The alkaloid Arecoline is a cholinergic agonist (Acetylcholine effects)
Arecoline is an alkaloid-type natural product found in the areca nut, the fruit of the areca palm (Areca catechu). It is an oily liquid that is soluble in water, alcohols, and ether. Other substances contained in the nut are:tannin, gallic acid, nipecotic acid, a fixed oil gum, a little terpineol, lignin, various saline substances and three alkaloids, arecaidine , guvacoline(or norarecoline) and guracine. The total alkaloid content of a nut can reach the 0,45% the most abundant is arecoline which (with arecaidine) is about 15 times more potent than guvacoline and guracine. In a nut there are about 105,45 ng/mg(nut) of arecoline.(Smart Drugs)
Areca catechu is the areca palm or areca nut palm, (Malay: Pinang), a species of palm which grows in much of the tropical Pacific, Asia, and parts of east Africa.
This palm is often erroneously called the Betel tree because its fruit, the areca nut, is always chewed along with the betel leaf, a leaf from a vine of the Piperaceae family (Piper Betel).
Areca nuts are grinded and mixed with lime (Calcium Hydroxide) and Piper Betel leaves to form a little ball called "Betel quid". This is chewed or kept in the mouth to allow the slow release of the active principles ( mainly arecoline). Indeed arecoline due to its lipophyllic characteristics readily enters brain and intracellular space to fulfil its effects.
The adding of tobacco to the chewing mixture is a relatively recent introduction, because it was introduced from the American continent in colonial times. The practice of chew the Areca nut probably comes from a region of Malay called Pinang which just means: "Areca nut". (Wikipedia. Keywords: Arecoline, areca nut, Betel, Areca Catechu).
The use of Areca nuts is common in the asiatic populations ( from West Pacific to South Asia)and in the asiatic communities moved to Europe and USA. In the second case the use seems to be linked to religious reasons. The most active consumers of Areca nuts are the British Hindu communities (up to 80% of adolescents and adults), instead Sikh and Muslim (indian and pakistani) groups don't use Betel quid very much.
About 200 millions people commonly chew Betel Quid from West Pacific to South Asia, it's been also estimated that about 600 millions people consume Areca nut worldwide, so the 10 -20 % of the mondial population assumes this fruit somehow. Only three other psycoactive molecules are more frequently used than the arecoline contained in the Areca nut: caffeine, nicotine and ethanol.
In Italy neither the arecoline, neither the arecaidina neither the entire plant or parts of it are inserted in the Table I of the list of Drugs and Psycotrope substances according to the art.14 of the DPR n. 309/90.
There are not specific legislative restrictive provisions regarding Areca-nut or its active principles in the various countries of the European Community or in the USA.
(By "Smart Drugs". Simona Pichini, Ilaria Palmi, Emilia Marchei, Manuela Pellegrini, Roberta Pacifici, Piergiorgio Zuccaro. Dipartimento del Farmaco - Osservatorio Fumo Alcol e Droga
Istituto Superiore di Sanità - Roma)
Category: Parasympathomimetics / cholinergic agonists / acetylcholinesterase inhibitors.
Molecular Formula: C8H13NO2 (molecular mass= 155,1).
Systematic Name : 1,2,5,6-Tetrahydro-1-methyl-3-pyridinecarboxylic acid
methyl ester; methyl1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylate.
CAS Registry Number : 63-75-2.(Source: MedlinePlus. Druginfo. Keyword: Betel nut)
UVmax: arecoline does not present a significant absorbtion peak, it absorbes from 230 to 360 nm.
Solubility: arecoline is soluble in water, ether and chloroformium.(Source: "Smart Drugs")
An alkaloid obtained from the Areca nut (Areca catechu), fruit of a palm tree.
It's one of the three major natural natural cholinomimetic alkaloid toghether with pilocarpine and muscarine.
Alkaloids are naturally occurring chemical compounds containing basic nitrogen atoms. The name derives from the word alkaline and was used to describe any nitrogen-containing base. They are usually classified by their common molecular precursors, based on the metabolic pathway used to construct the molecule. When not much was known about the biosynthesis of alkaloids, they were grouped under the names of known compounds, even some non-nitrogenous ones (since those molecules' structures appear in the finished product; the opium alkaloids are sometimes called "phenanthrenes", for example), or by the plants or animals they were isolated from. In the case of arecoline the name derives from the one of the plant from which it comes: Areca Catechu.
The nitrogen heterocycle arecoline is classified under the alkaloid group of the Pyridine, along with nicotine ,arecaidine and many other molecules.
Other examples of alkaloids are well-known active principles produced by a large variety of organisms, including bacteria, fungi, plants, and animals (caffeine, morphine, cocaine, quinine, LSD, theophylline, mescaline, codeine, strychnine, atropine, serotonin, dopamine ecc...)
It is an agonist at muscarinic acetylcholine receptors(Wikipedia. Keyword: Alkaloids).
It is used in the form of various salts as a ganglionic stimulant, a parasympathomimetic, and a vermifuge, especially in veterinary practice. It has been used as a euphoriant in the Pacific Islands and other parts of south Asia.(Wikipedia and "Smart Drugs")
Uses based on tradition or theory
(Areca nuts extracts or chewable Betel nuts)
In the past (but sometimes still today) the nuts of Areca Catechu were used in India as an antihelmintic and according to traditional Ayurvedic medicine, chewing areca nut and betel leaf was a good remedy against bad breath (halitosis). They were also said to have aphrodisiac properties.
In Malaysia they were used to treat headaches, arthritis and joint pain. In the Philippines, Thailand, Indonesia and China they were used to relieve toothache. In the Philippines, they were used specifically as a stimulant. In Indonesia they were drunk as an infusion and used as an antibiotic. They were also used in an infusion to cure indigestion, as a topical cure for constipation, as a decongestant and as an aid to lactation.(Wikipedia).
