mouthwash that is neem-located in agreements of allure antigingivitis effect, & results told that A. indica mouthwash is active in dropping down periodontal records as chlorhexidine.

In another study, Specific neem extract’s antibacterial effects on bacterial strains were assessed. The antibacterial efficacy of petroleum ether and chloroform extract against Streptococcus mutans has been proven by research results. The outcomes also show that the chloroform extracts have potent antibacterial properties[Lekshmi PN et-al,2012; Rahmani et-al,2018]

[5.11] Others activity:

Cardioprotective activity: The neem tree extract is well known for its cardioprotective qualities as a traditional medicine. In this regard, the majority of the cardiovascular, biochemical, and histopathological parameters are significantly restored by A. indica extract at doses of 250–1000 mg/kg. Neem extract exhibits comparable cardioprotective properties to Vitamin E, according to the study’s further findings [Peer PA et-al,2008; Rahmani et-al,2018]
Hepatoprotective activity: Rats were used as test subjects for examining the leaf extract’s hepatoprotective effects. High levels of AST and ALT were dramatically lowered by aqueous leaf extract. Furthermore, liver damage was also discovered to be lessened as seen macroscopically and histopathologically [Bhanwra S,et-al,2000, Rahmani et-al,2018].
Liver function: Liver activities include protecting the liver from harm, which aids in blood purification. Neem leaf reduces chemically caused liver damage by stabilising serum marker enzyme levels and elevating levels of antioxidants, such as those contained in vitamin C and E and natural carotenoids, which combat free radicals and avert damage. Antioxidants are also discovered to be found in neem leaf [Bhowmik et-al,2010]
Neuroprotective activity: Neem’s antioxidant components have a neuroprotective effect, preventing brain damage in stroke victims by promoting lipid peroxidation and raising ascorbic acid (Vitamin C) levels in the brain.[Bhowmik et-al,2010]

6]CONCLUSION:

Neem is known for its potential health effect and studies have proven it and termed as “Village Pharmacy’’. Neem has been the subject of more than 1000 scientific studies, revealing more than 400 bioactive structurally different components. Consumers are turning to natural plants and their products to treat illnesses as a result of the rising cost of modern treatment. Due to the presence of numerous biologically active components that are effective against cancer, abnormal lipid levels, elevated sugar levels, liver damage, renal toxicity, and many other conditions, Azadirachta indica (Neem) is one of the most significant medicinal herbs that have been used for centuries. These factors suggest that this significant medicinal plant should be incorporated into the current medical system in order to benefit the population. To separate, purify, and characterise the numerous biologically active components found in various portions of this plant, more research is necessary. These ingredients can be used for both preparation and the prevention and treatment of various health-related diseases and a number of dietary supplements and functional meals for human[Asghar et-al,2022].More researches are need still going on and yet many potential health benefit of neem are still need to be discovered.

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