DARK Classics in Chemical Neuroscience: Arecoline

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DARK Classics in Chemical Neuroscience: Arecoline Andrey Volgin, Alim Bashirzade, Tamara Amstislavskaya, Oleg Yakovlev, Konstantin Demin, YingJui Ho, Dongmei Wang, Vadim Shevyrin, Dongni Yan, Zhichong Tang, Jingtao Wang, Mengyao Wang, Erik Alpyshov, Nazar Serikuly, Edina Wappler-Guzzetta, Anton Lakstygal, and Allan Kalueff ACS Chem. Neurosci., Just Accepted Manuscript • DOI: 10.1021/acschemneuro.8b00711 • Publication Date (Web): 21 Jan 2019 Downloaded from http://pubs.acs.org on January 22, 2019

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ACS Chemical Neuroscience

DARK Classics in Chemical Neuroscience: Arecoline Andrey Volgin1, Alim Bashirzade1, Tamara Amstislavskaya1, Oleg Yakovlev2,3, Konstantin Demin2,3, Ying-Jui Ho4, Dongmei Wang5, Vadim Shevyrin6, Dongni Yan5, Zhichong Tang5, Jingtao Wang5, Mengyao Wang5, Erik Alpyshov5, Nazar Serikuly5, Edina Wappler-Guzzetta9, Anton Laksygal3,12 and Allan Kalueff5,6,7,8,9,10,11,12,13 1Scientific 2Institute

Research Institute of Physiology and Basic Medicine, Novosibirsk 630117, Russia

of Experimental Medicine, Almazov National Medical Research Centre, St. Petersburg

194156, Russia 3Institute

of Translational Biomedicine, St. Petersburg State University, St. Petersburg 199034,

Russia 4Department 5School 6Ural 7The

of Psychology, Chung Shan Medical University, Taichung, Taiwan

of Pharmacy, Southwest University, Chongqing 400700, China

Federal University, Ekaterinburg 620002, Russia International Zebrafish Neuroscience Research Consortium (ZNRC), Slidell, LA 70458,

USA 8Anatomy

and Physiology Laboratory, Ural Federal University, Ekaterinburg 620002, Russia

9ZENEREI

Research Center, Slidell, LA 70458, USA

10Laboratory

of Biological Psychiatry, Institute of Translational Biomedicine, St. Petersburg

State University 199034, St. Petersburg, Russia 11Group

of Bioscreening, Institute of Experimental Medicine, Almazov National Medical

Research Centre, Ministry of Healthcare of Russian Federation, St. Petersburg 194156, Russia 12Russian

Scientific Center of Radiology and Surgical Technologies, Ministry of Healthcare of

Russian Federation, St. Petersburg 197758, Russia 13Laboratory

of Translational Biopsychiatry, Scientific Research Institute of Physiology and

Basic Medicine, Novosibirsk 630117, Russia Funding source: The research was supported by the Russian Foundation for Basic Research (RFBR) grant 16-04-00851 to А.V.K. K.A.D. is supported by RFBR grant 18-34-00996 and Special Rector’s Fellowship for SPSU PhD students. Funders had no involvement in the study design, data collection or analysis, and MS preparation. Conflict of interest: Authors declare no conflicts of interest.

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Abstract

Arecoline is a naturally occurring psychoactive alkaloid from areca (betel) nuts of the areca palm (Areca catechu) endemic to South and Southeast Asia. A partial agonist of nicotinic and muscarinic acetylcholine receptors, arecoline evokes multiple effects on the central nervous system (CNS), including stimulation, alertness, elation and anxiolysis. Like nicotine, arecoline also evokes addiction and withdrawal symptoms (upon discontinuation). The abuse of areca nuts is widespread, with over 600 million users globally. The importance of arecoline is further supported by its being the world’s forth most commonly used human psychoactive substance (after alcohol, nicotine and caffeine). Here, we discuss neuropharmacology, pharmacokinetics and metabolism of arecoline, as well as social and historical aspects of its use and abuse. Paralleling clinical findings, we also evaluate its effects in animal models and outline future clinical and preclinical CNS research in this field.