Its traditional uses can obtain useful effects but actually they can be very different from one case to another; that's why they cannot be suggested (Wikipedia and MedlinePlus Herbs and supplements. Drugs info).
According to a study by the Research Institute of Chemistry, University of Karachi (Pakistan), the Areca Catechu ethanol extracts proved to have antidepressant effects.
Antidepressant Effects of Ethanol Extract of Areca catechu in Rodents
There are some studies that cited arecoline hydrobromide (the synthetic phamacological form of arecoline the structure of which can be seen below) as a treatment to improve the intellectual capabilities in the patients with Alzheimer's disease.
Clinical pharmacokinetics of arecoline in subjects with Alzheimer's disease.
In that study Arecoline proved to have a U-shaped dose-response relationship.
In the following study blinded, placebo controlled sperimentation were done on nine patients affected by mild moderate Alzheimer's disease. The intravenous low infusion of arecoline at low doses proved to improve memory in 6 of them without side effects.
Memory improvement without toxicity during chronic, low dose intravenous arecoline in Alzheimer's disease.
In this study is explained the relation between infusion doses and therapeutic effects of arecoline on nine patients affected by Alzheimer's disease. It became clear that cognitive test scores improved at different doses of arecoline.
Differential response to the cholinergic agonist arecoline among different cognitive modalities in Alzheimer's disease.
There are three main ways that have been tried to treat memory loss in Alzheimer's: increasing ACh production by increasing the availability of ACh precursors (lecithin, choline); inhibiting ACh degradation by inhibiting acetylcholinesterase (physostigmine, tacrine hydrochloride); and directly stimulating cholinergic receptors by using cholinomimetic agents (arecoline, RS-86). But the study conclude that all of the therapies don't produce consistent improvement on memory loss at present.
Alternatives in the treatment of memory loss in patients with Alzheimer's disease.
This study tested the possibility of arecoline performance to improve more memory measures other than picture recognition memory task. It was observed that although individual patients vary in their response to a given dose of arecoline, their responses are consistent across types of tasks.
Effects of acute infusion of the muscarinic cholinergic agonist arecoline on verbal memory and visuo-spatial function in dementia of the Alzheimer type.
Arecoline carcinogenic and long-term toxic effects together with "the lack of M1 selectivity and efficacy due to dose limiting side effects associated with M2 and M3 muscarinic receptor subtype stimulation have produced disappointing result" caused its dismissal.("Effect of novel N-arylurea- substituted 3-morpholino arecoline derivatives as muscarinic receptor 1 agonists in Alzheimer’s dementia models").
Fiurthermore as we will see in pharmacokinetics its oral bioavailability was very low.
However new studies like "Effect of novel N-arylurea- substituted 3-morpholino arecoline derivatives as muscarinic receptor 1 agonists in Alzheimer’s dementia models" and others tested arecoline derivates which proved to have an improved selectivity for M1 receptors and lower toxicity.
The utility of muscarinic agonists in the treatment of Alzheimer's disease.
Effect of novel N-aryl sulfonamide substituted 3-morpholino arecoline derivatives as muscarinic receptor 1 agonists in Alzheimer's dementia models.
The Arecoline based muscarinic agonists have been found to overcome the
limited oral activity and short duration of action of classical agonists and they are relatively specific in their action between central and peripheral effects. Arecoline oximes and/or oxadiazoles,9 arecoline thiadiazoles, arecoline oxazoles, arecoline amides10 are few arecolines
with the above advantages. Stucturally modified arecolines were tested to overcome these limitations. Tetrahydropyridine analogues provide semirigid template and have good affinity for the M1 receptor but The lack of M1 selectivity and efficacy due to dose limiting
side effects associated with M2 and M3 muscarinic receptor subtype stimulation have produced disappointing results. The derivatives with electron donating group at para
position of the sulfanamide showed considerable high affinity and potency for the M1 receptor in vitro and useful antidementia activity in vivo model tested. This finding can be attributed due to the delocalization of electrons from electron donating group towards the oxygen of sulfonyl group through benzene ring, which influences the affinity of the compound for the receptor.
Muscarinic receptor 1 agonist activity of novel N-arylthioureas substituted 3-morpholino arecoline derivatives in Alzheimer's presenile dementia models.
Effect of novel arecoline thiazolidinones as muscarinic receptor 1 agonist in Alzheimer's dementia models.
This article was released before "Effect of novel N-aryl sulfonamide substituted 3-morpholino arecoline derivatives as muscarinic receptor 1 agonists in Alzheimer's dementia models." it represent another effort in the research of new cholinergic agonists with selective muscarinic M1 activity.
The major problem in this reserch field is to create new molecules with enough affinity to their receptor and enough binding specificity to avoid the important collateral effects caused by a cholinergic agoinist. At present we have the techniques and the aknowlegments to modify the substances but the sites in which they can be modified are not infinite as cannot be infinite the possibilities of attachments to the molecules ( because oof 3D structure, chemical properties and dimensions).
Arecoline and some of its pharmacological derivates.
At present the only drugs approved by FDA to cure the intellectual impairments in Alzheimer's disease are of another class. They are acethylcholinesterase inhibitors (tacrine, donepezil, rivastigmine, and galantamine).
Fisher center for Alzheimer
From arecoline is possible to obtain some cocaine analogs which can be used to treat cocaine abusers and maintain them on treatment programs of slow withdrawing from the drug. These programs follows the methadone-type approach and help to maintain the patients on the long treatment programs.
