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At least 19 recordsLinked to original sources
PubMed1971

The metabolic interconversion of arecoline and arecoline 1-oxide in the rat.

1. Tritiation of arecoline hydrochloride by catalytic exchange in aqueous media (done by The Radiochemical Centre) gave arecaidine hydrochloride of high specific radioactivity; this on treatment with diazomethane gave [(3)H]arecoline, which was oxidized with peroxyacetic acid to [(3)H]arecoline 1-oxide. 2. Arecoline 1-oxide gave arecaidine 1-oxide on acid hydrolysis and 1,2-dihydro-1-methylnicotinic acid methyl ester on thermal decomposition. 3. [(3)H]Arecoline hydrochloride was metabolized in the rat into the (3)H-labelled derivatives of arecoline 1-oxide, arecaidine 1-oxide, arecaidine, N-acetyl-S-(3-carboxy-1-methylpiperid-4-yl)-l-cysteine and an unidentified metabolite; some unchanged arecoline was also excreted. [(3)H]Arecoline 1-oxide gave the same metabolities, but in different amounts. 4. The possible relevance of these findings to betel-nut carcinogenesis is discussed.

Animals↗
PubMedDate not supplied

Effect of acute arecoline, tacrine and arecoline + tacrine post-training administration on retention in old mice.

The amnesias characteristic of Alzheimer's disease and other age-related dementias are refractory to conventional pharmacotherapy. A recent treatment strategy is to combine drugs to improve their memory enhancing effect. We previously reported that in young weakly trained mice, the combination of arecoline and tacrine was more effective on a mg/kg basis than either drug administered alone. This was true whether the route of administration was intracerebroventricular, subcutaneous or oral. We now report that 24 month old mice trained to avoid footshock in a T-maze show poor retention when tested one week later. Subcutaneous administration of arecoline, tacrine (also referred to as tetrahydroaminoacridine, THA) and arecoline plus tacrine administered immediately after T-maze footshock avoidance training enhanced retention of 24 month old mice compared to the saline-injected control. Since the combination was as effective as the single drug treatments even though 96% less arecoline and 99.7% less tacrine was administered, the combination showed marked potentiation of drug action of memory processing.

Aging↗
PubMed1988

Effect of acute arecoline, tacrine, and arecoline + tacrine post-training administration on retention in late middle-aged mice.

The amnesias characteristic of Alzheimer's disease and other age-related dementias are refractory to conventional pharmacotherapy. A recent treatment strategy is to combine drugs, particularly cholinergic drugs, to improve their memory enhancing effect. We previously reported that in young, weakly trained mice, the combination of arecoline and tacrine was more effective on a mg/kg basis than either drug administered alone. This was true whether the route of administration was intracerebroventricular, subcutaneous, or oral. These drug treatments have also been found to improve retention in 24-month-old mice. Mice 24 months of age show very poor recall one week after training. Failing memory must develop over time but may only be detected in mice younger than 24 months of age when the retention test interval is substantially longer. We now report that 18-month-old mice trained to avoid footshock in a T-maze show poor retention when tested two months after training and drug administration. Subcutaneous administration of arecoline, tacrine, and arecoline plus tacrine all enhanced retention of 18-month-old mice compared to the saline-injected control. The combination was as effective as the single drug treatments even though 96% less arecoline and 99.7% less tacrine were administered.

Age Factors↗
PubMed1991

Influence of arecoline on immune system: II. Suppression of thymus-dependent immune responses and parameter of non-specific resistance after short-term exposure.