Key words: Arecoline, animal models, clinical effects, nicotine-like action, alkaloid

List of abbreviations: CNS – the central nervous system, CTM - Chinese Traditional Medicine, EEG – Electroencephalographic, GABA - gamma-aminobutyric acid, GAT-1 - GABA transporter 1, IARC - International Agency for Cancer Research, ROS – reactive oxygen species, SOD superoxide dismutase


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1. INTRODUCTION. A BRIEF HISTORY OF ARECOLINE Arecoline (N-methyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester, Fig. 1) is a naturally occurring psychoactive alkaloid from the areca (betel) nut of the areca palm (Areca catechu) endemic to Southeast Asia, the East African seaboard and the Western Pacific1, 2. Historically prevalent in this region, chewing areca nuts is also practiced by Asian immigrants in other countries2, 3. With over 600 million users of areca nut products globally, arecoline (1) is critically important, representing the world’s forth most commonly used human psychoactive substance (after alcohol, caffeine and nicotine)4. The major constituents of areca nut are polysaccharides (~20-25%), polyphenols (including flavonoids and tannins, 10-30%), fibres (~10-15%), fats (~10-15%), proteins (~5-10%) and alkaloids (~0.3-0.7%), including arecoline1, 5. Areca nuts are usually consumed by chewing for 5-20 min without swallowing. The history of areca nut consumption counts millennia, as these nuts became symbolic of the culture of some oriental nations6. The earliest evidence of areca nut use, found in Thailand, is dated around 9000 AD2. Areca nuts are also mentioned as medicines in Tun-huang manuscripts of Northwest China2. Early Polynesians, which colonized the Southwest Pacific 3600 years ago, brought areca nuts with them2. More recently, the areca nut use has been widely spreading. For eample, in India, areca nuts and leaves are used in Buddhist ceremonies as offerings, and are often chewed to freshen breath7. Various preparations of areca nuts often combine them with the leaf of the Piper betle and slaked lime, usually referred as “betel quid”8 (Piper betle is the tropical vine belonging to the Piperaceae family, which also includes pepper and kava9). With the emergence of commercial areca nut products several decades ago, this market has grown markedly in sales and expanded globally. In Vietnam, a wedding cannot occur without areca nuts, as it is customary for the groom’s family to visit the bride’s home with areca nuts, to officially ask permission10. Bangladeshi pregnant women regularly chew areca nuts to prevent morning sickness11. Finally, Asian immigrants have brought areca nuts to the Malay peninsula, Southeast Africa and Europe12, collectively contributing to the widespread use and abuse of arecoline and areca nuts globally. ACS Paragon Plus Environment

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2. CHEMISTRY Although the first attempts to assess active ingredients of areca nuts were made in 182213, currently more than 60 active compounds have been identified, including arecoline, arecaidine, guavacoline, guavacine (Fig. 1) and 12 other alkaloids with basic heterocyclic piridine or piperidine structures (three of which, arecatemines A-C, have been isolated most recently)1, 14. Arecoline is a key, biologically active alkaloid of areca nuts, with its content totaling ~0.3-0.6%1. Arecoline isolation from plants was first reported in 1888 by E. Jahns, a German pharmacist from Göttingen1, 15. Other related alkaloids - arecaidine, guavacoline and guavacine have also been identified at the same time13, 15, 16. Arecoline is a colorless oily alkalinic liquid which is soluble in water, ethanol, ether and chloroform13, 15. Its hydrobromide salt is colorless water-soluble crystals with the melting temperature of 167–168 oC13,

15.

Boiling or pressure

treatment with hydrochloric acid, as well as heating with alkaline, result in arecoline hydrolysis at its ester group, generating arecaidine13, 15 which is also present in areca nuts. This compound (2, Fig. 1) contains carboxyl group whose esterification by methanol produces arecoline. 3. SYNTHESIS Arecoline can generally be extracted from plant material or produced synthetically. The first large-scale extraction of arecoline from plants, reported in 192717, was based on arecoline extraction in diethyl ether from powdered areca nut mass treated with water solution of potassium hydroxide. The path of chemical synthesis of arecaidine and arecoline was initially proposed by Jahns13. This synthesis starts from potassium salt of nicotinic acid and iodomethane, which produce methyliodide of methyl nicotinate when heated to 150oC. Its subsequent reduction with tin in hydrochloric acid produces a mixture of N-methylhexahydronicotinic acid and Nmethyltetrahydronicotinic acid (arecoline) separated by their different solubility in chloroform. However, the final chemical structure of arecoline, including the exact position of its double bond in the ring, has been established later using directed synthesis (Fig. 2)18. First, N-(3,3diethoxypropyl)-3,3-diethoxy-N-methylpropanamine (5) is obtained through the condensation of 3-chloro-1,1-diethoxypropane with methylamine in benzene heated in an autoclave. Isolated after ACS Paragon Plus Environment

