Nerium indicum (Linn.): A potential phytomedicine against various health problems

Nerium indicum (Linn Apocyanaceae family) is wild plant and commonly known as “Kaner”. It is used against various health problems in India and China as ethno medicine. India and China is among the oldest civilizations on earth. Ethnomedicines are developed in ancient time by experiences sharing with nature. Aim of the present study is to explore the ancient knowledge of phytomedicine in context of modern science. Vedic period is the oldest cultural representation of human civilization. Ayurvedic system of medicine was developed in ‘Susruta Samhita’ and ‘Charak Samhita’. Nerium indicum (Linn.) is one of the thousands of plants mentioned in Ayurvedic system of India as important medicine for the treatment of various ailments. The lowers and leaves of N. indicum have been used to stimulate cardiac muscle, relieve pain and eliminate blood stasis. Present reviewmainly deals with the phytomedicinal properties such as analgesic, anti-diabetic, anti-oxidant, anti-bacterial, anti-viral, insecticidal/molluscicidal, hepatoprotective, neuroprotective, anticancer, anti-hyperlipidemic, anti-feedent activity of N. indicum. Its role as bioindicator in predicting the environmental condition is also discussed. N. indicum contains glycoside, oleandrin, tannin, volatile oil 0.25%. Glucoside, neriin and oleandrin are found in leaves of this plant. Nerium indicum is one of the wild plants, which is commonly used in various cultures as ethnic medicine. Although recent researches on its medicinal properties had established its therapeutic value in treatment of ailments, yet lot of studies are still required to explain its potentials as safe phytomedicine.


INTRODUCTION
Nerium indicum Linn., usually known as 'Kaner' and belongs to the family Apocyanaceae. N. indicum is ornamental plant having leathery leaves and lowers of different colours. It is native of Indian sub continent and widely distributed in Mediterranean region, subtropical Asia (Chetwani et al., 2017). In the traditional systems of aurvedic medicine, N. indicum is used to cure variety of human ailments. In ancient Indian Ayurvedic book 'Charak Samhita ', karvir (N. indicum) was recommended for the management of Twark Roga. Its stem bark juice is used in cure of ear pain in traditional ethnic treatment in Tamil Nadu India (Muthu et al., 2006). Traditionally it is used in cure of epilepsy, skin diseases, wound healing reproductive problem, gastro-intestinal infection, malaria, hypertension, diabetes (Tagarelli et al., 2010;Tantiado, 2012). Various constituents isolated from different part of N. indicum showed wide spectral biological activities such as its cardiotonic, diuretic properties (Zia et al., 1995). Its leaves are also used against snake bites. The cardiotonic and diuretic properties is mainly due to the active component oleandrin. Roots have been used externally for the cure of different types of cancers, leprosy, headache, ringworm and other skin complains (Nagargoje and Phad, 2013). N. oleander caused severe cardiac arrhythmia and severe diarrhea, sometimes with blood (Tokarnia et al., 1996). Its 11-dihydroxyhexadecanoic acid and its glycoside have been reported as anti-cancer and anti-microbial agents (Siddiqui et al., 1987). Root, bark and seed of N. indicum contain cardiac glycosides, which have paralyzing action on the spinal cord. Oil of N. indicum root is very effective in treatment of leprosy and skin disease (Saini, 2010). The leaves and bark are used as heart tonic, diuretic, expectorant, diaphoretic and emetic (Patel, 2010b;Jawarkar et al., 2012). Root boiled in water is helpful, in treatment of skin complaints, herpes and ringworms infections (Nagargoje and Phad, 2013). A very little dose of leaf juice is used against snake or other venomous bites (Nagargoje and Phad, 2013). Root part is used in hemorrhoids, various type of cancer, ulceration and leprosy treatment (Vinayagam and Sudha, 2011;Chauhan et al., 2013). N. indicum plant consists of cardiac glycosides in its leaves, stem and lowers. The barks consist of toxic glycoside: rosaginin and nerlin, volatile oil (Chetwani et al., 2017). Flowers also have alkaloid, glucoside, carbohydrate, lavonoid and tannins' and phenolic compound (Patel, 2010a). N. indicum leaves decoctions are used in the treatment of scabies, and to reduced swelling. Shah and Chakraborthy (2010) have been reported antibacterial and anti-in lammation activities of N. indicum. Different part of the N. indicum used as a molluscicides, insecticide and rat poison (Singh and Singh, 1998;Shah and Chakraborthy, 2010;Nagargoje and Phad, 2013).