Arecoline, a major alkaloid of arecanut was screened to explore its modulatory influence on cell-mediated immune response in a murine model system. The in vivo and in vitro effects were evaluated at subtoxic concentrations of arecoline. Delayed type hypersensitivity (DTH) reactions to sheep red blood cells (SRBC) were evaluated in male mice. When treated subcutaneously with 20 mg/kg bw (1/5 of LD50) dose of arecoline for 1, 2 or 3 weeks, the DTH reactions were significantly suppressed. At arecoline concentration of 10 mg/kg bw, there was a moderate reduction in DTH response, while no appreciable change was observed at a dosage of 5 mg/kg bw. The effects were not dependent on the duration of treatment. In contrast, treating with arecoline continuously for 4 days following SRBC immunization showed significant suppression in DTH reactions at both 10 and 20 mg/kg bw doses. When treated after 12 h following immunization with 20 mg/kg bw arecoline, significant reduction in DTH reactions were seen. While moderate reduction in response was observed with arecoline dosage of 10 mg/kg bw, there was no alteration in response at the dose level of 5mg/kg bw. Recovery experiments in mice revealed that arecoline mediated effects are of a reversible nature. Arecoline treatment did not appreciably alter the host resistance to endotoxin shock. In vitro experiments revealed both dose-dependent and time-dependent cytotoxic effects of arecoline when spleen cells were incubated with varying concentrations of arecoline. Concomitant exposure of arecoline at concentrations of 10(-6) - 10(-4) M with con A, markedly suppressed both 3H-thymidine incorporation and interleukin-2 production of splenic cells. In contrast, concomitant exposure of arecoline with IL-2 did not alter 3H-thymidine incorporation in the IL-2 dependent cytolytic T-lymphocyte line (CTLL), except at the concentration of 10(-4) M arecoline. From these studies it is concluded that the dose-dependent suppressive effects of arecoline on DTH response to SRBC and on certain in vitro lymphocyte functions are more clear than the host resistance to endotoxin shock.

Animals↗
PubMed2001

Adverse effects of arecoline and nicotine on human periodontal ligament fibroblasts in vitro.

BACKGROUND, AIMS: The habit of betel nut chewing impinges on the daily lives of approximately 200 million people. Betel quid chewers have a higher prevalence of periodontal diseases than non-chewers. This study examined the pathobiological effects of arecoline, a major component of the betel nut alkaloids, on human periodontal ligament fibroblasts (PDLF) in vitro. METHOD: Cell viability, proliferation, protein synthesis, and cellular thiol levels were used to investigate the effects of human PDLF exposed to arecoline levels of 0 to 200 microg/ml. In addition, nicotine was added to test how it modulated the effects of arecoline. RESULTS: Arecoline significantly inhibited cell proliferation in a dose-dependent manner. At concentrations of 10 and 30 microg/ml, arecoline suppressed the growth of PDLF by 20% and 50% (p < 0.05), respectively. Arecoline also decreased protein synthesis in a dose-dependent manner during a 24-h culture period. A 100 microg/ ml concentration level of arecoline significantly inhibited protein synthesis to only 50% of that in the untreated control (p < 0.05). Moreover, arecoline significantly depleted intracellular thiols in a dose-dependent manner. At concentrations of 25 microg/ml and 100 microg/ml, arecoline depleted about 18% and 56% of thiols (p < 0.05), respectively. This suggests that arecoline itself might augment the destruction of periodontium associated with betel nut use. Furthermore, the addition of nicotine acted with a synergistic effect on the arecoline-induced cytotoxicity. At a concentration of 60 microg/ml, arecoline suppressed the growth of PDLF by about 33% and 5 mM nicotine enhanced the arecoline-induced cytotoxic response to cause about 66% cell death. CONCLUSION: During thiol depletion, arecoline may render human PDLF more vulnerable to reactive agents within cigarettes. Taken together, people who combine habits of betel nut chewing with cigarette smoking could be more susceptible to periodontium damage than betel nut chewing alone.

Areca↗
PubMed1994

Effect of acute and chronic arecoline treatment on cerebral metabolism and blood flow in the conscious rat.