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distillation, product 5 (following treatment with hydrochloric acid) then forms a cycle, generating N-methyl-1,2,5,6-tetrahydropyridine-3-carbaldehyde (6)18. The generated aldehyde is further converted to the oxime by mixing with hydroxylamine. The reaction of oxime with thionyl chloride produces nitrile which is then converted into arecaidine after a two-stage hydrolysis by heating with concentrated hydrochloric acid and then with barium hydroxide. Arecaidine can be esterified into arecoline18. The peak of interest in the development of new methods for arecoline synthesis occurred in the 1940-1950s. A simpler modification of the method of synthesis described above has been suggested by Mannich, and utilizing heating methylamine hydrochloride mixed with formalin, water and acetaldehyde to 70o C for 15 h19. The resultant aldehyde (6) turns into oxime after treatment with a solution of hydroxylamine in methanol. Refluxing the oxime with acetic anhydride leads to nitrile, which is converted to arecaidine and then arecoline. The latest development of this method allowed increasing the final yield of arecoline20. As the first stage of this process, sodium acetate is used as a catalyst in the condensation of acetaldehyde, methylamine, and formaldehyde. The generation of oxime has also been simplified, instead of methanolic solution of hydroxylamine utilizing an aqueous solution of hydroxylamine hydrochloride and sodium acetate. Hydrolysis of nitrile and estherification of arecaidine are performed in one step by heating the nitrile with concentrated sulfuric acid in a comparatively small quantity of methanol. Another method of arecoline synthesis (Fig. 2) involves ethyl acrylate reaction with methylamine

autoclaved

in

absolute

ethanol21,

generating

diethyl

3,3'-

(methylazanediyl)dipropionate (7). Its subsequent cyclisation with sodium amide in xylene produces ethyl N-methyl-4-oxopiperidine-3-carboxylate (8), which is then electrolytically reduced in water solution of sulfuric acid to 4-hydroxy-N-methylpiperidine-3-carboxylic acid (9). Its esterification and reaction of the obtained ester (10) with phosphoroxychlorid in refluxing xylene generates arecoline.


6

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Finally, the idea of arecoline synthesis from nicotinic acid remains rather popular. The most common modern approach (Fig. 2) involves nicotinic acid methyl ester (11) which is heated in toluene or acetone solution with methyl iodide to generate quaternary salt (12)22-24. After isolation, quaternary salt is next reduced by metal hydrides (e.g., sodium (or potassium) borohydride or sodium tris(acetoxy)borohydride)22-25 in cooled absolute methanol or in water under a benzene layer, to generate arecoline. This process can also be performed in toluene with triethylamine without isolating the intermediate quaternary salt, using methyl iodide (or a cheaper sulfuric acid methyl ester) to obtain it25. The reduction of the quaternary salt is provided by sodium borohydride or sodium tris(acetoxy)borohydride25. 4. PHARMACOLOGY For the purpose of this review, we will focus our discussion on arecoline as a key, biologically active ingredient of areca nut extracts. Numerous other alkaloids from areca nuts are beyond the scope of this paper. Although arecoline and its metabolites have multiple effects on a wide range of target organs26-28, here we discuss neuroactive properties of arecoline, pertinent to the Dark Classics series of this journal. Arecoline readily crosses the blood brain barrier and has multiple psychoactive properties, acting as a non-selective partial agonist of muscarinic and nicotinic acetylcholine receptors at their α4/β2 and α6/β3 subunits4. Additionally, arecoline also actibates α7 subunits of nicotinic receptors when co-applied with an allosteric modulator (e.g., PNU-120696)4. Arecaidine, the main metabolite of arecoline, potently inhibits the gamma aminobutyric acid (GABA) and beta-alanine uptake, ans structurally resembles the nipecotic acid, a GABA transporter I (GAT-1) antagonist29. Albeit enhancing inhibitory effects of GABA, arecaidine, unlike the nipecotic acid, does not affect glycine uptake29. Pure arecoline is an oil, and is usually administered as water-soluble salts30. They have long been used as ganglionic stimulants, laxatives, antihelmintics and parasympathomimetic drugs, especially in veterinary practice31. Due to high affinity to acetylcholine receptors, arecoline is relevant for studying Alzheimer’s disease and its treatments32. In humans, depending on the dose and individual responsivity, arecoline and chewing areca nuts produce similar cognitionACS Paragon Plus Environment

