Areca catechu : A phytopharmacological legwork

Arecacatechu , commonly known as supari, consists of dried ripe nuts that came under Arecaceae family, which is cultivated in the tropical region of India and Southeast Asia. It is a prevalent traditional herbal medicine that is chewed to separate collected fluid in the alimentary canal and for killing worms. Areca catechu seed contains alkaloids (arecoline, arecaine, arecaidine, guvacoline, guvacine, and choline), tannin, gallic acid, gum, and various minerals such as copper, calcium, phosphorus, and iron. The chemical constituents of this plant have been used as antidiabetic, stomatitis, bleeding gums, gingivitis, conjunctivitis, glaucoma, leucorrhoea, urinary disorders, anorexia, diarrhea, blood pressure regulating activity, antiulcerogenic, antioxidant activity, anticonvulsant activity, central nervous system stimulant activity, antifertility, oxytocic activity, antivi-ral activity, anthelmintic, and foul breath. It showed a dose-dependent toxicity profile, and various research has been done regarding its safety analysis and it would be considered safe when administered in the prescribed dose. The purpose of the present paper is to make available an up-to-date review on the ethnic, traditional description, morphology, phytochemistry, and the pharmacological and toxicological profile of this plant. Furthermore, the possible advances, trends, and a perspective for forthcoming research of this plant have also conversed.


INTRODUCTION
Herbs are natural origin products. Depending on several factors, their chemical composition varies throughout the globe, from active decoctions to the use of natural herbal extracts following Western practices of mainstream medicine. These products turn out to be one of the most significant resources for evolving new lead compounds and frameworks for drug development. Natural products are experiencing an unusual demand, meeting the imperative need to develop novel effective drugs, and are playing an important role in the discovery of drugs to cure various human diseases (Yuan et al., 2016).
Traditional medicines have been used since ages. They are used not because of their therapeutic outcome, but because of the combination of belief, rituals, and experience of times and culture (Firenzuoli & Gori, 2007). The development of novel drugs depends purely on recent technologies appearing to accomplish something quite challenging in modern drug delivery system. In discovering new drugs, the first choice of the pharmaceutical industry is the selection of new lead compounds based on synthesis and combinatorial chemistry; however, the substantial efforts made during this have not resulted in the projected drug productivity (Ahsan et al., 2018). Some prominent pharmaceutical firms are facing prodigious challenges to develop novel products. Over the past several years, growing attention has consequently been paid to molecules of natural origin during the search for new drugs in amalgamation with new technology. Among natural-origin lead compounds, the herbal-origin plants and their constituents are the first choice as they are easily available in large quantity (Ngo et al., 2013).
Areca catechu, commonly known as supari, consists of dried ripe nuts that come under the family Palmae or Arecaceae, which is cultivated in the tropical region of India, Malaysia, Sri Lanka, East Indies, Philippines Islands, South China, and part of East Africa (Rashid et al., 2015). Chewing the areca nut with betel leaves (betel quid) is a traditional habit in India and in many Asian countries (Ling et al., 2001). It is predicted that around 400 million people generally chew betel quid (which chiefly consists areca nut, lime, and the betel leaf) daily (Gilani et al., 2004;Lim & Kim, 2006). The palm or areca tree reaches up to a maximum height of 10-20 m (33-66 ft). Although it is adapted to grow in a variety of different soil types, proper drainage facility and high moisture holding capacity is required for normal growth of areca plants. The kernel yield is estimated at 2.5-8 kg per palm annually (Staples & Bevacqua, 2006). Areca nut (seed) contains gum, gallic acid, tannin, alkaloids (namely, arecaine, arecoline, arecaidine, guvacine, guvacoline, and choline), and several minerals such as copper, calcium, phosphorus, and iron. Areca catechu is the only one of 54 different Areca species identified to contain alkaloids (Buckingham et al., 1989). The Arecaine is the chief constituent of the Areca nut (Nadkarni, 1976). Indians have fewer dental caries when compared with the Western population because of the fact that areca nut is widely chewed in the Indian subcontinent, which has been recognized to decreasing dental caries probably by inhibiting Gram-positive microorganisms that are accountable for dental caries (Gupta & Ray, 2004;Hung et al., 2002).
The chief constituent of A. catechu is tannins. Tannins (also termed as tannic acid) are water-soluble polyphenols that are found abundantly in many plant foods. These compounds are responsible for reductions in feed intake, feed efficiency, growth rate, net metabolic energy, and protein metabolism in experimental animals. Consequently, foods rich in tannins are thought to be of low nutritional value. Tannins containing food components act by inhibiting enzymes such as hyaluronidase and 5-lipoxygenase, which constitute the action as anti-inflammatories, keratolytic agents, and antimicrobials (Chung et al., 1998). Tannins do not function exclusively as primary antioxidants (i.e., they donate electrons or hydrogen atom), but they also function as secondary antioxidants. They tend to chelate the metal ions, Fe (II), and interfere with one of the reaction stages in the Fenton reaction; this action retards the oxidation (Karamać, 2009). The other mechanism that is postulated states that tannins inhibit lipid peroxidation, thus activating the inhibition of cyclooxygenase. These therapeutic properties are assumed to be ascribed to the ability of tannins to show properties of free radical scavengers by activating antioxidant enzymes .
Areca catechu has numerous pharmacological actions including effects on digestion, antiparasitic effects, antioxidant effects, nervous and cardiovascular systems, anti-inflammatory and analgesic effects, antibacterial and antifungal effects, regulatory effects on lipids and blood glucose, anti-allergic effects, as well as effects on other diseases . Traditionally, A. catechu has frequently been utilized to promote digestion and kill parasites; the seed is the foremost part of A. catechu used as medicine (Jung, 2016).