The drugs used were substances that elicited some of the same effects in the user as cocaine itself, but without causing the same degree of euphoria.
Synthesis of Cocaine analogs from Arecoline
Chemistry and Pharmacology of the Piperidine-Based Analogues of Cocaine.
Identification of Potent DAT Inhibitors Lacking the Tropane Skeleton
These piperidines obtained from arecoline hydrobromide showed to have a significant binding activity at the dopamine transporter and in the inhibition of [3H]dopamine uptake.
Their affinity is very similar to that of the Tropanes They can be considered because they can be considered truncated analogues of cocaine or more precisely truncated analogues of the WIN series of Tropanes. That's why their affinity is very similar to that of the Tropanes.
(a link for a definition of Tropanes)
Since 1921 arecoline has been used as a preferred treatment for cestodes in dogs(especially Echinococcus granulosus and Taenia spp.). The acetarsol, hydrobromide and carboxyphenylstilbonate salts have been used for this purpose. Because of its relative low efficacy and its severe side effects, it is no longer recommended as a therapeutic drug in dogs and cats.(Surely it is no longer used for this purpose in Italy because it is not included in the Italian Veterinary Pharmachological Reference Book). Oral administration causes paralysis of the worms and catharsis, so the worms are expelled alive and intact. Lower doses are used as a laxative. This action makes arecoline a useful diagnostic agent, which may give valuable information on whether a group of dogs on a farm is infected with or not.
Veterinary Dictionary: arecoline
Finally new studies have been made to assess the utility of cholinomimetic drugs (NO donors arecoline derivates) on anti-atherosclerosis therapy.
Synthesis and vascular relaxing activity of arecoline derivatives coupled with nitric oxide donors
The absorption and the human methabolism of arecoline is still mostly unknown.
This substance can enter the body in many ways: per os, intramuscular injection, intravenous injection and intranasal absorption.
Intestinal permeability through drugs (among which there was arecoline and arecaidine) has recently been tested in vitro but because of the oral first pass metabolism due to the properties of arecoline it cannot be considered a frequent way of access.
Comparative in vitro permeability of human vaginal, small intestinal and colonic mucosa.
Dermal absorption was tested by Hayes et al. in 1989 in healthy volunteers who had received transdermal doses at 3mg/h the time–concentration profile showed a maximum plasma concentration of 4–5 ng/mL at 5–10 h after dermal application (IARC Monographs. BETEL-QUID AND ARECA-NUT CHEWING, pg. 122).
Oral administration is the main entrance way worldwide mostly with Betel quid chewing but or less frequently in the past as arecoline pharmacologic derivates. This is also the less effective for clinical purpouse due to a first pass oral metabolism.
That's why the other three ways began to be used.
The Psychopharmacology of Herbal Medicine
Strickland et al. (2003) assessed the absorption of arecoline and its level in plasma among eight fasting men (20–29 years of age). Freshly dried areca nuts were pulverized and assayed
for arecoline content (mean value, 0.17%); the powder was then suspended in bioadhesive
gel and placed in the buccal cavity so as to deliver 0, 5, 10 or 20 mg arecoline. At 15, 155
and 365 min after placement, arecoline could be detected by GC–MS in blood plasma in
amounts that increased with dose and time (IARC Monographs. BETEL-QUID AND ARECA-NUT CHEWING; pg.122).
In the oral cavity if assumed as Betel quid arecoline is hydrolized into arecaidine (this explains its short half life) in presence of lime but early reports also showed that various nitrosamines may be formed from areca alkaloids and that these are causative of human oral cancer. These nitrosamines include the nitrosamines of guvacine and guvacoline, together with 3 methylnitrosopropionitrile. What remains unclear is if arecoline is metabolized in the body to any of these other alkaloids or to other derivatives that may also form nitrosamines.(see TOXICITY for further information on arecoline carcinogenicity)
A metabolomic approach to the metabolism of the areca nut alkaloids arecoline and arecaidine in the mouse.
To test the intravenous injection Arecoline hydrobromide was dissolved in sterile 0.9% saline solution and was infused continuously through a peripheral intravenous catheter by a battery-operated infusion pump worn about the waist.
The drug was administered continuously for approximately 2 weeks at a rate that was increased daily from 0.008 to 1.7 mg/hr (free base). The infusate was freshly prepared daily, and the catheter insertion site was changed every 2 to 3 days.
The chart shows the data about the plasma arecoline concentration profile during and after an infusion of 5 mg of arecoline in 30 minutes. A detectable plasma concentration was reached after 5 minutes. The concentration then increased to near steady-state levels by the end of the infusion. After drug administration was terminated, plasma arecoline concentrations decreased biexponentially and were undetectable by 60 to 90 minutes.
Clinical pharmacokinetics of arecoline in subjects with Alzheimer's disease.
The intranasal absorption was also tested to cure Alzheimer and proved to have a bioavailability of the 85% when compared with bioavailability following intramuscular administration.
Intranasal absorption of physostigmine and arecoline.
In man, after entering the blood stream arecoline (which is simply a methyl ester of Nmethyltetrahydronicotinate) is rapidly hydrolyzed to its carboxylic acid, arecaidine, by plasma
and organ esterases ("Clinical pharmacokinetics of arecoline in subjects with Alzheimer's disease.").
In experimental rat models arecoline is rapidly metabolized in both liver and kidney (essentially 100% and approximately 87%, respectively). Arecoline was not metabolized by either blood or brain homogenates to any significant degree (IARC Monographs. BETEL-QUID AND ARECA-NUT CHEWING; pg.128).
