Accumulating evidence suggests that more than 70% of the current drugs have originated from nature (Newman et al., 2003). Furthermore, more than 50% of the worldwide population relies on plants for their primary healthcare even today. One such precious medicinal plant is the neem tree, Azadirachta indica, which belongs to the mahogany family of Meliaceae and thrives best in subtropical semi-arid to arid areas.
It is one of the first medicinal plants mentioned in the Siddha medicine, which is the oldest medical systems known to mankind. Neem is also one of the most respected trees in Indian heritage. The utility of this plant in driving away the mosquitos and fever was reported way back in 1803 (James & Lond, 1903). In Persian, neem is called Azad Dirakht (meaning free tree) while in Swahili, the plant is Muarubaini (meaning treat 40 different diseases).
It is originally native of Myanmar but spread to India, Africa, Central America, Caribbean area, and the Philippines. Neem is an evergreen plant, its crown has a round shape, and the leaves are rather large typically pinnate with a size of about 30 cm. The efflorescence is represented by small scented white flowers and is abundant in springtime. At 5 years of age, the tree starts producing yellow smooth olive-like fruits of about two centimeters. Within a white hard capsule, one or two seeds resembling almonds are enclosed. The seeds contain high concentrations of azadirachtin, the best characterized and used active principle of the neem tree. This plant has been used to cure multiple acute and chronic diseases in different parts of Asia and Africa.
In India, the oldest known properties are traditionally attributed to the tree’s wood. In any case, termite-resistant wood is used for furniture, and art items. The bark contains high levels of tannins and a rubbery amber-colored lattice used to dye clothes, which is also used in popular medicine ointments. The oil prepared from the seeds has been extensively used in ayurveda, unani and homeopathic medicines for centuries. The common Indian reference for the tree is “the village pharmacy”; as a matter of fact, fruits, seeds, leaves, and roots are used as a remedy against many ill-being predicaments.
The actual situation at the present time is that a few compounds have been purified from the whole oil, e.g., nimbin, nimbinin, and nimbidin, but certainly the secondary metabolite, azadirachtin, constitutes the most proliferous application. A number of beneficial effects for human health have been attributed to neem compounds; for instance, fruit, leaves, bark, and roots of the neem tree have been reported to combat fungal infections, inflammation, and viral and bacterial infections. Antitumor and antiproliferative activities have been also ascribed to its extracts. Neem tree extracts seem also to exert a negative control on type II diabetes (Saxena & Vikram, 2004). Various parts of neem have been extensively used to treat human ailments since ancient time. For example, the neem twigs have been used by millions of people for cleaning teeth. The therapeutic uses of neem have been recorded in a 350 years old palm leaf manuscript conserved in the Centre for Traditional Medicine and Research (CTMR) library in Chennai, India. The palm leaf manuscript describes the utility of neem for following purposes: (i) flower for the prevention and treatment of bile disorders, (ii) leaf for ulcers, and (iii) bark for central nervous system, paralysis and psychiatric disorders. Neem has been used as a deterrent for smallpox and other infectious diseases and is known to possess potent anti-plasmodial activity. The plant has also been used for urinary tract problems, leprosy, gastrointestinal problems, hair problems, ulcers, diabetes, and blood pressure. Traditionally, the plant is known to possess potential to ward off evil spirits. The plant has been used against malaria in Nigeria, India, and other parts of Asia (Agarwal et al., 2020). It has also been used to eradicate bugs from beds, books, grain bins, cupboards, and closets. In Indonesia, neem leaves are used as a diuretic and for treating diabetes, headache, heartburn, and stimulating the appetite (Sujarwo et al., 2016).
There is extensive knowledge on the agricultural and health benefits of neem extracts. Modern day science has (re)discovered industrial and environmental applications for neem extracts. In 2018, a study a peer reviewed study was published where powdered banana corm was evaluated for mercury adsorption in contaminated water bodies. The banana corm composite by itself managed to remove only up to 60-80% of the mercury at different pH levels of water (Marichelvam et al., 2018). However, the addition of neem leaf activated charcoal, ensured 100% removal of mercury, with itself accounting for an additional 30-40% removal. In contrast to conventional activated charcoal, only 5 mg of adsorbent was required to remove maximum amount of mercury in one liter of a contaminated water sample. In a later study in 2020, some interesting observations were made regarding the benefits of neem oil blends with SiO2 nanoparticles as an effective high load lubricant. Firstly, with as low as 0.3% concentration of nanoparticles neem oil exhibited viscosity levels most suited to reduce the coefficient of friction levels to 0.05 for 8kgf loads (Mahara et al., 2020). This presents an interesting application for neem oil as a base oil lubricant for medium and large industrial equipment. It also exhibited 30% better results than other common non edible oils like mongongo, jatropha and pongamia owing to its better acceptance of the nanoparticles and optimal viscosity. Silver nanoparticles have become a subject of interest in recent material innovations due to their unique drug catalysis and cryogenic properties. A variety of preparation techniques have been defined possible from laser ablation to microwave processing. A study from Andhra University published that UV–Visible spectrophotometer demonstrated absorbance that a 4% acidified neem saw dust concentration at 100°C amalgamated the transformation of silver particles into silver nanoparticles. Showing absorbance at 450 nm the silver nanoparticles were synthesized by acidified neem saw dust (Girish et al., 2019).