Height
The palm climbs or reaches up to a maximum height of 10-20 m (33-66 ft).

Leaves
Eight to 12 leaves are present as fascicles at the top of the stems.
The leaves are 1.3-to 2.7-m long (together with petiole) and are light green to green in color; the blades are multitudinous, lanceolate, and both surfaces of leaves are glabrous having a length of 30-60 cm and total widths of 2.5-4 cm. The superior blades are connate in shape with an uneven tooth-like crack found at the apex (Heatubun et al., 2012).

Worldwide
Betel nut or Areca nut is recognized scientifically as A. catechu, which is a relative of the fruit coconut (Cocos nucifera) (Artero & Santos, 1914
Although it is adapted to an extensive range of soil types, drainage and high moisture holding capacity are required. The growth rate is moderate, about 0.5 m/year (20 in/year) (Staples & Bevacqua, 2006).
The palm tree and nuts of A. catechu have been shown in Figure 1.

Flavonoids
Flavonoids are common constituents of numerous plants worldwide.

Alkaloid
Alkaloids hold prominent biological actions and are thought to be the principal active constituents in plant-derived medications (Amirkia & Heinrich, 2014). Areca catechu is the only herbal-origin plant comprising alkaloids of the family Arecaceae (Qi et al., 2006). The four most important alkaloids that have been isolated from the areca nut are arecaidine (1.5 mg/g weight), arecoline (7.5 mg/g weight), guvacine (2.9 mg/g weight), and guvacoline (2.0 mg/g weight) (Chu, 2001). All these isolated alkaloids are related chemically; among them, arecoline is volatile and colorless in nature resembling chemical nicotine.

Mineral content
The mineral matter includes calcium (0.05%), phosphorus (0.13%), and iron (1.5 mg/100 g). It also contains vitamin C (416.2 mg) and vitamin B6 (286.9 mg) (Raghavan & Baruah, 1958). The list of chemical constituents found in part of the plant along with their structure has been mentioned in Table 1.