The study "A Metabolomic Approach to the Metabolism of the Areca Nut Alkaloids Arecoline and Aracaidine in the Mouse" found eleven metabolites of arecoline(I) in experiments in the mouse: arecaidine(II), arecoline N-oxide(III), arecaidine N-oxide(IV), N-methylnipecotic acid(V), N methylnipecotylglycine(VI), arecaidinylglycine(VII), arecaidinylglycerol(VIII), arecaidine mercapturic acid(IX), arecoline mercapturic acid(X), and arecoline N-oxide mercapturic acid(XI), together with nine unidentified metabolites.
Rat liver homogenate was able rapidly and quantitatively to hydrolyze arecoline to arecaidine. While a meager amount of arecaidine production occurred in mouse blood and brain, liver and kidney carried out this reaction virtually quantitatively. Inhibitor studies strongly suggested that the conversion of arecoline to arecaidine was mediated by carboxylesterase.
A metabolomic approach to the metabolism of the areca nut alkaloids arecoline and arecaidine in the mouse.
Elucidation of the rapid in vivo metabolism of arecoline.
Using specific carboxylesterase inhibitors this study proves that liver and kidney carboxylesterases of mice were primarily responsible for the arecoline metabolism in the mouse.
The metabolomics of (±)-arecoline 1-oxide in the mouse and its formation by human flavin-containing monooxygenases.
See below for the most important findings of this study.
Arecoline metabolic map built on the metabolites identified from the analysis of urinary samples in mouse (numbers refers to the names cited above in the text)
Although arecoline and arecaidine are extensively metabolized to multiple products in mice, none appears to be due to cytochrome P450. The oxidation reactions appear exclusively to be N oxidations, certainly carried out by FMO enzymes ("The metabolomics of (±)-arecoline 1-oxide in the mouse and its formation by human flavin-containing monooxygenases."). The other metabolites observed were either reductions or conjugations.
In man, if not stopped by the oral first pass metabolism, arecoline can immediately cross the blood-brain barrier with a brain/plasma concentration ratio close to unity.("Clinical pharmacokinetics of arecoline in subjects with Alzheimer's disease.")
In the study "Clinical pharmacokinetics of arecoline in subjects with Alzheimer's disease." the arecoline mean half life and clearance were also measured :
"Parameter" "Mean +/- SD" "Range"
t1/2(min) [0,95 +/- 0,54] [0,20-2,45]
Cl (L/min) [13,6 +/- 5,8] [6,6-25,8]
During continuous intravenous infusion of arecoline at therapeutically relevant dosing rates, the steady-state plasma concentration is linearly related to the infusion rate, showing an absence of autoinduction of its own biotransformation and clearance.
The metabolism of arecoline seems to end, at least in mice, with urinary excretion of its metabolites ("A metabolomic approach to the metabolism of the areca nut alkaloids arecoline and arecaidine in the mouse").
Traces of arecoline can be found and measured in some biological matrixs: meconium, umbilical cord blood, fetal urine, placenta, keratinic matrix(from hair).(Smart Drugs)
Arecoline acts very similarly to nicotine ,which has a comparable structure. Indeed both these molecules are alkaloids.
Arecoline is a full agonist of acethylcholine muscarinic receptors, if peripherally administered subtly reduces the cortical and subcortical levels of acethylcoline.Arecaidine the major arecoline metabolite lacks the typical parasympathomimetic effects of arecoline.
This can lead to typical cholinomimetic effects like bradycardia, hypotension, bronchospasm, myosis, tonus increment and salivary, gastric, pancreathic, bronchial and lacrimal glands secretion increment. These effects are mediated by the interaction with the M1 and M2 muscarinic receptors of the target organs innervated. All the muscarinic acethylcholine receptors are Gprotein-coupled receptors which use a second messenger.
M acetylcholine receptor
Bradycardia and hypotension are short-term effects soon followed by heart rate acceleration and increase of blood pressure (The Psychopharmacology of Herbal Medicine). Intravenous or subcutaneous administration of arecoline in human subjects, who were pretreated with a peripheral cholinergic blocker, caused a cardio-acceleratory response in all studies, and a pressor response in some. These findings suggest that arecoline exerts a central cholinergic mechanism which then activates a descending sympathetic effect. Surely some sympathomimetic effects could be obtained by the interaction of cholinomimetic drugs(like pilocarpine and arecoline itself) when they interacts with the targets organ innervated by sympathetic cholinergic fibers. These postgangliar fibers use acethylcholine to activate their effectors in which muscarinic receptors are ready to reply to the stimulation. This is an exeption on the sympathetic system (which normally have adrenergic postgangliar fibers) that can be found in sweat glands and deep muscle blood vessels. In the first case the stimulation can lead to a profuse secretion, in the second case to a net vasodilatation.
In some studies it was found that arecoline and arecaidine were stimulators of catecholamine release from chromaffin cells in vitro. These findings were not in agreement with those of Lim and Kim("Arecoline inhibits catecholamine release from perfused rat adrenal gland").
So arecoline and arecaidine can in part explain the sympathetic effect of betel quid chewing and its action on the elevation of catecholamines in blood but the sites of activation could not be decided.
Arousal and the hyperthermic responses described in betel chewing are thought to be due to a sympathetic and cholinergic mixed mechanism. It's not clear what could be the role of arecoline and arecaidine in that phenomenon.
Effects of Betel chewing on the central and autonomic nervous systems.
Neurological aspects of areca and betel chewing.
Central and autonomic effects of arecoline are discussed here: cardiovascular effects(heart rate), hyperthermic effects(skin), reaction time, effects on EEG, variations of plasmatic concentration of adrenaline and noradrenaline. These effects seemed to be habit-related and dose-dependent furthermore some of them must implicate a sympathetic activation.