Treatment with the muscarinic agonist arecoline improves memory retention in patients with Alzheimer's disease (AD). In animal models, arecoline selectively increases local cerebral glucose utilization (LCGU). We examined (1) whether these focal increases in metabolism were coupled to local cerebral blood flow (LCBF) and (2) whether the effect of arecoline on LCGU and LCBF was dependent upon duration of drug administration. In groups of young Fischer-344 rats, LCGU and LCBF were determined in 59 brain regions by the [14C]2-deoxyglucose and the [14C]iodoantipyrine autoradiographic methods following either the acute administration of arecoline (2 mg/kg and 15 mg/kg) or the chronic three week administration of arecoline (50 mg/kg/day). In general, LCBF correlated closely with LCGU following arecoline 2 mg/kg administration, but heterogeneous regions were present. Following treatment with arecoline 15 mg/kg, the two parameters became uncoupled with LCBF increasing disproportionately in relation to LCGU. Coupling between LCBF and LCGU was preserved during chronic arecoline treatment (50 mg/kg/day) but some regions, such as the hippocampus, were uncoupled with LCGU increasing to a greater extent than LCBF. Thus, we demonstrate that acute and chronic administration of arecoline can differentially modulate LCBF and LCGU. Since clinical administration of arecoline can improve cognitive function in patients with AD, understanding the ability of arecoline to selectively alter LCBF and LCGU in regions such as the hippocampus may offer insight into the pathophysiology of AD and provide direction for the development of definitive therapy for neurodegenerative disorders.

Animals↗
PubMed2001

Synergistic effects of nicotine on arecoline-induced cytotoxicity in human buccal mucosal fibroblasts.

Areca quid chewing has been linked to oral submucous fibrosis and oral cancer. Arecoline, a major areca nut alkaloid, is considered to be the most important etiologic factor in the areca nut. In order to elucidate the pathobiological effects of arecoline, cytotoxicity assays, cellular glutathione S-transferase (GST) activity and lipid peroxidation assay were employed to investigate cultured human buccal mucosal fibroblasts. To date, there is a large proportion of areca quid chewers who are also smokers. Furthermore, nicotine, the major product of cigarette smoking, was added to test how it modulated the cytotoxicity of arecoline. At a concentration higher than 50 microg/ml, arecoline was shown to be cytotoxic to human buccal fibroblasts in a dose-dependent manner by the alamar blue dye colorimetric assay (P<0.05). In addition, arecoline significantly decreased GST activity in a dose-dependent manner (P<0.05). At concentrations of 100 microg/ml and 400 microg/ml, arecoline reduced GST activity about 21% and 46%, respectively, during a 24 h incubation period. However, arecoline at any test dose did not increase lipid peroxidation in the present human buccal fibroblast test system. The addition of extracellular nicotine acted synergistically on the arecoline-induced cytotoxicity. Arecoline at a concentration of 50 microg/ml caused about 30% of cell death over the 24 h incubation period. However, 2.5 mM nicotine enhanced the cytotoxic response and caused about 50% of cell death on 50 microg/ml arecoline-induced cytotoxicity. Taken together, arecoline may render human buccal mucosal fibroblasts more vulnerable to other reactive agents in cigarettes via GST reduction. The compounds of tobacco products may act synergistically in the pathogenesis of oral mucosal lesions in areca quid chewers. The data presented here may partly explain why patients who combined the habits of areca quid chewing and cigarette smoking are at greater risk of contracting oral cancer.

Analysis of Variance↗
PubMed1997

Cytotoxic and cytostatic effects of arecoline on oral mucosal fibroblasts.

