Areca Nut / Betel Nut / Supari /সুপারি / (Bengali)

General features: The English name of this plant is Areca catechu. It belongs to Arecaceae family of Areca genus and is one of the palm varieties that grows in tropical regions of South Pacific, South Asia, and some areas of East Africa. The term Areca  seems to be originated from ancient Dravidian languages of Southern India. The plant is a native of Philippines, Malaysia, India, and Indonesia. It is hugely cultivated in New Guinea, India, Bangladesh, Sri Lanka, Laos, Myanmar, Thailand, Vietnam, Southern China, several places of South Pacific Islands, and West Indies [1]. In English, the tree is also called Areca nut palm, Betel nut palm, or Indian nut palm. The fruit, areca nut (AN) is called “Supari” (সুপারি) in both Bengali and Hindi. The dried ripen seeds are often chewed with Betel leaf (Paan in Bengali) which comes from a vine belonging to Piperaceae family. The Areca nut tree is 60 – 70 ft tall with 5 – 6 inches diameter trunk. The leaves are 5 – 7 ft long, pinnate, crowded with plenty of leaflets. The fruit, Areca nut (AN) which is colloquially called ‘betel nut’ is in fact not actually a nut. It is commercially available in dried, hard, and cured form. In fresh form, the husk is green and inside seed is soft to be sliced by a knife. The husk turns yellow or orange in dry or ripe conditions and the fruit inside becomes hardened turning to woody texture which can only be sliced by using a special cutter. The dried sliced nuts are chewed wrapped with betel leaves with a touch of slaked lime (Calcium hydroxide). People often spice up the wrap by adding numerous spices like clove, cardamom, mint, and catechu (dried gum of acacia tree) or even using flavored tobaccos (popularly called Jarda). Assembling them in a wrap offers fresh peppery and minty taste displaying alluring scarlet color on lips also extending freshness to mouth. The chewing of AN with betel leaf acts as mild stimulant providing warm sensation inside body while adding extra alertness [2]. Arecoline is the active ingredient responsible for this CNS stimulation almost comparable to nicotine. Inserting tobacco (Jarda) in the mix adds extra potency because of the nicotine [3]. Additionally, AN contains numerous phytochemicals including several alkaloids which employ vasoconstricting effects [4]. According to traditional Ayurvedic medicine, chewing AN with betel leaves removes bad breath. Further, powdered nuts act as dentifrices (tooth cleaning powder). Oral administration of this dried AN suspension in water removes tapeworms and several parasites of the intestine. The effect is owing to the presence of various alkaloids [5].

In recent days, AN has been claimed to act as a mild narcotic. But it has been in use for thousands of years and exceedingly popular in most part of India. Interestingly, far away from the South Asia, in ancient Greece, legendary physician and scientist, Theophrastus (371 – 287 BC) mentioned about AN in his book “Historia Plantarum”. Even so, it was completely unknown to the Western World until the European explorers of Portugal, Holland, and Spain landed in the Southeast Asia around 16th century. Archeological evidence indicates its use dates back to 13000 years ago. About 600 – 700 million people, one tenth of the world population chew betel nuts every day. In India and South Asian countries including South Pacific Islands, people grow it in the yard for beautification and for uses too. In India it is frequently offered to the God during Pujas. People believe that it would ward off the evil eye. Georg Eberhard Rumphius (1627 – 1702 AD), the German-born botanist working for Dutch East India Company in present day Indonesia, in his book on natural history of Southeast Asia interprets the chewing of areca nut along with betel leaf, and lime as an example of human ingenuity since each one of the items is unpleasant if consumed individually. But the combination offers satiety or gratification. It suppresses hunger, freshens breath, and acts as a substitute for tobacco as a mild stimulant [6]. The nuts also provide a rush of stamina and euphoria. Excessive use AN with betel leaf discolorizes teeth and often leads to oral cancers. In spite of its few beneficial actions, the World Health Organization has labeled it as a carcinogen.