Arecoline inhibits catecholamine release from perfused rat adrenal gland
Vasomotor effects of the cholinomimetic drugs which are muscarinic receptors' agonists are probably mediated by the muscarinic M3 receptors which can be found in the smooth muscles of the blood vessels(especially on coronaries and lung vessels) as well as in some endocrine and esocrine glands(salivary and others).
Regarding vessels the stimulation lead to vasodilatation(an exception in the parasympathomimetic system) with a mechanism that involve the production of NO by the target cells stimulated via M3 muscarinic receptors(Gprotein coupled receptors).
Synthesis and vascular relaxing activity of arecoline derivatives coupled with nitric oxide donors
M acetylcholine receptor
The wikipedia page for full information over this important acethylcholine receptor structure, isoforms, pharmacology applications, functions.
Mechanism of vascular relaxation by cholinomimetic drugs with special reference to pilocarpine and arecoline.
The role in vascular relaxation of cholinomimetic drugs used in glaucoma was studied. The study suggest that the vascular relaxationinduced by pilocarpine and arecoline was to be dued mostly to a mechanism of competition with spasmogens and not to their muscarinic cholinergic activity which was lower than the Acethylcholine one.
Vasodilatory effects of cholinergic agonists are greatly diminished in aorta from M3R-/- mice.
The receptors involved in acethylcholine vasodilatation could be of different classes there are reports which demonstrated that vasodilation elicited by acetylcholine is abolished in cerebral arteries isolated from muscarinic M5 receptor-deficient mice, while effects of acetylcholine on coronary and carotid artery remain intact. Other studies suggested the role of M1 receptors in the vasodilatation in the pulmonary vasculature study was designed to determine if the endothelium-dependent vasodilatory actions of acetylcholine are present in thoracic aorta isolated from muscarinic M3 receptor knock out (M3R−/−) mice. The vasodilatation effects of acethylcholine and some of its agonists (with M3 muscarinic activity) were studied on samples of mice's aorta previously constricted with phenylephrine. The result suggest that the endothelium-dependent vasodilation elicited by acetylcholine in aortae from WT mice is markedly depressed, if not absent, in preparations isolated from M3R−/− mice.
Muscarinic (M) receptors in coronary circulation: gene-targeted mice define the role of M2 and M3 receptors in response to acetylcholine.
This study try to determine the M receptors mediating responses to ACh in coronary circulation using mice deficient in M2 or M3 receptors. The results suggest that relaxation to ACh in coronary circulation is mediated predominantly by activation of M3 receptors.
Contribution of the M3 muscarinic receptors to the vasodilator response to acetylcholine in the human forearm vascular bed.
Another experiment in which it was proved the major role of M3 receptors in Ach-induced endothelium-dependent vaodilatation.
The stimulation of M1 and M3 receptors on the smooth muscles of lungs can cause instead the bronchoconstriction which(together with the enhancement of esocrine glandular secretion) can explain the ashma exacerbation sometimes induced by betel nut chewing.
Neurochemical examination of the brain material from Alzheimer’s patients has demonstrated the loss of the presynaptic marker enzyme, choline acetyltransferase, and the muscarinic receptors of the M2 subtype which are mainly responsible for causing deficits in central cholinergic transmission in Alzheimer’s patients. The postsynaptic muscarinic receptors, which are primarily of the M1 subtype, seem to a large extent to survive the loss of cholinergic nerve endings. These findings have led to attempts at restoring cholinergic transmission by means of cholinomimetic drugs such as acetylcholinesterase (AChE) inhibitors and muscarinic agonists, the hypothesis being that enhancement of cholinergic neurotransmission function would alleviate the symptoms of the diseases, and particularly the deficits in cognition and memory.". From:
Effect of novel N-arylurea- substituted 3-morpholino arecoline derivatives as muscarinic receptor 1 agonists in Alzheimer’s dementia models
The first drugs developed were acethylcholinesterase inhibitors(tacrine, donepezil, rivastigmine, and galantamine), they are also the only drugs approved by FDA to treat Alzheimer.
Fisher center for Alzheimer
These compounds provide some symptomatic relief for Alzheimer’s patients for a limited period of time but have some unwanted side effects like: nausea, vomiting, diarrhea associated with non selective activation of muscarinic receptors in the gastrointestinal tract.(Hollander et al., 1986; Moos et al., 1988)
Muscarinic and nicotinic agonists should have a lower propensity for these consequences.
Pharmacological investigation of muscarinic receptor subtypes using both functional and binding studies has identified three distinct muscarinic receptor subtypes, M1, M2 and M3.
Identifying M1 selective muscarinic agonists which are capable of crossing the blood–brain
barrier is the subject of active research for pharmacological application.("Effect of novel N-arylurea- substituted 3-morpholino arecoline derivatives as muscarinic receptor 1 agonists in Alzheimer’s dementia models")
M1 selective muscarinic agonists were selected since they are present in the hyppocampus and cerebral cortex the brain regions associted with memory and cognitive functions(Wall et al., 1991; Levey 1996; Caulfield et al.,1983; Hagan et al., 1987; Messer et al., 1990).
In contrast M2 and M3 receptors are localized in in smooth muscle and exocrine glands, and likely mediate the unwanted side effects associated with nonselective compounds.
At present only a small number of muscarinic agonists have been tested in clinical trials, the first were oxotremorine, pilocarpine, and arecoline. They appeared to suffer from low efficacy at M1 receptors, a lack of subtype selectivity which lead to unwanted side-effects especially in the gastrointestinal system. Furthermore ,as we will see in pharmacokinetics, the oral bioavailability of arecoline was very low.
The utility of muscarinic agonists in the treatment of Alzheimer's disease.
