Arecoline hydrobromide is a brain-penetrant non-selective partial agonist of muscarinic acetylcholine receptors M1-M5 (EC50=7nM, 95nM, 11nM, 410nM, 69nM respectively) and a nicotinic acetylcholine receptor agonist. Arecoline hydrobromide causes smooth muscle contraction and stimulates central cholinergic neurotransmission by activating the cholinergic pathway. Arecoline hydrobromide inhibits the PI3K/AKT pathway, ACAT1 tetramer, and hERG potassium channel. Arecoline hydrobromide is used in studies related to cognitive disorders such as Alzheimer's disease, rheumatoid arthritis, diabetic complications, parasitic infections, and oral cancer[1-4].
In vitro, treatment of HaCaT cells with 0-100μg/mL Arecoline hydrobromide for 24-72 hours decreased cell viability and metabolic activity, inhibited cell proliferation, induced G1/G0 phase cell cycle arrest, generated reactive oxygen species, upregulated HMOX-1, FTL, G6PD, GCLC, GR and IL-1α mRNA expression, and suppressed catalase activity[5]. Treatment of H1299 cells with Arecoline hydrobromide for 1-5 days reduced ACAT1 enzyme activity and Y407 phosphorylation, disrupted ACAT1 tetramer formation, increased pyruvate dehydrogenase complex flux, decreased glycolysis rate and lactate production, elevated oxygen consumption rate and intracellular ATP level, and inhibited cell proliferation[6]. Treatment of A549 and K562 cells with Arecoline hydrobromide for 48 hours decreased cell viability[7].
In vivo, free drinking of 6-20mg/kg Arecoline hydrobromide by C57B1/6Ncr mice for 2 weeks improved memory retention performance in the T-maze active avoidance task[8]. Feeding of C57BL/6 mice with 0.2% cuprizone diet combined with drinking water containing 2.5-5mg/kg Arecoline hydrobromide for 12 weeks increased the percentage of spontaneous alternation behavior in the Y-maze and elevated the MBP/β-actin ratio in the prefrontal cortex[9]. Intraperitoneal injection of 5mg/kg Arecoline hydrobromide twice daily for 10 days in type 1 diabetic Wistar rat model elevated serum insulin levels, lowered blood glucose, increased liver glycogen content, improved intraperitoneal glucose tolerance, elevated serum testosterone, FSH, and LH levels, and increased coagulating gland fructose and seminal vesicle sialic acid contents[10].
References:[1] Gao W, He Y, Zhang Y, et al. Comprehensive Insights into Arecoline Hydrobromide: Pharmacology, Toxicity, and Pharmacokinetics. Med Sci Monit. 2024 Nov 11;30:e945582.
[2] Wei X, Zhang J, Niu J,et al. Evaluation of arecoline hydrobromide toxicity after a 14-day repeated oral administration in Wistar rats. PLoS One. 2015 Apr 16;10(4):e0120165.
[3] Gregory GG, McConnell JD. The toxicity and efficiency of arecoline hydrobromide in the Tasmanian hydatid control program. Aust Vet J. 1978 Apr;54(4):193-5.
[4] Chen Q, Jiang Z, Zhang J, et al. Arecoline Hydrobromide Enhances Jejunum Smooth Muscle Contractility via Voltage-Dependent Potassium Channels in W/Wv Mice. Physiol Res. 2021;70(3):437-446.
[5] Thangjam GS, Kondaiah P. Regulation of oxidative-stress responsive genes by arecoline in human keratinocytes. J Periodont Res. 2009;44(6):673-682.
[6] Fan J, Lin R, Xia S, et al. Tetrameric acetyl-CoA acetyltransferase 1 is important for tumor growth. Mol Cell. 2016 Dec 1;64(5):859-874.
[7] Ragab AE, Badawy ET, Aboukhatwa SM, et al. In Vitro Characterization of Inhibitors for Lung A549 and Leukemia K562 Cell Lines from Fungal Transformation of Arecoline Supported by In Silico Docking to M3-mAChR and ADME Prediction. Pharmaceuticals. 2022 Oct;15(10):1171.
[8] Flood JF, Smith GE, Cherkin A. Memory retention test performance in mice: Improvement by chronic oral cholinergic drug treatment. Pharmacol Biochem Behav. 1984;21(1):169-173.
[9] Xu Z, Adilijiang A, Wang W, et al. Arecoline attenuates memory impairment and demyelination in a cuprizone-induced mouse model of schizophrenia. NeuroReport. 2019 Jan;30(2):134-138.
[10] Saha I, Das J, Maiti B, et al. A Protective Role of Arecoline Hydrobromide in Experimentally Induced Male Diabetic Rats. Biomed Res Int. 2015;2015:136738.