Betel quid (BQ) chewing shows strong correlation to the incidence of oral submucous fibrosis and oral cancer in Taiwan. Arecoline, the main areca alkaloid, is considered to be one of the etiologic factors in BQ. To elucidate the role(s) of arecoline in the pathogenesis of BQ chewing related oral mucosal lesions, we used oral mucosal fibroblasts to study the effects of serum concentration, cell density, and incubation time on the cytotoxic response to arecoline. At a concentration less than 0.2 mM, arecoline was not cytotoxic to oral mucosal cells after 1, 3, and 6 days of incubation. After 3 days of incubation, the cytotoxic and cytostatic effects of arecoline became evident when the cells were exposed to higher concentrations of arecoline (0.2 mM) and serum (10% FCS). Exposure of cells (1 x 10(4) cells/well) to 0.2 mM of arecoline in 0.5% FCS for 3 and 6 days led to a 20% and 23% decrease, respectively, in the cell number, whereas exposure of cells (1 x 10(4) cells/well) to 0.2 mM arecoline in 10% FCS led to a 38% and 53% decrease, respectively, in cell number. At a higher cell density (5 x 10(4) and 1 x 10(5) cells/well), 0.2 mM arecoline led to less cytotoxicity (38% and 21% of decreasing in cell number, respectively) after 6 days of incubation. Our results indicated that arecoline was not mitogenic to oral mucosal fibroblasts, and that the cytotoxic and cytostatic effects of arecoline on oral mucosal fibroblasts could be modulated by the changes in the cell density, serum concentrations, and incubation time.

Arecoline↗
PubMed1998

Arecoline desensitizes carbachol-stimulated phosphatidylinositol breakdown in rat brain cortices.

To understand the effects of arecoline administration on the muscarinic cholinergic signaling pathway, rats were injected with arecoline, 10 mg/kg i.p., and the carbachol-stimulated phosphoinositide breakdown in rat brain cortical slices was examined. In vivo administration of arecoline resulted in inhibition of carbachol-stimulated phosphoinositide turnover in rat brain cortical slices. Arecoline was a partial agonist with peak effects of 30% of the maximum as obtained with carbachol. Coaddition of arecoline inhibited the carbachol-stimulated phosphoinositide breakdown. Pretreatment of rat brain cortical slices with arecoline in vitro resulted in a dose-dependent inhibition of carbachol-stimulated [3H]inositol monophosphate accumulation. The inhibition occurred rapidly, with half-maximal inhibition occurring at 15 min and maximal inhibition achieved within 60 min. The inhibition of phosphoinositide breakdown was recovered 1 h after arecoline was removed. When synaptoneurosomes were used for the ligand binding studies, arecoline pretreatment was found to have decreased the maximal ligand binding (Bmax) without inducing any marked change in binding affinity (K(D)). The influence could be recovered by incubating the synaptoneurosomes in the absence of arecoline for 2 h. Taken together, these data suggest that the underlying mechanism by which phosphoinositide turnover is inhibited is arecoline-induced receptor sequestration.

Animals↗
PubMed1983

Arecoline induced nicotinic and muscarinic stimulation of the superior cervical ganglion of cat.

Arecoline (10-500 micrograms) stimulated the superior cervical ganglion (s.c.g.) of cat following intra-arterial injection into the ganglion. The ganglion stimulating effect of arecoline was weaker than that of dimethylphenylpiperizinium (DMPP) but stronger than that of pilocarpine. Similarly, the time course of response to arecoline was slower than that of DMPP but faster than that of pilocarpine. The gangliomimetic effects of arecoline, nicotine and DMPP are prevented by hexamethonium, tetraethylammonium and high doses of nicotine and arecoline. Eserine potentiated the response to arecoline but not that to DMPP and nicotine. Response to submaximal preganglionic stimulation and KCl were potentiated by arecoline and pilocarpine but not by DMPP and nicotine. The responses to arecoline and pilocarpine were also prevented by atropine which did not alter the responses to DMPP and nicotine. It is suggested that arecoline stimulated the muscarinic as well as nicotinic receptors in the s.c.g. of cat and that acetylcholine is likely to be involved partially in the gangliomimetic effects of arecoline.

Animals↗
PubMed1995

Neuroendocrine responses to intravenous infusion of arecoline in patients with Alzheimer's disease.