Phytoconstituents
Polysaccharides puri ied from leaf and lower of N. indicum have higher soluble sugar. The sugar has large number of stereo-isomerism, because they contain many asymmetrical carbon atoms. Neriin and oleandrin, glucosides found in leaves of N. indicum have same properties as digitalin. The oleandrin is highly toxic (Chopra et al., 1986). The plant having digtoxin properties like steroid glyco-side. The stems and lower have higher levels of phenol, lipids, respectively (Vijayvergia and Kumar, 2007). Phytochemical glycoside, neriodorin, neoriodorein and kreabin are the main constituents of N. indicum root. The bark contains scopoletin, scopolin (Sharma et al., 2013). It also contains tannins, aromatic oil, wax and lobe in and yellow coloured stable oil. Neriodin, nerium D, rutin and anhydro-oleandrin are also reported in root of N. indicum. The root consists of bitter glycosides fenolinic acid and aromatic oil (Nagargoje and Phad, 2013). Presence of a-amyrin, b-sitosterol were noted in alcoholic extract of root, bark, whereas odoroside betulinic acid, oleonolic acid Sharma et al. (2013) were found in the ether extract.

Phytomedicinal properties
N. indicum is very poisonous plant as it contains powerful cardiac toxin. Therefore, it is used with extreme caution. The root is powerful resolvent and used in the form of plasters and is applied to tumors. It is only used externally. It is prepared in form of powder and mixed with water to form paste and then applied to lesion and ulcer on the penis (Nagargoje and Phad, 2013). Bark is better used as cathartic, febrifuge in intermittent fever. Oil prepared from the root, bark is applied in treatment of leprosy and skin diseases of the scaly nature (Nagargoje and Phad, 2013). Seeds of N. indicum are poisonous, abortifacient. They are used as purgative in dropsy and rheumatism. The part of entire plants is used as anti-cancerous agent. The lower, leaves, latex, bark and roots are used against corns, warts, cancerous ulcer, carcinoma, ulceration and hard tumors (Zibbu and Batra, 2010).

Anti-diabetic properties
Ingestion of leaves of N. indicum before a meal reduced the postprandial level in type II diabetic patients (Ishikawa et al., 2007). According to them active principal compound 3-O-caffeoylquinic acid and 5-O-caffeoylquinic acid inhibit α-glucosidase in non-competitive manner. The effect of different extract on glucose tolerance test in normal rats was evaluated. After 30 minutes of glucose administration the peak of blood glucose level increased rapidly from the fasting value and then subsequently decreased. Mwafy and Yassin (2011) reported the antidiabetic activity of aqueous extract of the leaves on streptozotocin-induced diabetics' models in rats. Signi icant 128% and 18.5% changes in serum glucose level and insulin level at the 4th day of observation was noted respectively. Sikarwar et al. (2009) have been reported the effect of chloroform/ethanolic extract of N. indicum leaves on alloxaninduced diabetic rat model were reported by. Treatment with dose of ethanolic extracts (300mg/kg b.w.) of N. indicum signi icantly (P<0.01) reduced the blood glucose level as compared to diabetic control on the 7 th day of the study. Different extract of N. indicum has different effects on glucose level. Chloroform and ethanolic extracts (500 mg/kg b.w.) has shown signi icant reduction of blood glucose after one hour, three hours of is taken, respectively. Whereas aqueous extract of the same plant has no signi icant, effect in reducing the glucose level (Sikarwar et al., 2009).