These unwanted effects (especially the enhancement of the gastrointestinal glands secretion and peristalsis) were previously exploited in the veterinary medicine to eliminate gastrointestinal parasites(cestodes).(Cestodocidal drugs).
In addition to playing a role in cognitive function, M1 receptors promote alfa-secretase activity (Nitsch et al., 1992; Buxbaum et al., 1994; Wolf et al., 1995), which results in the secretion of nontoxic derivatives of amyloid precursor protein (APP).
Such an action can lower the rate of beta-amyloid deposition following long-term administration.Muscarinic agonists also may have neuroprotective activity. Presenilin mutations lead to elevated levels of A-beta and downregulation of the Akt
pathway promoting tau protein phosphorylation and apoptosis (Weihl et al., 1999) and elevated glycogen synthase kinase activity is associated with hyper-phosphorylation of tau proteins, a key component of neurofibrillary tangle formation in Alzheimer’s disease.
An activation of muscarinic receptors can lead to the stimulation of Akt, through the posphatidylinositol-3-OH kinase pathway (Murga et al., 1998; Murga et al., 2000). This inhibits apoptosis and promotes cell survival preventing the formation of neurofibrillary
tangles.("The utility of muscarinic agonists in the treatment of Alzheimer's disease.").
Another arecoline action that can play a role on memory is the elevation of cerebral flow and glucose metabolism in cerebral areas with a cholinergic innervation(with the involvement of both nicotinic and muscarinic acethylcholine receptors) among which there is hyppocampus.
The effects in the extrapiramidal areas were related to the intensity of arecoline-induced tremor which is instead caused by the arecoline inhibition of GABA (The Psychopharmacology of Herbal Medicine).
For cholinomimetic fibers innervation and cerabral blood flow see also:
Activation of the intracerebral cholinergic nerve fibers originating in the basal forebrain increases regional cerebral blood flow in the rat's cortex and hippocampus.
The presence of cholinergic fibers in the basal forebrain could represent another way to regulate the regional cerebral blood flow using a Ach,NO-dependent mechanism.
If the cholinergic fibers found in basal forebrain have a vasodilative function, impairment of this system may result in dysfunction of the higher central nervous system.
The vasodilating factor is NO which seems to be produced by NOS positive neurons very close to the innervated cholinergic vessels.
Ach obtains its effects by the interaction with both muscarinic and nicotinic receptors and the increase in cortical blood flow elicited by this cholinergic vasodilative system is independent of systemic blood pressure and is not coupled to cortical metabolic rates.
Regulation of regional cerebral blood flow by cholinergic fibers originating in the basal forebrain.
This article made by the same authors of the previous one seems to be more complete in the development of the argument. It comprehensvely describes the cholinergic fiber system found in the basal forebrain, the Ach release, the muscarinic and nicotinic receptors involved, the response of NOS-positive neurons to Ach, the production and the effects of the NO produced on the smooth muscles of cerebral vessels. furtehrmore there are some elucidative figures which summarizes the results of the various experiments.
It still remains unclear if these fibers are part of the autonomic nervous system.
Cholinergic neural regulation of regional cerebral blood flow.
This review attend to describe various types of stimulation of the cholinergic vasodilatation system in the basal forebrain (pharmacological and non-pharmacological).
Effects of age on cholinergic vasodilation of cortical cerebral blood vessels in rats.
Here is reported the impairement of the cholinergic vasodilatation system in the basal forebrain following aging. From the data collected the authors conclude that the cause of this disfunction is a decreased activity of the nicotinic ACh receptor after its stimulation whith Ach by the cholinergic fibers of the basal forebrain.The article confirms the importance of the cholinergic vasodilatation system in the regulation of regional cerebral blood flow (at least in rats).
In human subjects with Alzheimer's disease, intravenous infusion of arecoline caused elevations of ACTH, cortisol and beta endorphin indicating an activation of the hypothalamic-pituitary-adrenal axis.(The Psychopharmacology of Herbal Medicine)
This arecoline action was previously proved on a study involving rats where it was found that the HPA axis stimulation was probably made centrally, mainly via secretion of CRH.
The muscarinic cholinergic agonist arecoline stimulates the rat hypothalamic-pituitary-adrenal axis through a centrally-mediated corticotropin-releasing hormone-dependent mechanism.
The arecoline hydroromide derivates used in the treatment of cocaine abusers are truncated analogs of cocaine that lack its two-carbon bridge.
They possess a significant DAT activity but without a locomotor activity in mice. This means that they can be cocaine antagonists because they can bind a part of the DAT binding domain.
In DAT a significant portion of the cocaine binding domain on the dopamine transporter is distinct from that of either dopamine or amphetamine. This distinction may be sufficient to allow properly designed drugs to prevent cocaine binding without inhibiting dopamine uptake.
The research upon arecoline derived piperidines moves in this direction. They proved to be able to bind DAT inhibiting dopamine uptake but this didn't result in an increasing of locomotor activity(evidence of an almost complete inhibition of DAT similar to that achieveable with cocaine) that's why they can be considered a first pass on the research for cocaine antagonists.
Chemistry and Pharmacology of the Piperidine-Based Analogues of Cocaine. Identification of Potent DAT Inhibitors Lacking the Tropane
Arecoline is also a competitive inhibitor of GABA; it is able to bind to GABA receptors stopping its inhibitory effects on the nervous transmission producing stimulating and euphorigenic effects opposite to the Benzodiazepines' ones. This eccitatory action can become toxic resulting in acute tremor. Arecoline major metabolite, arecaidine, can have similar effects acting as a substrate-competitive inhibitors of GABA uptake but probably it is not able to pass the blood-brain barrier by itself. This fact suggest that the central effects of Areca catechu may involve transmitters other than GABA.(Effects of Betel Chewing on the Central and Autonomic Nervous Systems).