We have reported that arecoline, a muscarinic receptor agonist replicably enhanced verbal memory in five of nine subjects with Alzheimer's disease (AD). To investigate the mechanism of cognitive improvement, circulating hormone measurements were made during high-dose acute and low-dose chronic intravenous (i.v.) arecoline administration to AD patients. Acute hormone responses were measured during, and for 6 h after, infusion of arecoline 5 mg i.v. over 30 min. Chronic responses were measured in cognitive responders during continuous i.v. infusion of arecoline escalating over 2 weeks (0.5-40 mg/day) and then during a 1 week infusion of the dose optimizing cognition (4-16 mg/day). Acute arecoline administered to 14 subjects produced unpleasant side-effects (e.g. nausea, vomiting), mean adrenocorticotrophic hormone (p = .0006), cortisol (p = .0001) and beta-endorphin (p = .0001) levels were elevated. During chronic arecoline treatment, no side-effects occurred and plasma cortisol, adrenocorticotrophic hormone and beta-endorphin levels were unchanged in nine subjects overall and in five cognitive responders. Thus, high-dose arecoline activates the hypothalamic-pituitary-adrenal (HPA) axis and may increase other anterior pituitary hormone levels, likely representing a 'stress response', but cognition-enhancing, low doses of arecoline do not produce a glucocorticoid response. Hence, arecoline-induced memory improvement is not due to the induction of 'stress' nor to the elevation of peripheral corticosteroid levels.

Adrenocorticotropic Hormone↗
PubMed1999

Arecoline cytotoxicity on human oral mucosal fibroblasts related to cellular thiol and esterase activities.

Betel quid (BQ) chewing is associated with an increased risk of oral submucous fibrosis (OSF) and oral cancer in India and many south-east Asian countries. Recently, we have shown that arecoline is cytotoxic to cultured human oral mucosal fibroblasts. This study investigated protective effects of various agents against the cytotoxicity of arecoline and its mechanisms. Arecoline, at concentrations of 0.2 and 0.4 mM, decreased the cell numbers by 38% and 63%, respectively. At a concentration of 2 mM, N-acetyl-L-cysteine [a glutathione (GSH) synthesis precursor] could prevent arecoline-induced cytotoxicity. The decrease in cell numbers was reduced to 17% relative to control. Extracellular addition of esterase at a concentration of 0.1 U/ml could almost completely protect the oral mucosal fibroblast (OMF) from arecoline-induced cytotoxicity. Arecoline is a muscarinic receptor agonist. However, atropine, a muscarinic receptor antagonist was unable to protect the cells from arecoline cytotoxicity at a concentration of 10 microM. Pretreatment of OMF with 50 microM buthionine sulfoximine (a cellular GSH synthesis inhibitor) or 0.5 mM diethylmaleate (a cellular GSH depleting agent) potentiated the cytotoxic effects of arecoline. These results indicate that cytotoxicity of arecoline on OMF is associated with cellular GSH levels and esterase activities. Factors that induce the GSH synthesis or esterase activity of oral mucosal cells can be used for future chemoprevention of BQ chewing-related lesions.

Acetylcysteine↗
PubMed2003

The up-regulation of cyclooxygenase-2 expression in human buccal mucosal fibroblasts by arecoline: a possible role in the pathogenesis of oral submucous fibrosis.