PHARMACOLOGICAL ACTIVITIES
Areca catechu has a long history as a medicinal plant worldwide, based on its wide spectrum of biological and pharmacological activities. Tra-ditionally, it has been utilized to destroy parasites and also used in the treatment of dysentery, abdominal distension, constipation, and promote digestion (Jung, 2016). Areca nut demonstrates significant analgesic and anti-inflammatory, wound healing antidepressant, and anti-HIV activities (Nur Sazwi et al., 2013).

Antioxidant
The methanol extract of A. catechu showed higher antioxidant actions than the other form of extract (Wetwitayaklung et al., 2006). Ethanolic extract of A. catechu showed potent antioxidative, free radical foraging, and antihyaluronidase activity. The antioxidant properties of the extract was quite lower than butylated hydroxytoluene when compared it was similar to tocopherol and was higher than ascorbic acid (Kim et al., 1997). Also, some compounds isolated from the areca nut have been reported to possess notable DPPH radical-scavenging activities . Areca catechu showed stronger antioxidant activity than Salvia miltiorrhiza and Ulmus davidiana, with IC 50 of 20 and 6.0 μg/ml, respectively (Ahn, 2009).

Hypoglycemic activity
Arecoline was examined and reported to possess hypoglycemic activity in a different animal models of diabetes when administered subcutaneously. The administration of the subcutaneous alkaloid portion of A. catechu into alloxanized rabbits exhibited a significant hypoglycemic result that lasted for 4-6 h (Chempakam, 1993). Areca nut extract inhibited blood glucose elevation by inhibiting glucosidase activity; α-glucosidase inhibitors are used worldwide for the treatment of diabetes lowering postprandial hyperglycemia (Senthil & Begum, 2008).

Antihypertensive
The subfraction of the areca nut that contains plentiful tannins displayed a potent antihypertensive activity at a dose of 100 and 200 mg/kg (peroral [p.o.]) in instinctively hypertensive rats via angiotensinconverting enzyme (ACE) inhibition. Areca tannin has been proposed as possessing the blood pressure controlling effect through its capability to constrain the pressor response to the hormone angiotensin I and II (Chung et al., 2007). The extreme antihypertensive effect of a fraction of areca nut at a dose of 15 mg/kg intravenous was about five times as huge as that of captopril at the same dose (Inokuchi et al., 1986).
Areca II-5-C, a constituent isolated from seeds of A. catechu L., displayed the most effective ACE inhibitory action in vitro (Chung et al., 2007). The antihypertensive activity of A. catechu was therefore investigated in spontaneous hypertensive rats (SHR). At a dose of 15 mg/kg, the extreme antihypertensive effect of areca II-5-C in SHR was demonstrated when administered via intravenous route (Inokuchi et al., 1986).

Aphrodisiac activity
The oral administration of the extract of A. catechu L. and Pedalium murex L. at a dose of 150 mg/kg body weight displayed a significant rise of sexual activity in male rats. Areca catechu group showed a significant increase in sperm count as compared to the control group. There was a continued increase in the sexual activity of normal male rats without showing any noticeable adverse effects signifying that A. catechu has aphrodisiac potential (Anthikat et al., 2013).

Antidepressant
The ethanolic extract of A. catechu at a dose of 40-80 mg/kg instigated a significant decrease in the immobility time interval without distressing spontaneous motor activity. This result proposes that the ethanol extract of areca nut holds antidepressant activities (Kuo et al., 2005).
The aqueous ethanolic extract of A. catechu and aqueous fractions constrain monoamine oxidase (MAO) in homogenates of rat brain. The aqueous portion appears to be the most effective inhibitor of MAO and its response is quite similar to that of clorgyline (MAO inhibitor) (Dar et al., 1997).