A study from Ethiopia on the use of neem leaf as protein based fodder for goats published results that with neem leaf as the sole supplement showed similar results to using a commercial concentrate mixture to improve weight gain (Dida et al., 2019). This implies that neem leaf could substitute the use of protein rich concentrate feeds. The result of this study also showed that dry matter digestibility was significantly influenced by the lignin concentration in the neem diet. In sole neem leaf supplementation higher crude protein intake results could have created a better environment by providing more nitrogen for rumen microorganisms which in turn improved digestibility of dry matter during the study period. The significant improvement in crude protein and dry matter digestibility with sole neem leaf diet could be attributed to the better compatibility of crude protein content of the neem leaf, since quality of crude protein intake is directly related to better crude protein digestibility (McDonald et al., 2002).
The more rarer studies are being conducted on cancer, making neem a promising source of alternate treatment (Agarwal et al., 2020). As a natural resource, neem extract has the advantages of easy availability, low cost and safety to humans, which collectively make neem derived compounds valuable candidates for medical therapy of any kind. The anticancer actions of neem extract are associated with modulations in tumor cells including inhibition of excessive proliferation, induction of cell death, suppression of angiogenesis, restoration of cellular redox balance, and enhancement of immune response against tumor cells. The neem leaf extract can also alleviate leukopenia caused by combination of cisplatin and 5-FU. It was also found to increase the number of cytotoxic T cells and NK cells and thereby making the chemotherapy less immune compromising (Ghosh et al., 2009). Quite simply, the extract and components from neem are known to target cancer cells selectively with minimal side effects on normal cells. For example, administration of neem leaf glycoprotein in mice and rats does not produce changes in the hematological system, organ microstructure and immune cells of these animals (Agarwal et al., 2020).
Although, these studies suggest that neem and its constituents such as nimbolide possess anti-cancer activities, potential of these agents in cancer patients remains a work in progress. A study conducted at Lucknow Medical College in 2018, produced favorable cytotoxic results for neem as a counteractive measure for poaching the breast cancer cell line MDA-MB-231. The combined treatment of neem extract and alkaline pH levels, decreased the growth and survival of cancer cells. Neem extract at a concentration of 1600 μg/mL and pH 8.6 caused 78% mortality in breast cancer cells (Chen et al., 2009). Due to the complex nature of cancer, single agent regimens have significant limitations, and the clinical therapeutic efficacy can be improved by combining of multiple agents. Interestingly, neem has been shown to improve the efficacy of other anticancer drugs besides its anticancer functions as a single agent. The combination of neem-derived gedunin and cisplatin further decreases the proliferation of treated ovarian cancer cells by almost 50% compared to the cells treated with only cisplatin (Chen et al., 2009). The combination of sub-lethal dose of ethanolic neem lead extract and cisplatin also provides synergistic effects in decreasing the viability of breast and cervical cancer cells compared to individual compound alone.
Preclinical studies have primarily established neem as a potential preventive and therapeutic agent against various types of cancer. With the profile of bioactive components in neem not completely clear, identification of effective anticancer components and study of individual components require further research. Although the preclinical findings and limited in vivo observations so far are encouraging, more extensive studies in animal models are needed to validate current knowledge on the functions of neem and explore the effects of neem on the other properties of tumor cells, such as in- creased cell mobility and metastasis. Full understanding of the underlying anticancer mechanisms of neem is required before neem can be tested for its therapeutic efficacy in clinical settings. Identification and characterization of individual anticancer components of neem are also prerequisites for the development of neem based therapeutic regimens. The potential of using neem to enhance the efficacy of other chemotherapeutic agents or as adjuvant in immunotherapy and radiotherapy is also worth further exploration. Taken together, current studies suggest that neem components have high potential for consideration as effective anticancer agents with minimal or no side effects during therapy.
References
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