GABA receptors are chloride channels, similar in structure to acetylcholine receptors and are found in many tissues of the body where arecal alkaloids can also be expected to have physiological effects; for example, arecaidine is as active as GABA in stimulating collagen synthesis by buccal fibroblasts.
Arecoline's effect on GABA may also explain cases of short-term hypoglycaemia: GABA and its receptor are found in islet beta cells together with one of the GABA shunt enzymes, glutamate decarboxylase (GAD) which is an antigen strongly associated with the appearance of GAD antibodies at the onset of type 1 diabetes in man. Since arecal alkaloids act as GABA receptor inhibitors they could, by blocking the inhibitory effects of GABA on glucagon and somatotrophin secretion, increase their release.
An immediate effect of a rise in glucagon is insulin release with subsequent hypoglycaemia
but chronic hyperglucagonaemia; over time this can lead to hyperglycaemia and eventually diabetes. On the other hand reduced expression of GAD is produced by GABA inhibition and this in turn reduces autoimmune responses to GAD in rat islets and brain. Since arecal alkaloids are likely to inhibit GABA receptors in the islets, as they do in the brain, it is
possible that areca chewing provides protection from progression from type 2 to type 1
Metabolic effects of the consumption of Areca catechu.
The antidepressant effects seem to be determined by a mechanism of MAO inhibition.
Behavioral and biochemical studies of dichloromethane fraction from the Areca catechu nut
Arecoline addiction and dependence seems to be due to a dopamine mediated effect(The Psychopharmacology of Herbal Medicine).
For further information see also the item: Nicotine
Metabolic effects of the consumption of Areca catechu.
Here can be found some of the information reported in this section.
Cardiuvascular side effects
Arecoline and Betel Nut assumption is related with cardiovascular pathologies. High levels of homocysteine have been reported. They are associable to an higher risk of ischemic cardiopathies. Arecoline can cause a vasospasms in coronaries. This is probably due to an endothelial damage following Arecoline parasympatomimetic action. The central mixed stimulation of both the parasympathetic and sympathetic systems lead to bradycardia and hypotension soon followed by tachycardia and hypertension.
In habitual users of Betel Nut several cases of extrasystoles have been reported. Tachycardia begins within 2 minutes from the assumption and lasts at least 20 minutes. The mean heart rate increment diminishes with the increase of frequency of betel chewing. This observation suggests a mechanism of tolerance due to the repeated assumptions.
Betel Nut chewing can lead to the outcome of insulin-independent diabetes.
Chronic use of Betel nut can cause a decrement of B12 levels in blood(Smart Drugs) but also thiamine and vitamin D seems to be depleted by this habit. It is not clear if vitamin depletion is associated only to arecoline or to other substances contained in the quid.(Betel nut. Areca catechu L.)
Intestinal unwanted effects
The oral administration of arecoline can cause irritation and peristalis increment with emesis and diarrhea.
Betel nut chewing have been associated with an increased occurrance of peptic ulcers in bowel. "Chewers have an increased rate of salivary secretion with resultant dilution of amylase and K+. Effects on the mucosa include increased acid back-diffusion and reduction in mucous secretion, effects associated with haemorrhagic peptic ulceration in animals and likely to contribute to the increased risk of peptic ulceration in man." The administration of sodium bicarbonate or therapeutic agents blocking acid secretion corrected these dangerous effects.
Role of histamine and acid back-diffusion in modulation of gastric microvascular permeability and haemorrhagic ulcers in betel-quid-fed rats.
Regular consumption of areca nut leads to abnormal liver function with increases in serum aminotransferases in rodents suggesting hepatocellular damage. It is not known whether such damage might increase the risk of cirrhosis or of the liver.
(Metabolic effects of the consumption of Areca catechu)
"Other problems can include increased blood calcium levels and kidney disease ("milk alkali syndrome"), possibly due to calcium carbonate paste sometimes used for preparing betel nuts for chewing.
Betel nut chewing is very noxious for all the constituents
The oral health consequences of chewing areca nut.
This review focus the attention on the lichenoid lesions induced by Areca Nut chewing. Oral leukoplachia and oral submucous fibrosis are the most dangerous preneoplastic lesions found in Areca nut chewers.
Oral mucosal lesions associated with betel quid, areca nut and tobacco chewing habits: consensus from a workshop held in Kuala Lumpur, Malaysia, November 25-27, 1996.
The oral lesions induced by Areca nut chewing are particular and can be distincted by lesions caused by other causes, thet' why an atempt was made to describe precisely what a Betel quid is, the existing types of Betel quid, and their ingredients.
Quid-related lesions should be categorized conceptually into two categories: first, those that are diffusely outlined and second, those localized at the site where a quid is regularly placed.
Oral mucosal lesions associated with use of quid.
Etiology of oral submucous fibrosis with special reference to the role of areca nut chewing.
Tissue-culture studies involving human fibroblasts, areca nut extracts and areca nut alkaloids supported this etiologic hypothesis by showing fibroblastic proliferation and increased collagen formation.
Other hypothesis involved nutritional factors like chili but many studies confirmed the predominant role of Areca nut in the etiology of this precancerous lesion.
Arecoline can exacerbate ashma.( The Psychoharmacology of Herbal Medicine and Smart Drugs)
Dependence and tolerance
Does areca nut use lead to dependence?
"Long-term users may form a dependence on the effects of betel, and discontinuing use may cause signs of withdrawal, such as anxiety or memory lapse."
Other signs can be allucinations, humour alterations, reduction of attention, sleeping difficulties, increase of appetite.(Smart Drugs)
Pregnancy and Breastfeeding
Betel nut is not recommended during pregnancy and breastfeeding due to the risk of birth defects or spontaneous abortion. (Betel nut. Areca catechu L.)