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enhancing, psychostimulant, euphoric, pro-arousal, aphrodisiac, anxiolysis and sedative effects4, 33

(Table 1). Arecoline has a wide spectrum of pharmacological effects beyond CNS, modulating

cardiovascular, digestive and endocrine systems as well as evoking a wide range of somatic effects, such as hypersalivation, hypotension, vertigo, miosis, tremor and bradycardia (Table 1)34. Acute arecoline intoxication can be reduced by atropine or scopolamine treatment. Addiction is commonly associated with arecoline use. For example, areca nut chewing induces positive subjective effects, including relaxation, better concentration and euphoria (Table 1). Like with other drugs of abuse, withdrawal syndrome has also been reported clinically, causing mood swings, anxiety, irritability and insomnia following arecoline discontinuation8. Acute psychoses with hallucinations, grandiosity and persecutory delusions are occasionally observed in heavy

habitual

areca

nut

users,

especially

predisposed

to

a

mental

illness34.

Electroencephalographic (EEG) analyses show widespread cortical desynchronization following arecoline exposure, supporting its arousal-like pharmacological profile35. Areca nut use-induced extrapyramidal syndrome, presenting as rigidity, bradykinesia and jaw tremor36 and seizures (likely due to GABA inhibition)35 are also described in the literature. Both arecoline and arecaidine promote the release of catecholamines from chromaffin cells, elevating plasma norepinephrine and epinephrine, hence causing sympathetic activation35. Finally, arecoline attenuates antioxidant defense in neurons by decreasing their glutathione levels and the activity of superoxide dismutase, as well as by increasing the expression of proapoptotic proteins (cytochrome C, Bax, caspases 3 and 9) and lowering the expression of the antiapoptotic protein Bcl-233. In oral cavity, arecoline undergoes nitrosation and produces cancerogenic Nnitrosamines37, which has led to its classification as a Group 1 (carcinogenic to humans) agent by the International Agency for Cancer Research (IARC)38. Animal (experimental) models are indispensable tools for studying CNS pathogenesis and drugs39, 40. In rodents, a single intraperitoneal (i.p.) administration of arecoline dose-dependently inhibits locomotor activity and shortens ethanol-induced loss of the righting reflex. Arecoline alleviates ethanol intoxication in mice, reducing their ethanol-induced sleep41, and potentiates ACS Paragon Plus Environment

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mouse hyperactivity and behavioural sensitization induced by morphine42. Other pharmacological effects of arecoline in rodents are briefly summarized in Table 2, including antidepressant-like action43, hyperactivity44, reduced conditioned avoidance45 and amnesia46. Arecoline produces discriminative stimulus (DS) control in rats in dose-dependent manner, likely mediated through central M-receptors47, which are involved in both depression- and anxiety-like behavior and also regulate dopaminergic signaling in the ventral tegmental area and nucleus accumbens48. New preclinical models also continue to emerge, further advancing translational research of arecoline-related substances. For example, the zebrafish (Danio rerio) has recently emerged as a new model organism in neusroscience research and CNS drug discovery49. Long-term arecoline treatment of zebrafish embryos evokes dose-dependent general developmental retardation50, whereas acute exposure impairs embryonic development and causes hypolocomotion51. In adult zebrafish, acute exposure to both arecoline and the areca nut extracts evokes highly reproducible dose-dependent anxiolytic-like behavior with stereotypic peripheral ‘surface’ swimming along the walls of the tank (AVK and TGA labs pilot studies), strikingly resembling anxiolytic and stimulant effects of nicotine in these fish52, 53. Notably, these effects are blocked by antimuscarinic drugs atropine and scopolamine, implicating central muscarinic receptors in these responses. Together, these findings support the growing utility of novel model organisms like zebrafish to study CNS effects of arecoline, also suggesting similar, evolutionalily conserved CNS effects of arecoline in humans, mammals and fish models. Furthermore, arecoline evokes robust changes in skin coloration in some species. Since skin color pigment cells (melanocytes) are controlled by neuroendocrine mechanisms, such responses may predict CNS activity of the drugs54-56. For example, norepinephrine regulates melanophore aggregation (skin darkening, via β-adrenoceptors) and dispersion (paling, via αadrenoceptors) in reptiles, amphibians and fish55, depending on species and receptor type57. Cholinergic drugs also potently modulate melanoprhore aggregation58,