Analgesic properties
Flower extracts of N. indicum caused signi icant inhibition 89.14% and 93.20% of control writhing responses at oral doses of 250 mg/kg body weight of mice, respectively, whereas the root extract showed analgesic activity with 59.18% and 95.92% writhing inhibition at 125mg/kg and 250mg/kg body weight of mice, respectively. The results were found to be dose dependent and highly effective in comparison to the control. The stem extracts showed only 6.78% and 27.89% inhibition of writhing response at oral doses of 125mg/kg 250mg/kg body weight of mice, respectively. The analgesic activity of stem extract was lower in comparison to the crude lower and root extract, whereas crude leaf extract of N. indicum showed 100% inhibition of writhing re lex. Ahamed et al. (2006) noted that administration of the crude leaf extract reduced the pain sensation produced by acetic acid as mice did not show writhing re lex.

Anti-ulcer properties
On the basis of experiments it was noted that treatment with leaf extract of N. indicum at 250 and 500 mg/kg body weight in indomethacin-induced ulcer resulted 65.97% and 69.63% protection in rats, with an ulcer index of 5.416 and 4.833, respectively. Furthermore, in pylorus ligation-induced ulcer in rats, 250 and 500 mg/kg body weight dose resulted an ulcer index of 5.666 and 4.583, respectively, which was lower than that of the control (14.083) (Patel et al., 2011).

Anti-oxidant properties
Reactive oxygen species (ROS) are the causative agents to many disorders in physiology of body. The methanolic extract of leaves/ lower of N. indicum was analyzed for anti-oxidant activity (AOA) in terms of DPPH (diphenylpicrylhydrazyl) free radicals. Enzymatic anti-oxidant activity such as superoxide dismutase, glutathione peroxidase and catalase of N. indicum lowers were 10% to 30% more pronounced than leaves. Methanol extract of N. indicum lowers are more potent anti-oxidant than leaves (Vinayagam and Sudha, 2011). Mohale et al. (2016) reported the antioxidant activity of ethyl acetate extract of N. indicum lowers. According to them treatment with this extract caused signi icant increase in the endogenous antioxidants, superoxide dismutase (SOD), catalase (CAT), and reduced glutathione (GSH) in blood and brain of rats (Mohale et al., 2016). Several plant based products contain tremendous ROS scavenging capacity (Dey and Chaudhari, 2014). Several free radical scavenging elements were recognized in hydromethanolic extract of the leaf, stem and root of N. indicum (Dey et al., 2012;Dey and Chaudhuri, 2013).Leaf displayed excellent hydroxyl radical, peroxynitrite, hypochlorous acid. Whereas stem, indicate the presence of nitric oxide and DPPH (diphenylpicrylhydrazyl) radical scavenging capacity. N. indicum root displayed lipid peroxidation, superoxide anion, hydrogen peroxide and singlet oxygen scavenging activity (Dunn et al., 2011).

Anti-viral properties
N. indicum exhibited considerable anti-viral activity against herpes simplex virus and showed no cytotoxic effects (Rajbhandari et al., 2001). Antiin luenza viral activity with 50% inhibition was noted at dose of 10 µg/ml N. indicum methanolic extract. Singh et al. (2013) demonstrated that an aqueous extract of plant (AnvirzelTM) containing oleandrin compound of Nerium is effective against HIV in human. This product AnvirzelTM reduced the potentiality of HIV to infect new cells. Oleandrin extract from leaves of Nerium, down regulated HIV coat protein 120g expression at 10 mg/ml concentration (Chauhan et al., 2013).