History of betel nut use: The exact time frame of areca / betel nut use is uncertain. Archeological evidence unearthed from the caves of Thailand, Indonesia, and Philippines indicate that in combination with betel leaf and lime, the concoction has been used for about 4000 years, as noticed inside the Spirit Cave of Thailand. However, the evidence of other places like in East Timor, Indonesia suggests that its use dates back to 13,000 – 4000 years ago since betel stained teeth are found inside many caves of that region. The recent document of betel nut use in Philippines shows that it could be ancient about 3000 BC. The practice of betel chewing is thought to have originated in Southeast Asia and afterward traveled to the Pacific islands. Many historians even suggest that chewing of betel nut with leaf is not initiated in the Southern India. It was possibly introduced before the breakup of Proto-South Dravidian which presumably occurred around 1500 BC. Evidence further indicates the practice of chewing of areca / betel nut might have taken place in pre–Vedic Indus Valley Civilization. Far afterward, it turned into a tradition of Southern India and Sri Lanka but only within the royal families which was permeated later among the common masses since the concoction provides relaxing and breath freshening action. The legendary Arabic historian and famed traveler of 14th century, Ibn Battuta arrived in India in Tughluq dynasty via Khyber Pass during the reign of most erratic Sultan, Muhammad bin Tughluq. In his history book or travelogue, Battuta mentioned the use of betel leaves and nuts within masses. The use was socially acclaimed, which amazed him, particularly in the event of greeting guests or invitees. He described it with high opinion [7]. Around 1568 AD, the Spanish navigator and explorer, Alvaro de Mendana (1542 – 1595 AD) observed the chewing of areca nut and betel leaf with smudge of caustic lime is a customary practice among the Solomon Islanders which stained their mouths red. The islanders of Santa Isabel often offered it to him as a token of friendship whenever they used to meet with him. The addition of tobacco in chewing mixture is a recent novelty started from the British colonial era [6].

Use of betel nuts as folk medicine: Besides acting as a mild stimulant, the nuts and associated plant parts are used for various medicinal purposes particularly to remove intestinal worms. According to the Chinese folk medicine, betel nuts help digestion, removes plaques, and expels worms [8]. The practice of betel nut chewing is always denounced by the dentists even in the early days. In Sri Lanka and some parts of India AN is used to make several Ayurvedic medicines. Decoction prepared by using suspended powdered nuts in water is often orally administered to get rid of tape worms or intestinal parasites. Additionally, extractions prepared by boiling nuts and plant parts in aqueous medium loaded with chockfull of alkaloids are also consumed to cure several ailemnts like stomachache, venereal diseases, rheumatism, and fever [6].

Chemical components and major physiological effects: A large varieties of phytochemicals have been isolated and identified from AN that includes alkaloids, tannins, flavonoids, triterpenoids, steroids, and fatty acids [9]. Clinically, AN can exert several pharmacological roles in certain diseases like malaria, ascariasis (round worm infection), arthritis, enterozoic (intestinal parasites), stagnation of food, diarrhea, edema, and beriberi. The CNS excitement and betel nut chewing gains major popularity. But the practice of long-term or chronic chewing might induce oral submucosal fibrosis and even oral cancers. There are also a few adversarial factors involved, like esophageal and uterine cancers and reduction of sperm counts, including occurrence of occasional asthma problems from chronic use [10]. Basically, AN exerts physiological effects on most of the human organs eg, brain, heart, GI tract, and reproductive tissues. It is also able to aggravate pre-existing conditions like neuronal injury, myocardial infarction, cardiac arrhythmias, hepatotoxicity, asthma, obesity, type-2 diabetes, prostate hyperplasia, hyperlipidemia, and infertility. It affects the immune system by suppressing T-cell activity and decreasing the release of cytokines. Based on those perspectives, AN is a controversial matter.

Alkaloids and associated effects – The total alkaloid content of betel nut / AN is estimated to be around 0.3 – 0.7 %. In recent days, AN alkaloids are important to study because of their versatile physiological role. Among them arecoline is the most prominent one. It is the major active as well as a toxic component. It is a pyridine type alkaloid capable of rapidly permeating through blood-brain barrier owing to its high lipophilicity [11]. However, its level declines after reaching peak ripeness [12].

Recently two new alkaloids have also been identified which are acatechu A and acatechu B whose exact physiological actions are not known yet. Mostly four alkaloids are amply synthesized within AN. They are arecoline, arecaidine, guvacoline, and guvacine. The parasympathetic and muscarinic activities of areca nuts are mostly due to arecoline which works by stimulating both muscarinic and nicotinic receptors. The continual users experience euphoria, warmth, increase of alertness, wellbeing, salivation, palpitation, antimigraine feeling, and enhanced ability to work. The use of AN also produces dependency while enhancing concentration, relaxation, postprandial satisfaction, and subsequent withdrawal syndrome associated with insomnia, irritability, anxiety, and mood swings comparable to amphetamine [13]. Arecoline, arecaidine, guvacine, and guvacoline offer neurosuppressive activity of γ-amino butyric acid (GABA) by blocking the receptors inhibiting the uptake which in fact contributes to the euphoria thereby making resistant to benzodiazepine also predisposing to seizures [14]. Arecoline creates palpitation, increases blood pressure, raises body temperature, also causing flushing and sweating, even constipation [15]. The nuts stimulate adrenal chromaffin cells to release Catecholamine / epinephrine enhancing the heart rate owing to central sympathetic response that leads to fall of diastolic component for peripheral cholinergic action and increase of systolic component in the case of non-habitual users [16]. On the other hand, AN does not alter the cerebral blood flow of internal carotid artery and middle cerebral artery. It has been noticed that arecoline can block high-density lipoprotein (HDL) receptor enabling to inhibit the uptake of low-density (LDL) lipoprotein by the liver thereby enhancing atherogenesis and its parasympathetic effect causing spasm of the coronary arteries which eventually predispose to coronary artery disease [17].