59.

Arecoline evokes

melanosome dispersion (skin paling) following epinephrine- or norepinephrine-induced aggregation in Bathygobius58, whereas its administration in plaice60 and zebrafish (AVK lab pilot ACS Paragon Plus Environment

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study) induces immediate skin darkening, consistent with cholinergic profile of this drug in vivo, and supporting the uility of aquatic models for skin coloration-based phenotyping of arecoline and related drugs. Further studies are neeed to more fully dissect between nicotinic, muscarinic and other putative CNS effects of arecoline in vivo. 5. DRUG METABOLISM AND PHARMOKINETICS Metabolist of arecoline and other areca nut alkaloids is complex and poorly understood2628.

Most fully it has been examined by the ultra-performance liquid chromatography/time-of-flight

mass spectrometric analysis of mouse urine, reporting eleven metabolites of arecoline and arecaidine (Fig. 3), as well as some additional unidentified metabolites8. The three main pathways of arecoline metabolism include its hydrolysis to arecaidine (2), N-oxidation to arecoline N-oxide (13), and mercapturic acid conjugation to arecoline mercapturic acid (20)8 (Fig. 3). The conversion of arecoline to arecaidine is mediated by carboxylesterase8, arecaidine and arecoline N-oxide, recent studies of rat urine

61. 62

In addition to formation of have reported metabolizing

arecoline into guavacoline by N-demethylation mediated by cytochrome P450, as well as hydrogenation of arecoline double bound to form N-methylnipecotic acid methyl ester. However, the formation of arecoline mercapturic acid (20) has not been detected. Generation of Nmethylnipecotic acid methyl ester may be due to metabolism of arecoline mercapturic acid (20)8. It is also likely that arecoline metabolites are formed before its hydrolysis into arecaidine, which also undergoes N-oxidation and mercapturic acid conjugation (metabolites 14, 19)8. Arecaidine also participates in double-bond reduction, generating N-methylnipecotic acid (15), that conjugates with glycine to form N-methylnipecotylglycine (16). Arecaidine also conjugates with glycine and glycerine to form arecaidinylglycine (17) and arecaidinylglycerol (18)8. Most recent studies of arecoline metabolites in rat plasma and urine following oral administration of areca nut extract63 generally support these findings, but have also detected arecoline N-oxide dimer, whose chemical structure is currently unlear. Analyses of areca nut metabolism in human saliva by liquid chromatography–tandem mass spectrometry show arecoline metabolizing into arecaidine and N-methylnipecotic acid 25–30 min ACS Paragon Plus Environment

