Prospects for the Use of Cannabinoid Receptor Ligands for the Treatment of Metabolic Syndrome and Atherosclerosis: Analysis of Experimental and Clinical Data

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Abstract

An antagonist of central cannabinoid CB1 receptors rimonabant causes weight loss in patients with obesity and metabolic syndrome, improves blood lipid parameters, increases the adiponectin level, decreases the rate of glucose and glycosylated hemoglobin in patients with diabetes mellitus
type-2. However, rimonabant adverse effects include depression, anxiety, nausea, and dizziness which are apparently due to the blockade of central CB1 receptors. In mice with a high-calorie diet, we defined that the blockade of peripheral CB1 receptors prevents obesity, steatosis of the liver, improves lipid and carbohydrate metabolism. Experimental studies suggest that peripheral CB2 receptor agonists have antiatherogenic effect. To validate the expediency of clinical research of CB2 receptor agonists in patients with atherosclerosis the comparative analysis of antiatherogenic properties of cannabinoids should be performed. In addition, experiments are needed on the combination use of cannabinoids with well-known antiatherogenic agents, such as statins.

About the authors

L. N. Maslov

Tomsk National Research Medical Centre, Russian Academy of Sciences

Author for correspondence.
Email: maslov@cardio-tomsk.ru
ORCID iD: 0000-0002-6020-1598

Доктор медицинских наук, профессор, руководитель лаборатории экспериментальной кардиологии Научно-исследовательского института кардиологии.

Адрес: 634012, Томск, ул. Киевская, д. 111А.

SPIN-код: 5843-2490

Russian Federation

R. S. Karpov

Tomsk National Research Medical Centre, Russian Academy of Sciences

Email: tvk@cardio-tomsk.ru
ORCID iD: 0000-0002-7011-4316

Доктор медицинских наук, профессор, академик РАН, научный руководитель Научно-исследовательского института кардиологии.

Адрес: 634012, Томск, ул. Киевская, д. 111А.