BACKGROUND: Aberrant and persistent tissue inflammation are believed to play an important role on the occurrence of tissue fibrosis. Cyclooxygenase (COX)-2 is an inducible enzyme responsible for prostaglandin synthesis in certain inflammatory diseases. The purpose of this study was to compare COX-2 expression in normal human buccal mucosa and oral submucous fibrosis (OSF) specimens and further explore the potential mechanism that may lead to induce COX-2 expression. METHODS: Fifteen OSF specimens and six normal buccal mucosa were examined by immunohistochemistry. Primary human buccal mucosa fibroblasts (BMFs) were established and challenged with arecoline analyzed by reverse transcriptase polymerase chain reaction. Furthermore, to elucidate whether induction of COX-2 is associated with cytotoxicity, aspirin (a non-selective inhibitor of COX enzyme) and NS-398 (a selective COX-2 inhibitor), were added to test their protective effects. RESULTS: COX-2 expression was significantly higher in OSF specimens and expressed mainly by epithelial cells, endothelial cells, and cells with fibroblast morphology. In vitro studies indicated that BMFs did not express COX-2 constitutively. However, when the cells were treated with 80 micro g/ml arecoline, COX-2 expression was up-regulated as early as half an hour. This indicates that COX-2 expression is an early cellular response and regulated by arecoline at transcriptional level. In addition, pre-treatment with glutathione (GSH) precursor, 2-oxothiazolidine-4-carboxylic acid (OTZ), led to a decrease in induction of COX-2 mRNA by arecoline. GSH synthesis inhibitor, buthionine sulfoximine (BSO), was found to increase arecoline-induced COX-2 mRNA levels. Moreover, both of aspirin and NS-398 at non-cytotoxic doses are not able to prevent arecoline-induced cytotoxicity. This indicates that arecoline cytotoxicity is not directly via the induction of COX-2 expression. CONCLUSIONS: Taken together, these results suggest that COX-2 expression is significantly up-regulated in OSF tissues from areca quid chewers and arecoline may among other constituents be responsible for the enhanced COX-2 expression in vivo. The regulation of COX-2 expression induced by arecoline is critically dependent on the cellular GSH concentration.

Arecoline↗
PubMed1982

Tolerance to the disruptive effects of arecoline on schedule-controlled behavior.

The roles of dispositional, physiological, and behavioral factors in the development of tolerance to the effects of arecoline on operant behavior were assessed. In Experiment I, rats were trained to press a lever on a variable-interval 15-s schedule for milk reinforcement. Dose-effect relationships were assessed prior to and during chronic arecoline (1.74 mg/kg/day) treatment. After 21 days of arecoline administration prior to each session, the dose-effect relationship for total number of responses did not shift. However, the dose-effect relationship for total number of reinforcers shifted to the right. In Experiment II, rats were trained to respond on a fixed-ratio 20 schedule for milk reinforcement. Dose-effect relationships were assessed prior to and during chronic arecoline (0.87 mg/kg/day) administration. One group of rats received daily injections of arecoline prior to the session and a second group received arecoline injections 30 min after the session. Daily administration of arecoline resulted in a greater shift to the right of the dose-effect relationship for the presession group than it did for the postsession group. These data demonstrate the importance of behavioral factors in the development of tolerance to arecoline.

Animals↗
PubMed2000

Synergistic effects of peroxynitrite on arecoline-induced cytotoxicity in human buccal mucosal fibroblasts.

Epidemiological studies have demonstrated a clear association between betel nut chewing and an increased risk for oral mucosal lesions. Arecoline, the most abundant betel alkaloid, is considered the most important etiologic factor in betel nuts. In addition, most betel nut chewers are also smokers. In order to elucidate the potential toxicological implications of interactions of arecoline and peroxynitrite (a reaction product of cigarette smoking), cell viability, and cellular levels of glutathione (GSH) were investigated, using cultured human buccal mucosal fibroblasts. At a concentration higher than 0.8 mM, arecoline was cytotoxic to buccal mucosal fibroblasts in a concentration- and time-dependent manner. Arecoline also depleted intracellular GSH in a dose-dependent manner (P<0.05). The addition of extracellular peroxynitrite acted as a synergistic effect on the arecoline-induced cytotoxicity (P<0.05). Furthermore, at a concentration of 0.8 mM, arecoline depleted intracellular GSH by about 42%, while 2 mM peroxynitrite enhanced the arecoline-depleted GSH level further to 86% as compared with the control. During GSH depletion, arecoline may render the human buccal mucosal fibroblasts more vulnerable to other reactive agents within cigarette smoking. Taken together, we suggest that people who combine the habits of betel nut chewing with cigarette smoking could be more susceptible to oral mucosal damage than betel quid chewing alone.

Arecoline↗