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after areca nut chewing64. While some production of arecaidine and mercapturic acid occurrs in saliva, liver and kidney are more important for arecoline/areacidine metabolism8. However, the oxidation of arecoline into arecoline N-oxide by aflavin-containing monooxygenase8, 65 implicates kidneys (robustly expressing these enzymes), rather than liver cytochromes P450, in arecoline metabolism in humans. In rats, arecaidine (7–13%), arecoline N-oxide (7–19%) and Nmethylnipecotic acid (14–30%) are the main urine metabolites of arecoline8. Unchanged arecoline comprises 0.3–0.4%; arecaidine is excrered as unchanged substance (15–23%) and Nmethylnipecotic acid (15–38%)8. To better undertand arecoline pharmacology and toxicology, analyses of arecoline metabolites may be higly relevant8. In rats, its key metabolite is arecoline N-oxide, excreted unchanged (50%), as other N-oxide derivatives (20%), mercapturic acid and its metabolites (30%), as well as a carboxaldehyde derivative (produced directly from arecoline N-oxide)65. Various nutrosamines, including N-nitrosoguvacoline, 3-(methylnitrosamino)propionitrile and 3-(methylnitrosamino)propionaldehyde26-28, have been thought to form from areca alkaloids in the mouth, causing cancer in humans. However, rat experiments found no cancerogenic effects of these substances65, 66, raising the question as for whether areca nut alkaloids exert such actions67 However, recent findings show that arecoline N-oxide induces oxidative stress, cytotocicity, gentotoxicity, fibrose pathogenesis and oncogenesis66, 68. As arecoline N-oxide is one of areca nut alkaloids14, this necessitates further studies into pathobiological effects of N-oxide derivatives of arecoline and arecaidine. In urine, arecoline, arecaidine and arecoline N-oxide metabolize into conjugates of mercapturic acid8 which may interact with DNA and proteins, triggering toxicity that merits further scrutiny69. Oral administration of arecoline for 7 days increases the activity of rat hepatic enzymes CYP2B, 2E1, 2D, 3A, 2C and 1A270. The hepatic CYP2E1 induction generates ROS (reactive oxygen species) through the reduction of molecular oxygen to water by NADH- and NADPHdependent processes. ROS release induced by CYP2E1 play an important role in hepatic oxidative damage70. In the rat liver, arecoline elevates the levels of alanine aminotransferase, aspartate ACS Paragon Plus Environment

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aminotransferase, decreases superoxide dismutase (SOD) and other antioxidant enzymes70. Finally, the effects of arecoline on adipogenic differentiation (adipogenesis), lipolysis, and glucose uptake by fat cells was evaluated in mice. Arecoline inhibited adipogenic differentiation, induced adenylyl cyclase-dependent lipolysis, and interfered with insulin-induced glucose uptake, which may lead to hyperlipidemia and hyperglycemia/insulin-resistance71. 6. SOCIETAL AND ECONOMIC RELEVANCE With a long history of medicinal use, arecoline is a commonly used traditional medicine in Asia. Areca nut products have long been utilized as therapies in Chinese Traditional Medicine (CTM) and Ayurveda, especially as antihelmintics, aphrodisiacs and painkillers31. Its current medicinal uses include laxative and antihelmintic therapy72, also finding applications as antihelmintic and anti-infection agent in veterinary73. Since 1953, arecoline has officially been included in Pharmacopoeia of China74. The global geographical, social, gender and age distribution of areca nut consumtion is unique and differs markedly from any other known drug of abuse. First, despite active global migration, arecoline/areca nut consumption remains a predominantly Asian phenomenon (Fig. 4). Indeed, to the Indians, Malayans and Indonesians, areca nut chewing is as familiar as chewing gum to the Americans6. Women are 2-6 times more likely to chew Areca nuts than men (except India and Thailand, where both sexes equally practice it)2. Moreover, the abuse of areca nuts particularly targets multiple vulnerable groups of the population. For example, the most susceptible group to arecoline dependence is socioeconomically vulnerable blue-collar workers and uneducated people in urban areas75. The other group of abusers includes developmentally vulnerable adolescents, who begin to chew areca nuts out of curiosity, or obtain from peers76 for better concentration on work or study, and then become addicted. There is also an intergenerational parental effect, as consumption rises in children if marriage of their parents was unsuccessful, of a lower social status, or if either parent chews areca nuts77. Another vulnerable group of abusers is pregnant women, as areca nut chewing lowers drowsiness, fatique and sickness, also improving concertration11. Furthermore, while women often ACS Paragon Plus Environment