SPIN-код: 8263-2641

References

  1. Акимова Е.В., Каюмов З.Х., Гакова Е.И., Загородных Е.Ю., и др. Популяционные характеристики компонентов метаболического синдрома у мужчин 25–64 лет среднеурбанизированного сибирского города // Терапевтический архив. ― 2016. ― Т. 88. ― №3 ― С. 79−83. [Akimova EV, Kayumov RKh, Gakova EI, et al. Population characteristics of metabolic syndrome components in 25–64-year-old males of an average urbanized Siberian town. Ter Arkh. 2016;88(3):79−83. (In Russ).] doi: 10.17116/terarkh201688379-83.
  2. Хамедова М.Ш., Серебрякова В.Н., Трубачева И.А., Кавешников В.С. Распространенность отдельных компонентов метаболического синдрома среди педагогов. Сибирский медицинский журнал (Томск). ― 2013. ― Т. 28. ― № 3 ― С. 77−81. [Hamedova MS, Serebryakov VN, Trubacheva IA, Kaveshnikov VS. Prevalence of separate components of metabolic syndrome among secondary school teachers. Siberian Medical Journal. 2013;28(3):77−81. (In Russ).]
  3. Li R, Li W, Lun Z, et al. Prevalence of metabolic syndrome in Mainland China: a meta-analysis of published studies. BMC Public Health. 2016;16:296. doi: 10.1186/s12889-016-2870-y.
  4. Wong-McClure RA, Gregg EW, Barcelo A, et al. Prevalence of metabolic syndrome in Central America: a cross-sectional population-based study. Rev Panam Salud Publica. 2015;38(3):202−208.
  5. Wang J, Ruotsalainen S, Moilanen L, et al. The metabolic syndrome predicts cardiovascular mortality: a 13-year follow-up study in elderly non-diabetic Finns. Eur Heart J. 2007;28(7):857−864. doi: 10.1093/eurheartj/ehl524.
  6. Wang J, Ruotsalainen S, Moilanen L, et al. The metabolic syndrome predicts incident stroke: a 14-year follow-up study in elderly people in Finland. Stroke. 2008;39(4):1078−1083. doi: 10.1161/strokeaha.107.499830.
  7. Suslova TE, Sitozhevskii AV, Ogurkova ON, et al. Platelet hemostasis in patients with metabolic syndrome and type 2 diabetes mellitus: cGMP- and NO-dependent mechanisms in the insulin-mediated platelet aggregation. Front Physiol. 2015;5:501. doi: 10.3389/fphys.2014.00501.
  8. Maksimov ML, Svistunov AA, Tarasov VV, et al. Approaches for the development of drugs for treatment of obesity and metabolic syndrome. Curr Pharm Des. 2016;22(7):895−903. doi: 10.2174/1381612822666151209153047.
  9. Boyd ST. The endocannabinoid system. Pharmacotherapy. 2006;26(12 Pt 2):218S−221S. doi: 10.1592/phco.26.12part2.218S.
  10. Ruby MA, Nomura DK, Hudak CS, et al. Acute overactive endocannabinoid signaling induces glucose intolerance, hepatic steatosis, and novel cannabinoid receptor 1 responsive genes. PLoS One. 2011;6(11):e26415. doi: 10.1371/journal.pone.0026415.
  11. Yankey BN, Strasser S, Okosun IS. A cross-sectional analysis of the association between marijuana and cigarette smoking with metabolic syndrome among adults in the United States. Diabetes Metab Syndr. 2016;10(2 Suppl 1):S89−S95. doi: 10.1016/j.dsx.2016.03.001.
  12. Maslov LN, Khaliulin I, Zhang Y, et al. Prospects for creation of cardioprotective drugs based on cannabinoid receptor agonists. J Cardiovasc Pharmacol Ther. 2016;21(3):262−272. doi: 10.1177/1074248415612593.
  13. Matsuda LA, Lolait SJ, Brownstein MJ, et al. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 1990;346(6284):561−564. doi: 10.1038/346561a0.
  14. Bordicchia M, Battistoni I, Mancinelli L, et al. Cannabinoid CB1 receptor expression in relation to visceral adipose depots, endocannabinoid levels, microvascular damage, and the presence of the Cnr1 A3813G variant in humans. Metabolism. 2010;59(5):734−741. doi: 10.1016/j.metabol.2009.09.018.
  15. Tam J, Vemuri VK, Liu J, et al. Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity. J Clin Invest. 2010;120(8):2953−2966. doi: 10.1172/JCI42551.
  16. Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for cannabinoids. Nature. 1993;365(6441):61–65. doi: 10.1038/365061a0.
  17. Rajesh M, Mukhopadhyay P, Hasko G, et al. CB2 cannabinoid receptor agonists attenuate TNF-alpha-induced human vascular smooth muscle cell proliferation and migration. Br J Pharmacol. 2008;153(2):347−357. doi: 10.1038/sj.bjp.0707569.
  18. Ravinet Trillou C, Arnone M, Delgorge C, et al. Anti-obesity effect of SR141716, a CB1 receptor antagonist, in diet-induced obese mice. Am J Physiol Regul Integr Comp Physiol. 2003;284(2):R345−R353. doi: 10.1152/ajpregu.00545.2002.
  19. Hildebrandt AL, Kelly-Sullivan DM, Black SC. Antiobesity effects of chronic cannabinoid CB1 receptor antagonist treatment in diet-induced obese mice. Eur J Pharmacol. 2003;462(1−3):125−132. doi: 10.1016/s0014-2999(03)01343-8.
  20. Gary-Bobo M, Elachouri G, Gallas JF, et al. Rimonabant reduces obesity-associated hepatic steatosis and features of metabolic syndrome in obese Zucker fa/fa rats. Hepatology. 2007;46(1):122−129. doi: 10.1002/hep.21641.
  21. Merroun I, Sánchez-González C, Martínez R, et al. Novel effects of the cannabinoid inverse agonist AM 251 on parameters related to metabolic syndrome in obese Zucker rats. Metabolism. 2013;62(11):1641−1650. doi: 10.1016/j.metabol.2013.06.011.