Triterpenoids and steroids – AN also contain several triterpenoids. The major steroidal compounds are β – sitosterol, cycloartenol, and fernenol.

Tannins and flavonoids – Besides having a large reserve of alkaloids, the other major phytocomponents of betel nuts are tannins and flavonoids. Tannins provide mild bitterness or astringency to the fruit. The main ones include arecatannin, and Proanthocyanidin A and B. Plenty of flavonoids are also synthesized which have numerous biological activities like antibacterial, antitumor, and antioxidant. The ingredients are, catechin, luteolin, quercitin, glycyrrhizin, isorhamnetin, Chrysoeriol, jacareubin, flavan-3 – ol, flavan-3,4 diols, 4`,5`-dihydroxyl-3`,5`, 7`-trimethoxyflavone, 5`,7, 4`-trihydoxy-3`,5`-dimethoxy-dihydroflavone.

Tannins and Flavonoids

Fatty acids – Extraction by supercritical fluid and subsequent identification following GC/MS shows the presence of fatty acids like lauric acid, nutmeg acid, palmitic acid, stearic acid, hexadecanoic acid, and (E,E)-2,4-decadienaldehyde (nut peel) [10].

Miscellaneous phyto-compounds – In addition to a few quinones, derivatives of several phenyl propionic acids have also been identified which are presented below. Chrysophenol is a well-known antineoplastic drug. It can alleviate diabetic neuropathy while inactivating TGF-β/EMT signaling pathway [18]. The compound also protects bronchial cells from the harmful actions of cigarette smoke by repressing CYP1A [19]. Physcione can slow down the growth of several human cancer cells. It is non-toxic to normal healthy cells but prevents the growth of human lung cancer or tumor cells [20]. Resveratrol is known to be beneficial for cardiovascular problems. Ferulic acid exhibits numerous physiological functions acting as anti-inflammatory, antioxidant, anticancer, and antidiabetic compound [21].

Pharmacological effects: Practice ofchewing of areca / betel nut dates back to antiquity. It exhibits several merits despite the bitter and astringent taste. It expels wind, destroys intestinal worms, removes phlegm, subdues bad breath, and provides freshness to the mouth. As per modern pharmacology, this nut plays several important physiologic roles that are beneficial to health. It exerts antifatigue, antioxidant, antibacterial, antifungal, antihypertensive, anti-inflammatory, anti-depressant, analgesic, and anti-allergic activities [22]. In addition, it promotes digestive actions, inhibits platelet aggregation, and controls glucose and lipid levels in circulating blood [23]. However incremental studies in recent days have proven that AN is harmful toward health producing risk of cancers, cardiac problems, and chronic kidney diseases [17].

Effect on digestive system – It is proven that arecoline in AN stimulates sympathetic nervous system while interacting with the muscarinic acetylcholine receptor (mAChR – M4) promoting the secretion of saliva, sweat, and gastrointestinal peristalsis thereby improving the digestive function [24]. In addition to muscarinic effect the compound also acts as a partial agonist by potently activating the nicotinic acetylcholine (nAChR) of α4*  and α 6* also as a silent agonist of α7* subunits [25,26]. Arecoline’s action on nAChR is associated with an addictive nature which accounts for its habitual use created due to frequent chewing [26].

Effect on nervous system – AN has a strong impact on the nervous system. Regarding beneficial action, AN helps improve the learning memory. Arecoline of AN exhibits acetylcholine like activity which activates muscarinic receptors (mAChR) thereby stimulating the parasympathetic neurons. Simultaneously, it has inhibitory action on GABA that creates excitement as well as delight also [27]. Using aged rats to study for Alzheimer’s disease (AD) model and administering arecoline 10 mg / Kg for about six days shows improvement of the cognitive performance within elderly rats [28]. The result established that arecoline has a definite pharmacological role in correcting some symptoms of AD. Further studies have shown that arecoline has positive effects to enhance the memory of AD patients [29].

Effect on cardiovascular system – AN has antihypertensive and diuretic properties. As per Ayurvedic consideration, AN is mostly regarded as an herbal medicine. In addition to its antihypertensive action, AN has lipid lowering effect. Chewing the AN / betel nut accelerates heart rate, enhances body temperature, and frequently causes heavy sweating (due to cholinergic stimulation of parasympathetic neurons) and subsequently promoting blood circulation. Studies also have established that it has potent hypotensive activity [30].