Anti-bacterial properties
The anti-microbial activity of methanolic extracts of N. indicum, exhibited growth inhibition on selected bacterial strains viz. Bacillus species, Escherichia coli, Klebsiella species, Yersinia species, Enterococcus species (Ramya et al., 2010). Reddy (2010) reported in vitro anti-bacterial activity of N. indicum leaf extract at 2 mg, 4 mg, 6 mg, 8 mg/well. Recently, Chetwani et al. (2017) reported that N. indicum extracts viz. acetone, ethanol and aqueous have anti-bacterial activity against Pseudomonas aeruginosa. Among all these extracts acetone was most effective. Hussain and Gorsi (2004) noted the anti-bacterial activity of chloroformic/ethanolic/methanolic extract of root, bark and leaves against Bacillus pumilus, Bacillus subtilis, Staphyloccus aureus and Escherichia coli. Methanolic root extract demonstrate comparatively better anti-bacterial activity than bark and leaves. Organic solvent extract of different parts of the N. indicum displayed broad spectrum anti-bacterial effect against gram positive bacteria. It blocks the microbial growth, having micro biostatic effects. Methanolic, chloroform, hexane extracts have shown considerable antimicrobial activity of the plant (Chauhan et al., 2013). Siddiqui et al. (1990) showed insecticidal property of the Nerium leaves against sugarcane mites and citrus leaf minor. Guzman and Ambros (1992)noted the insecticidal activity of N. indicum against pest Blatta orientalis. Sap of N. indicum bark extracted in the proportion of 30, 20 and 10g per 200 ml of water, were as effective as the commercial household insecticide. The addition of 25 ml of kerosene with 100 ml of extracts resulted into higher activity. Root extracts of the plant are toxic to black carpet beetle larvae. Singh et al. (1993) observed that the latex of N. indicum is potent molluscicide. Its toxic effect is both time and dose dependent. Very low concentration (24 h LC 50 , 0.565 mg/l) of the N. indicum latex was effective against L. acuminata. Singh and Singh (1997) reported that different preparations of N. indicum leaf were toxic against Lymnaea acuminata. Puri ied fraction of leaf extract was 14 times more toxic to L. acuminata than standard molluscicide niclosamide. According to them molluscicidal activity was due to glycoside oleandrin present in the leaf extract of N. indicum (Singh and Singh, 1997). They studied the molluscicidal activity of bark of N. indicum against Lymnaea acuminata. According to them toxic components of N. indicum bark are soluble in water and ethanol. The toxicity of different bark preparations was both dose and time dependent. The 24h LC 50 of lyophilized aqueous extract of bark against L. acuminata was 34.5 mg/l. Low concentration of vacuum-dried ethanolic extract (24h LC 50 : 4.9mg/l) and puri ied bark (24h LC 50 : 0.87mg/l) was more effective to treat the vector snail L. acuminata Singh, 1997, 1998).

Hepatoprotective properties
Carbon tetrachloride induced a signi icant rise in serum glutamate pyruvate transminase (SGPT), serum glutamate oxaloacetate transminase (SGOT) and alkaline phosphatase (ALP) activity in liver cells. Treatments of rats with different dose of N. indicum extract signi icantly altered serum marker enzymes levels in carbon tetrachloride treated rats. The activity of the extract at dose was comparable to the standard drug silymarin. Hepatopancreatic activity of N. indicum was noted by various workers. Methanolic lower extract of N. indicum was evaluated for hepatoprotective activity in rats. Dose of 500 and 1000 mg/kg body weight prevented carbon tetra-chloride induced damage in liver cells of rats (Patel, 2010b). Singhal and Gupta (2012) reported that N. indicum methanolic extract of lower is potent hepatoprotective agent as evident by less in lammation and necrosis resulted from carbon tetrachloride induced liver damage. Normal liver architecture was restored at higher dose of the lower extract (Singhal and Gupta, 2012).

Anti-cancer properties
Nerium oleander leaf extract (NOE-4) used against human Burkitt's lymphoma (Raji cell) was significantly effective in a dose dependent manner. In study control Raji cells were not affected with human mononuclear cell (MNCs) mediated cytotoxicity (Dey and Chaudhari, 2014). Turan et al. (2006) studied the anti-leukemic effects of various extracts of the Nerium on HL 60 and K 562 cell lines. They noted that cytotoxic index on K562 cells were 66.2%, 57, 8%, 58.1% and HL 60 cells were 69.3, 66.5 and 62.8% for leaf, stem root extracts, respectively. ATP binding cassette transporter Pglycoprotein was affected by these extracts, which ultimately kill the K562 cells. Different extracts and compounds isolated from N. indicum were tested for their ef iciency as anti-cancer agents (Turan et al., 2006). Newman et al. (2007) noted the ef iciency of a major glycoside oleandrin on human pancreatic tumor cell, PANC-1. Oleandrin not only checked cell proliferation of PANC-1 cell but also arrests cell at G (2)/M stage of cell cycle. Oleandrin stimulated death of PANC-1 cells were governed by apoptotic pathway (Newman et al., 2007).