Antifungal activity
The Areca nut extract does not constrain the growth of mycelial fungal forms, for example, Aspergillus niger, Mucor sp., and Cladosporium Note: Concentration is depicted as per 3 ml of medium.
sp., but the growth of single-cell fungus such as Candida albicans was reserved by utilizing the tube method, and the concentration desirable for 100% inhibition was obtained to be 16.67 μg/ml (Anthikat et al., 2014). The effect of areca nut on Candida albicans has been mentioned in Table 2. The Areca nut extract was also analyzed for its inhibitory action against aflatoxin production of Aspergillus flavus.
Areca nut extract was revealed to constrain aflatoxin production by Aspergillus flavus (Anthikat & Michael, 2009). Additionally, some complexes isolated from the pericarps of A. catechu were responsible to show notable antifungal action against Colletotrichum gloeosporioides (Yenjit et al., 2010).

Antibacterial activity
A study reported that the different types of veterinary and human isolates, both Gram negative and Gram positive, were tested against A.
catechu extract by determining the evolution of the organisms utilizing the spectrophotometric method. It was obtained that both Gram-negative and Gram-positive microorganisms were vulnerable to the A.
catechu extract. The detail has been depicted in Table 3. The concentration required for 100% inhibition of the development of Gram-negative bacteria was depicted to be 3.3-7 μg/ml and for Gram-positive bacteria it was 16 μg/ml (Anthikat & Michael, 2009

Antimalarial
A study performed the antimalarial survival test in mice, which showed a 60% survival rate with A. catechu and butanol (BuOH)-treated group.
In this study, A. catechu and BuOH were investigated for antimalarial activity in vivo and in vitro and they showed potent antimalarial activity. In vivo, 4 days' suppressive and survival test showed a 39.1% inhibition effect after treating with 150 mg/kg/day on Plasmodium bergheiinfected mice (Jiang et al., 2009).

Anti-HIV activity
Numerous active constituents such as Areca tannin B1, procyanidins, and different extracts of the areca nut seed displayed HIV protease inhibition action (Marastoni et al., 2004).

Anti-allergic
A study reported that the areca extract is a forceful inhibitor of 2,4-dinitrophenyl group-bovine serum albumin, and compound 48/80 tempted degranulation in RBL-2H3 mast cells and also induced systemic anaphylaxis 46% in mice with IC 50 values of 52 and 53 mg/ml, respectively (Lee et al., 2004).
Areca catechu also suppresses the expression of TNF-α and the stimulation of mitogen initiated extracellular signal-regulated kinase ½ (ERK1/2), protein kinase that is perilous for the generation of inflammatory cytokines in mast cells, as specified by the repression of the activating phosphorylation of ERK1/2. These outcomes recommend that A. catechu may be beneficial for the treatment of several delayed and immediate allergic diseases (Rashid et al., 2015).

Anti-inflammatory
The ethanolic extract of A. catechu at a dose of (1 and 10 mg/kg/day

Antinociceptive effect
The methanolic extract of the stem of A. catechu showed an antinociceptive effect at different doses by reducing the total number of con-

Prevention of dental cavities
Indians have less dental caries when compared with the Western population. In reality, areca nut has been recognized to reduce dental caries possibly by inhibiting the Gram-positive microorganisms that are responsible for dental caries (Gupta & Ray, 2004). Laboratory research studies recommended that betel nut probably has antibacterial effects, which is responsible for the development of cavities ). Areca catechu nut is vitally used in the manufacture of dentifrice because of its astringent properties. The areca extract is considered to provide strength to the gum and remove foul breath. The seeds are converted to charcoal and then it is powered; this powder forms an excellent dentifrice (Rashid et al., 2015).

Burn wound healing
The burn wound healing property of A. catechu kernel was evaluated in normal as well as dexamethasone-treated rats. On the burn wound of animals, the ointment prepared from ethanolic extract of A. catechu nut is applied. The contraction rate of the wound was significantly augmented in Areca catechu-treated group at different doses when compared to normal control. In the drug-treated group, the period of epithelialization was faster when compared to the control group. A significant interruption in wound healing progression in the dexamethasone-treated group was observed when compared to control. Areca extract exhibited a significant reversal in the epithelialization period and wound contraction rate in the dexamethasone-repressed burn wound healing model (Verma et al., 2012).