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consume areca nuts during pregnancy, their offspring forms yet another (passive) group of arecoline consumers78, as most women are unaware of fetal dependence, CNS effects and other health risks related to arecoline abuse76. Presently, ~10-20% of the global population consumes areca nuts79. As a potent stimulant, arecoline may also be abused by athlets, and has received some attention from sport regulators. For example, the National Olympic Committee of Solomon Islands prohibits their consumption by athletes80. The internet has dramatically boosted the consumption of areca nuts, as suppliers of the raw product can be found for export, and anyone can buy areca nuts online81. In Asia, the national and regional companies producing areca nuts often use national recepies and multiple additives81, making their regulation extremely difficult82. Presently, arecoline and areca nut consumption is not generally controlled globally, although Australia prohibits their sale, and the United Arab Emirates outlaw them due to migrant workers importing this habit from Asia83. Despite being a Group 1 carcinogen by IARC, areca nuts are commonly sold as an unregulated agricultural product, often with no labels (to warn consumers about potential health risks), special taxation or pricing structure84. The world areca nut harvested area in 2015 was 847 000 hectars81, 84. In the USA, the sale and use (chewing and consumption) of areca nuts is not regulated as either food or drug, despite its rising availability81, 84. Although the use of areca nuts is discouraged in Western countries because of carcinogenic and dysesthetic effects85, commercially-manufactured non-perishable forms of areca nuts have been marketed, with the industry worth reaching hundred million US dollars82. Recently, however, some Pacific countries take steps towards limiting areca nut consumption84. For example, the Marshall Islands ban areca nut import, distribution or sale84. There is also a view that countries with high areca nut consumtion (Fig. 4) need special tax policies as a fiscal tool to regulate and, eventually, curb arecoline use86. 8. CONCLUDING REMARKS Arecoline use continues to spread globally (Fig. 4), despite overt negative side effects and serious health risks, as well as abuse potential and robust CNS responses. Nevertheless, arecoline ACS Paragon Plus Environment

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and related compounds also have a considerable potencial in medicine, with multiple positive neural effects (Table 1) that can be applied in neurology and psychiatry. Thus, futher translational research is needed to focus on molecular mechanisms of arecoline pharmacology in both clinical and animal models, and to develop low-risk analogs of this drug for future clinical uses. For instance, chemical derivatives of arecoline that may enhance cognitive effects (e.g., drugs with muscarinic M1-receptor seletivity), but have fewer side effects, may be developed. Another potentially promising line of research is using arecoline-like compounds to treat nicotine addiction (due to their cholinergic action), as well as abuse of other substaces, such as alcohol or cocaine (due to potential secondary action on the GABAergic and/or other neurotransmitter systems). Collectively, this calls for more research into arecoline pharmacology at multiple levels of systems biology, as well as further efforts to determine its legal status, based on careful analyses of public health risks, socioeconomic impacts, and potencial therapeutic clinical applications.

Conflict of interest: None

Funding source: The research was supported by the Russian Foundation for Basic Research (RFBR) grant 16-04-00851 to А.V.K. K.A.D. is supported by RFBR grant 18-34-00996 and Special Rector’s Fellowship for SPSU PhD students. Funders had no involvement in the study design, data collection or analysis, and MS preparation.

Acknowledgement: The authors thank Mrs. Lyudmyla E. Kalueva for providing an artwork (areca palm image) for this paper.

Author Contributions: All authors have extensively contributed to this manuscript. A.V.K., T.G.A. and E.J.H. conceived and coordinated the project, with conceptual input from V.A.Sh. All authors have participated in data collection, analysis and interpretation. A.D.V. and V.A.Sh drafted the manuscript. K.A.D., A.V.K., T.G.A., E.J.H. and V.A.Sh. participated in critical review ACS Paragon Plus Environment

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and further revision of the manuscript. All authors contributed to critical discussions and finalizing the manuscript before submission, and have approved its final form.


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Table 1. A brief summary of clinical effects of arecoline and areca nut consumption

Effects Mental

Acute effect

Long-term use, addiction

Sense of well-being, euphoria, alertness,

Improved long-term recall in a selective reminding

increased work capacity1, dizziness35,

task89 (but see no effects in other cognitive tasks),

psychoses87, improved cognitive abilities 88

psychomotor activation and improved mood90. Withdrawal from arecoline evokes dysphoric mood, anxiety and insomnia78