Neuroprotective properties
Polysaccharide J6 isolate from lowers of N. indicum can be used against Alzheimer's disease (Yu et al., 2007). Cortical Neurons stressed by beta-amyloid (Aβ) peptides or deprivations of nutrition from serum were potentially protected by N. indicum extract. A new polysaccharide from the lowers of N. indicum (named as J6) was investigated to study its neuroprotective effects against Aβ-induced apoptosis. Apoptosis caused by caspase-3 as well as the Aβ peptide was reduced signi icantly by pretreatments of the polysaccharide J6. Pretreatment activate survival signals Akt found in J2, J3, and J4 fractions. Dunn et al. (2011) demonstrated that oleandrin from leaves of N. indicum has potential to act as neuroprotective against in ischemic injuring oxidative damage and glucose deprivation. They formed that yellow luorescent protein tagged coronal brain slices had more protection from oxygen and glucose deprivation, when exposed to 1 µm oleandrin. This treatment also increased the α1 and α2 subunits of Na+/K+ ATPase in rat brain (Dunn et al., 2011).

Anti-hyperlipidemic properties
The anti-hyperlipidemic effect of petroleum ether chloroform, ethanol and aqueous extracts of N. indicum leaves was studied against in triton induced and atherogenic diet induced hyperlipidemic rats. Chloroform extract of N. indicum leaves caused a signi icant reduction in serum lipid pro ile i.e. like total cholesterol, triglycerides, low density lipoprotein (LDL) very low density lipoprotein (VLDL) and enhance the high density lipoprotein (HDL) in hyperlipidemic rats and their control (Patel, 2010a).

Bio-indicator
Dried lower can be used as bio-indicator as they show remarkable colour change. Dried lower are pink in colour. When treated with alkali it becomes green and reappears when acid is added. Portillo et al. (1994) reported that leaves of Nerium plant can be used as a bio-indicator, a tool used for measurement of lead produced by the ef luent of motor vehicle. Use of plant products in old Indian Aurvedic system against various diseases is well known.

Anti-feedant properties
Anti-feeding compounds can cause death impairment development or reproduction and may involve chronic as well as acute toxic effects. Spodoptera litura consumed minimum castor leaf sprayed with N. indicum leaf extract than fresh castor leaf. In addition to the leaf protection, enzymatic inhibition in insects is more, when it is consumed with castor leaf sprayed by Nerium leaf extract. It indicates that N. indicum leaf is an effective anti-feeding agent Dhanapakiam and Shanazbegum (1995).

CONCLUSION
Present review, deals with the information on the activities of different phytoconstituents of N. indicum against various diseases. N. indicum is source of mainly therapeutically important phytoconstituents such as glycoside, oleandrin, tannin, neriin, phytosterin, and I-strophnathin, rosaginin and nerlin, volatile oil, ixed oil, neriodori and neriodorein. In recent years, ethnomedicines are become a topic of global awareness. Plants have their own phytochemicals. Some of these chemicals have therapeutic importance in solving human health problems. N. indicum is a popular remedy used among the various ethnic groups. It is used in Ayurvedic and traditional practitioners of various ethnic groups in treatment of ailments. Researchers has explored the therapeutic potential of this plant as analgesic, antidiabetic, antiulcer, antioxidant, antibacterial, antiviral, hepato-protective, neuroprotective, anticancer, antihyperlipidemic, and anti-feedant activity. Instead of its use as insecticidal/molluscicidal and bio-indicators is also recommended by various workers. Although medicinal properties of different phytoconstituents of N. indicum are noted by various workers, yet lot of investigations are still required to explore its full potential in medical science of 21 st century.