Antimigraine activity
Areca catechu nut extract is a prevalent folk preparation for the cure of migraine in the southern part India. To demonstrate the claimed potential of the plant, a research was carried out by Bhandare et al. Conclusions of the study jointly indicate that the extract showed significant inhibition of inducible nitric oxide synthase, which may be the likely mechanism for its antimigraine action, provided the evidence, at least in part, for its folkloric use (Bhandare et al., 2011).

Antiparasitic effects
The areca nut is a traditional remedy usually used to destroy parasites including Lumbricus, tapeworms, pinworms, and so forth. In recent pharmacology, the antiparasitic properties of the areca nut have been broadly examined. Earlier investigations stated that the aqueous extract of areca nut can efficiently kill tapeworms, and the mechanism behind it is related to the paralytic result of the aqueous extract of areca nut on the scolex of the tapeworms. Additionally, the antiparasitic properties of the aqueous extract of areca nut in contrast to tapeworms can be improved by combining it with the extract of Cucurbita moschata. In the aqueous extract of areca nut, the chief constituent is arecoline and it was supposed to be responsible against tapeworms, and the mechanism was associated with the paralytic effect of areca nut. Also, it was stated that a 1% decoction of the areca nut efficiently kills blood flukes by causing disturbances in their nervous systems (Peng et al., 2015).

Immunosuppressant
Arecoline at lower concentration ceased the cell cycle of splenic lymphocyte with encouraged apoptosis at higher concentration in that way causing immunosuppression in betel nut chewing patient (Dasgupta et al., 2006).

Effect on gestation
The ethanolic extract of A. catechu at two different doses of 100 and 300 mg/kg has abortifacient and antiovulatory effects. Thus, the habit of mastication of betel nut may become a reason of abortion or interrupt normal gestation. The result was supported by analyzing the swab of rodent's vagina that was treated with different doses of areca nut (Shrestha et al., 2010). A summary of the pharmacological activity of A.
catechu along with its mediator/pathway has been depicted in Table 4.

Acute oral toxicity
A study regarding acute oral toxicity of A. catechu Linn. aqueous extract in Sprague Dawley (SD) rats stated that the LD 50 (lethal dose, 50%) was obtained and it was designated to be >15.0 mg/kg body weight.
The result indicated a significant increase in body weight (p < 0.05). No mortality was detected during the whole acute toxicity, that is, 14 days' study period. No noticeable variations were found in various activity parameters in the areca-treated group when it was compared to the control group (Sari et al., 2014).

Acute dermal toxicity
A study regarding acute dermal toxicity of A. catechu Linn. extract in SD rats was performed, as per Organisation for Economic Co-operation and Development (OECD) Guidelines 402 designated for acute toxicity protocols. The change in body weight, the possibility of mortality, overall signs, and behavior activity parameters were analyzed for 14 days to establish the LD 50 of the areca extract.
After 14 days of observation, the LD 50 was obtained to be >15,000 mg/kg body weight. There was a significant increase in body weight (p < 0.05) in animals of the treated group when compared to the normal control group. No mortality was detected during the entire 4 days' study period. A unit dose of 15,000 mg/kg of body weight did not produce any dermal treatment-related symptoms of toxicity in any of the treated group animals.
Overall, a unit dermal dose to A. catechu L. aqueous extract showed no toxic symptoms related to eczema, inflammation, rashes, and gross discoveries in female rats when administered at a dose of 15,000 mg/kg of body weight (Sari et al., 2016).