Tremors91, Attenuated sympathetic skin

Widespread cortical desynchronization (indicating

response92; gradually suppressed vagal activity93

arousal)35, dose-dependent promotion of REM sleep94

Сardio-

Rapid skin hyperthermia92, supraventricular

Tachycardia, hypertonia, sweating and fever 96,

vascular and

tachycardia95, lowered diastolic component due

atherogenesis, coronary spasms, cardiac arrhythmias34

respiratory

to the peripheral cholinergic effect, elevated

Neurological

systolic component, chest tightness, asthma34 Endocrine and

Elevated testosterone, plasma norepinephrine

Type II diabetes, hyperlipidemia, attenuated insulin-

metabolic

and epinephrine35, T3, T4 and suppression of

induced glucose uptake71, lower cholesterol

thyroid stimulating hormone34

absorption, increased fibrogenesis, vitamin D deficiency, lipolysis in adipocytes, increased serum transaminases and alkaline phosphatase34

Other

Upset stomach, diarrhoea, vomiting, increased

Risks of cirrhosis and liver cancer97, oral submucous

gastrointestinal motility (due to stimulation of

fibrosis, premalignant lesions, leukoplakia3, gastric

colonic muscarinic M3 receptors),

ulcers98

hypersalivation34


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Table 2. Summary of physiological effect of arecoline in rodents Behavior

Somatic effects

Endocrine functions

Antidepressant activity43, motor

Sister-chromatid exchanges in bone-

Hypoglycemia, elevated

restlessness44, reduced conditioned

marrow cells103, increased level of

glycogen level108, hypothyroid

avoidance45, amnesia46, reduced

hepatic CYP2E1 protein104, elevated

condition in metabolic

exploration46, impaired spontaneous

cGMP

the

stress109, inhibition of pineal-

locomotion99 and other behaviors 100,

cerebellum and the cerebrum105,

testis function110, stimulation

101,

arrested splenic lymphocyte cell

of testosterone production by

impairment of the righting reflex41 and

cycle and induced apoptosis106,

acting directly on Leydig

sleep induced by phenobarbital102,

direct muscarinic effect on the renal

cells111.

potentiated morphine-evoked

tubules (saluresis)107

reduced ethanol-induced

concentrations

of

hyperactivity and behavioral sensitization42


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Figure 1. Chemical structure of arecoline and related compounds: arecaidine, guavacoline and guavacine commonly naturally are occurring in areca palm (center, the artwork is provided by L.E.Kalueva and owned exclusively by AVK).

O

O O

OH

N

N

Arecoline (1)

Arecaidine (2) O

O

OH

O N H

N H Guavacoline (3)

Guavacine (4)


18

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Figure 2. Synthesis of arecoline (1, inset), including directed synthesis (A) and synthesis from ethyl acrylate and methylamine or nicotinic acid methyl ester (B).

A O

NH2 Cl

HCl

N

O

O

O O

OH

H

O

O

N

N

N

O

O

5

Arecoline (1)

Arecaidine (2)

6

O

B O

NH2

O

O

O

O

N O

O O

O

O

N

CH3I

11

N 8

7

9

O O

N

OH

N

O O

OH O

O

KBH4, or NaHB(OAc)3

I 12

OH O

N

Arecoline (1)


POCl3

O N 10

19


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Figure 3. Arecoline metabolic pathways in the mouse. Urinary metabolites include arecoline (1, inset), arecaidine (2), arecoline N-oxide (13), arecaidine N-oxide (14), N-methylnipecotic acid (15), N-methylnipecotylglycine (16), arecaidinylglycine (17), arecaidinylglycerol (18), arecaidine mercapturic acid (19), arecoline mercapturic acid (20), and arecoline N-oxide mercapturic acid (21)8

O

H N

H N

OH

O

S

O

O

O O

O

O

O

N

O O

N

O OH S

O O

N N

1

13

21

20

O OH O

N

O

O OH

OH

14

N H

N

N H N

O

O

2

O

N 15

OH O

16

OH S

O OH 19

N

N H

OH

O

N

O

OH

O O

N

OH O

17

18


20

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Figure 4. Global consumption (top panel) and production (inset, tons) of areca nuts (red – high, orange – low, yellow – immigrants only)112. Blue color denotes countries (Australia and UAE) currently banning areca nut consumption. As shown in the inset, in 2015, India has produced the majority of areca nut products (578 000 tons/year), flowed by China (121 000 tons/year), Indonesia (90 000 tons), and other countries in the regions.


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DARK Classics in Chemical Neuroscience: Arecoline

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