Miscellaneous effects – It has been identified that arecoline in AN is naturally occurring potent inhibitor of α – glucosidase. AN has been used for a long time as a folk medicine to treat postprandial hyperglycemia in diabetic patients [31,32]. Afterward it is pointed out that the component is arecoline. In vitro analysis has shown that the extract can inhibit both enzymes, α-amylase and α – glucosidase which are associated with type – 2 diabetes and hyperglycemia. Additionally, arecoline at 50 µg / ml dose is able to promote survival and growth of glial cells in vitro also can repair severe peripheral nerve damages. As a folk remedy, AN can treat beriberi and low back pain too [33]. Besides those ailments, AN is often used to control edema, curing jaundice, and exerting sedative actions [24].

Effect on endocrine and reproductive systems – Studies have shown that the major effective ingredient arecoline can increase the release of thyroid hormone (T3 and T4) while suppressing the thyroid stimulating hormone (TSH). At high doses arecoline activates hypothalamic-pituitary-adrenal (HPA) axis quite identical to the stress response. The regular use of AN often produces hypothyroidism. Additionally, regular use of AN enhances testosterone level. It also causes an increase of sialic acid in seminal vesicles and fructose in coagulating glands and promotes androgen receptor expression in prostate which leads to hyperplasia or hypertrophy creating enlarged prostate problem. Further, AN significantly lowers the sperm motility, sperm count even abnormalities which afterward ends up in infertility. But in case of chronic female chewers, the level of female hormones estradiol and progesterone stays unaltered [17].

Antiinflammatory and analgesic effects – AN exhibits analgesic, anti-inflammatory, and antioxidant activities. The analgesic action is mediated due to the involvement of central and peripheral pathways. At 500 mg / Kg dose the action is comparable to pentazocine (synthetic opoid activating κ – and µ – opioid receptors, acting as analgesic for moderate to severe pain) [34]. But its antiinflammatory action is mediated via reducing the release of prostaglandins, leukotrienes, histamines, IL-6, IL-1, also subsequently decreasing the expression of cyclooxygenase – 2 (COX-2) and increasing antiinflammatory cytokine IL-4 [34]. However, AN induces the production of PGE-2 and 6-keto-PGF1 from gingival keratinocytes (GK) and simultaneously lowers the level of intracellular glutathione promoting inflammation contributing to sub-mucous fibrosis and even oral cancers [35]. Prostaglandin endoperoxidase synthetase, an intracellular enzyme induced by AN has a significant role in carcinogenesis owing to the increased production of peroxyl radicals, malonaldehyde which is mutagenic. Eventually, it also activates carcinogenesis in extrahepatic tissues [36].

Effect on blood – AN induces platelet aggregation owing to the activation of phospholipase C and mobilization of intracellular Ca++ and subsequent production of thromboxane A2 leading to the release of growth factors thereby enhancing fibrogenesis which plays a significant role on cardiovascular system [37]. Further AN increases TNF – α and IL-1 secretion by the mononuclear cells dose dependent and time dependent way. Interestingly, the effect is blocked by curcumin / turmeric [38]. Additionally, AN is cytotoxic to splenocytes that lowers the production of IFN – γ and IL-2 but not IL-4. It suppresses the activation of T – cells and production of cytokine Th-1 following increased level of oxidative stress which interferes with immune system [39].

Effect on fetus – There are few adversarial effects noticed among the expected mothers who are the AN chewer. The fetuses show lower weight, length and often cause preterm birth. At low doses AN causes dilation of umbilical vessels by eNOS whereas at high concentration exerts arrest of endothelial cell differentiation also dysfunction as well. The effect is possibly due to arecoline [40]. Perinatal exposures to AN inflict harmful effects of carcinogenesis since actions of – SH enzymes, malonaldehyde, and cytochrome P-450 level becomes altered [41].

Toxicity: A large number of scientific data indicates that AN induces toxic effects either at large doses or in the case of chronic uses. The effects lead to dyspnea, tachycardia, palpitations, hypotension, tightness in chest, vomiting, nausea, dizziness, colic pain in abdomen, or occasionally myocardial infarction. Fortunately, the effects are mostly transient, and the patients recover quickly. In many parts of the world AN is considered to be an additive substance irrespective of age. Besides acting as a carcinogen to oral cavity, esophagus, pharynx, liver, or uterus it affects all the organs. The effects are due to alkaloid, arecoline. It increases heart rate, enhances blood pressure, inhibits GABA, and damages neurons without affecting memory or level of concentration. Chronic consumption produces hypothyroidism, prostate hyperplasia, infertility, and vitamin D deficiency. In addition to those there are more adversarial roles exhibited by AN [17].

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