Minimal active dose/concentration and route Reference
Antiparasitic effects

Cytotoxicity
Arecoline possesses cytotoxic effect via endothelium necrosis, whereas biochemical examinations indicate no considerable cellular leakage before mortality and detachment, in addition to no clear action on the mitochondrial role in viable cells. The toxicity of arecoline may thus be responsible for reducing vascularity in oral submucosal fibrosis (Ullah et al., 2014).
Arecoline, at a concentration below 0.8 μm/ml, amplified cell growth (all types of cell); at advanced concentrations (25-400 μg/ml), it showed a cytotoxic effect, thus triggering carcinoma in the oral squamous cell (Yang et al., 2004). Arecoline at a dose of 50-200 μM promotes neuronal cell demise. Catalase, nicotinamide adenine dinucleotide phosphate (NADPH), oxidase inhibitors (apocynin and diphenyleneiodonium chloride), and z-VAD-fmk, which is a caspase inhibitor; they can inhibit arecoline-mediated cell death. Furthermore, arecoline promoted reactive oxygen species (ROS) production and augmented protein expression and level of mRNA of NADPH oxidase 2, which can be diminished by NADPH oxidase inhibitors and catalase (Shih et al., 2010).

Embryotoxicity
Embryos treated with arecoline displayed retardation in general development in a dose-dependent manner. The underlying mechanism behind growth retardation mediated by arecoline in embryos is largely due to an overall cytotoxic effect brought by the diminution of intracellular thiols .

Genotoxicity
Genotoxic effectiveness of a raw betel nut aqueous extract with relation to the level of endogenous glutathione in mouse bone marrow cells and also in human peripheral blood lymphocytes specifies that the production of ROS by AEBN could somewhat contribute to the initiation of chromosomal abnormalities causing genotoxicity (Kumpawat et al., 2003).

Carcinogenicity
A study of initial molecular actions following exposure of chronic arecoline at a dose of 10 μm/ml into Swiss albino mice confirmed that betel nut encourages arecoline-induced carcinogenesis (Saikia et al., 1999).

Hepatotoxicity and testicular toxicity
Increased risks of hepatocellular carcinoma and cirrhosis were found in betel nut chewers that were free from hepatitis B/C infection, and these hazards were synergistically additive to those of hepatitis B/C infections (Wu et al., 2009).
But one more research work has accomplished a different outcome and it states that the outcomes of the study seem to specify that even long-term areca nut chewing may not promote hepatotoxicity. Minor modifications in liver function tests were fine inside acceptable limits, and no obvious biochemical signs of liver injury were detected. A more comprehensive study is needed with a bigger sample size to significantly arrive at a definite connection of the effect of chewing of areca nut on the liver (Singroha & Kamath, 2016). The principal constituent of areca nut is arecoline; its exposure may lead to serious testicular toxicity and hepatotoxicity as described in another report (Zhou et al., 2014). A detailed toxicological profile along with their doses has been mentioned in Table 5.

CONCLUSIONS
This article provides a summary of many specific characters of areca nut and their therapeutic effect of phytochemicals on various disease conditions. Biochemical compounds of areca-nut have been recently recognized as functionally active molecules, possessing antioxidant, hypoglycemic activity, antifungal, antimigraine, anti-allergic, and additional beneficial properties, as well as they exert protective effects against cardiovascular and other diseases. As mentioned in the article that further studies are required to know the underlying mechanisms and type of biochemical compounds involved in this beneficial effect and to ensure these studies, it would facilitate utilization in modern medicine.

SEARCH STRATEGY
These searches were confined only to the English language. The authors have used broad Major Exploded Subject Headings (MesH) terms and keywords (A. catechu, Supari, Areca nut, Betel nut) with the following prefix and suffix (phytochemistry, pharmacological use, toxicological, morphological, and geographical). With these words, we have searched EMBASE, PubMed, PsycINFO, Medline, Google, and Sci-enceDirect. First of all, the papers were collected whose open-access file was available; the abstract was copied from paper that was not accessible. Later following the guideline of Systematic Reviews and Meta-Analyses (PRISMA), the data that were not relevant to the theme of this paper were discarded; the remaining data were characterized according to their heading such as morphology and phytochemical.
All collected publications were reviewed manually and also checked regarding the references of interest.