Arecoline is able to pass placenta. In the literature there are some cases of newborn babies(born from mothers which chewed Betel nut) which presented a lower weight, hypotonia, delay of growth. Curiously in these babies there was also a lower frequency of neonatal jaundice.(Smart Drugs)
In primis they are linked with the cholinergic action of arecoline. Its use can diminish the effects of antimuscarinic drugs and potentiate the action of other cholinergic agonists, in the latter case a cholinergic toxicity syndrome can result.
In secundis they demonstrate the inhibitory action of arecoline on GABA because of the antagonism of the anxiolytic effect of Benzodiazepam and triciclic antidepressants.
Other interactions have been found with: amantadine, fenotiazine, olanzapine, molindone, loxapine, aloperidhol. They results in an increase of the extrapiramidal effects. (Smart Drugs)
The use of Betel nut can slow and raise heart rate so it is possible an interaction with beta blockers, calcium antagonists and digoxin.
Because arecoline can have an effect on glycaemia levels caution is advised when using other medications that alter glucose level in blood.
The arecoline citotoxicity and carcinogenic properties are potentiated by the contemporary use of alcohol and smoking.
The use of arecoline together with caffeine , guarana and ephedra(stimulant herbs) multiplicate arecoline excitatory activity.(Betel nut. Areca catechu L.)
Acute toxicity data of arecoline in animals
(from: Toxnet. ChemIdPlus)
Sistemic symptoms of arecoline toxicity are linked to its cholinergic activity.
A bible text for Arecoline, in particular for its carcinogenicity can be found at:
IARC Monographs:BETEL-QUID AND ARECA-NUT CHEWING.
IARC Monographs:SOME ARECA-NUT-DERIVED N-NITROSAMINES
This is the link to the index page of the Vol. 85 IARC Monographs(from here the documents are easier to handle):
IARC Monographs:Betel-quid and Areca-nut Chewing and Some Areca-nut-derived Nitrosamines. Vol.85
Because of the huge volume of information contained in those monograph it can be simplier to read the data summary:
Volume 85. Betel-quid and Areca-nut Chewing and Some Areca-nut-derived Nitrosamines Summary of Data Reported and Evaluation.
Other PubMed articles' links:
This case-control study aimed to assess the independent and interactive role of habitual betel quid chewing and known risk factors for hepatocellular carcinoma (HCC):
Habitual betel quid chewing and risk for hepatocellular carcinoma complicating cirrhosis.
Within this review, the authors discuss the molecular and cellular aspects of HNC carcinogenesis in Taiwan, an endemic betel quid chewing area.
Environmental carcinogens such as betel quid chewing, tobacco smoking and alcohol drinking have been identified as major risk factors for head and neck cancer. There is growing interest in understanding the relationship between genetic susceptibility and the prevalent environmental carcinogens for HNC prevention. Knowledge of molecular carcinogenesis of HNC may provide critical clues for diagnosis, prognosis, individualization of therapy and molecular therapeutics:
Head and neck cancer in the betel quid chewing area: recent advances in molecular carcinogenesis.
Here the authors, through a biological investigation, showed that arecoline, a major alkaloid of areca nut, might contribute to oral carcinogenesis through inhibiting p53 and DNA repair:
Arecoline, a major alkaloid of areca nut, inhibits p53, represses DNA repair, and triggers DNA damage response in human epithelial cells.
Current awareness and future perspectives on the role of Areca nut in betel quid-associated chemical carcinogenesis:
Role of areca nut in betel quid-associated chemical carcinogenesis: current awareness and future perspectives.
Areca (betel) is an important etiological factor linked to the high prevalence of oral carcinoma and other oral diseases in South Asians.Progressive down-regulation of involucrin during oral carcinogenesis was noted. Involucrin is a key component of the cornified envelop and a differentiation marker of keratinocyte. In this study, the authors found that 5 microg/ml non-toxic areca nut extract treatment resulted in the 0.5-fold down-regulation of involucrin and disruption in involucrin distribution in normal human oral keratinocyte (NHOK):
Areca nut extract treatment down-regulates involucrin in normal human oral keratinocyte through P13K/AKT activation.
Betel quid chewing has a strong correlation with oral leukoplakia, submucous fibrosis and oral cancer. For elucidation of its pathogenesis, in this study the authors investigated the effects of areca nut and inflorescence piper betle extracts and arecoline on the growth, total DNA synthesis and unscheduled DNA synthesis of cultured human gingival keratinocytes:
Effects of areca nut, inflorescence piper betle extracts and arecoline on cytotoxicity, total and unscheduled DNA synthesis in cultured gingival keratinocytes.
In this in vitro study, the authors have focused on the effects of arecoline and the role it could play in periodontal breakdown via its direct effects on human gingival fibroblasts:
Cytotoxicity and arecoline mechanisms in human gingival fibroblasts in vitro.
According to IARC Monographs:BETEL-QUID AND ARECA-NUT CHEWING; pg 133-134 in the citotoxicity of arecoline cannot be comprised the direct formation of ROS which are likely to be formed by the autoxidation of polyphenols contained in Piper Betel leaves of the Betel quid.
ALWAYS PAY ATTENTION TO THE FACT THAT IN THE BETEL QUID WITH WHICH ARECOLINE IS FREQUENTLY ASSUMED IS ALSO CONTAINED LIME (CALCIUM HYDROXIDE).
ITS PRESENCE AS A SIGNIFICANT INFLUENCE ON ITS CITOTOXICITY AND CAN EXPLAIN CASES OF MILK ALKALY SYNDROME ON CHRONIC BETEL CHEWERS.