  22. Boon MR, Kooijman S, van Dam AD, et al. Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity. FASEB J. 2014;28(12):5361−5375. doi: 10.1096/fj.13-247643.
  23. Van der Lans AA, Hoeks J, Brans B, et al. Cold acclimation recruits human brown fat and increases nonshivering thermogenesis. J Clin Invest. 2013;123(8):3395−3403. doi: 10.1172/JCI68993.
  24. Schmitz K, Mangels N, Häussler A, et al. Pro-inflammatory obesity in aged cannabinoid-2 receptor-deficient mice. Int J Obes (Lond). 2016;40(2):366−379. doi: 10.1038/ijo.2015.169.
  25. Van Gaal LF, Rissanen AM, Scheen AJ, et al. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet. 2005;365(9468):1389−1397. doi: 10.1016/S0140-6736(05)66374-X.
  26. Despres JP, Golay A, Sjostrom L, Rimonabant in Obesity-Lipids Study Group. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005;353(20):2121−2134. doi: 10.1056/NEJMoa044537.
  27. Pi-Sunyer FX, Aronne LJ, Heshmati HM, et al. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA. 2006;295(7):761−775. doi: 10.1001/jama.295.7.761.
  28. Scheen AJ, Finer N, Hollander P, et al. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet. 2006;368(9548):1660−1672. doi: 10.1016/S0140-6736(06)69571-8.
  29. Van Gaal L, Pi-Sunyer X, Despres JP, et al. Efficacy and safety of rimonabant for improvement of multiple cardiometabolic risk factors in overweight/obese patients: pooled 1-year data from the Rimonabant in Obesity (RIO) program. Diabetes Care. 2008;31 Suppl 2:S229−S240. doi: 10.2337/dc08-s258.
  30. Topol EJ, Bousser MG, Fox KA, et al. Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial. Lancet. 2010;376(9740):517−523. doi: 10.1016/S0140-6736(10)60935-X.
  31. Triay J, Mundi M, Klein S, et al. Does rimonabant independently affect free fatty acid and glucose metabolism? J Clin Endocrinol Metab. 2012;97(3):819−827. doi: 10.1210/jc.2011-2486.
  32. Bergholm R, Sevastianova K, Santos A, et al. CB1 blockade-induced weight loss over 48 weeks decreases liver fat in proportion to weight loss in humans. Int J Obes (Lond). 2013;37(5):699−703. doi: 10.1038/ijo.2012.116.
  33. Aronne LJ, Tonstad S, Moreno M, et al. A clinical trial assessing the safety and efficacy of taranabant, a CB1R inverse agonist, in obese and overweight patients: a high-dose study. Int J Obes (Lond). 2010;34(5):919−935. doi: 10.1038/ijo.2010.21.
  34. Chang CP, Wu CH, Song JS, et al. Discovery of 1-(2,4-dichlorophenyl)-N-(piperidin-1-yl)-4-((pyrrolidine-1-sulfonamido)methyl)-5-(5-((4-(trifluoromethyl) phenyl) ethynyl) thiophene-2-yl)-1H-pyrazole-3-carboxamide as a novel peripherally restricted cannabinoid-1 receptor antagonist with significant weight-loss efficacy in diet-induced obese mice. J Med Chem. 2013;56(24):9920−9933. doi: 10.1038/ijo.2010.21.
  35. Steffens S, Veillard NR, Arnaud C, et al. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice. Nature. 2005;434(7034):782−726. doi: 10.1038/nature03389.
  36. Montecucco F, Di Marzo V, da Silva RF, et al. The activation of the cannabinoid receptor type 2 reduces neutrophilic protease-mediated vulnerability in atherosclerotic plaques. Eur Heart J. 2012;33(7):846−856. doi: 10.1093/eurheartj/ehr449.
  37. Nissen SE, Nicholls SJ, Wolski K, et al. Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial. JAMA. 2008;299(13):1547−1560. doi: 10.1001/jama.299.13.1547.
  38. O’Leary DH, Reuwer AQ, Nissen SE, et al. Effect of rimonabant on carotid intima-media thickness (CIMT) progression in patients with abdominal obesity and metabolic syndrome: the AUDITOR Trial. Heart. 2011;97(14):1143−1150. doi: 10.1136/hrt.2011.223446.
  39. Dol-Gleizes F, Paumelle R, Visentin V, et al. Rimonabant, a selective cannabinoid CB1 receptor antagonist, inhibits atherosclerosis in LDL receptor-deficient mice. Arterioscler Thromb Vasc Biol. 2009;29(1):12−18. doi: 10.1161/ATVBAHA.108.168757.
  40. Lichtman AH, Wiley JL, LaVecchia KL, et al. Effects of SR 141716A after acute or chronic cannabinoid administration in dogs. Eur J Pharmacol. 1998;357(2−3):139−148. doi: 10.1016/s0014-2999(98)00558-5.
  41. Montecucco F, Burger F, Mach F, Steffens S. CB2 cannabinoid receptor agonist JWH-015 modulates human monocyte migration through defined intracellular signaling pathways. Am J Physiol Heart Circ Physiol. 2008;294(3):H1145−H1155. doi: 10.1152/ajpheart.01328.2007.
  42. Freeman-Anderson NE, Pickle TG, Netherland CD, et al. Cannabinoid (CB2) receptor deficiency reduces the susceptibility of macrophages to oxidized LDL/oxysterol-induced apoptosis. J Lipid Res. 2008;49(11):2338−2346. doi: 10.1194/jlr.M800105-JLR200.
  43. Zhao Y, Yuan Z, Liu Y, et al. Activation of cannabinoid CB2 receptor ameliorates atherosclerosis associated with suppression of adhesion molecules. J Cardiovasc Pharmacol. 2010;55(3):292−298. doi: 10.1097/FJC.0b013e3181d2644d.
  44. Willecke F, Zeschky K, Ortiz Rodriguez A, et al. Cannabinoid receptor 2 signaling does not modulate atherogenesis in mice. PLoS One. 2011;6(4):e19405. doi: 10.1371/journal.pone.0019405.
  45. Hoyer FF, Steinmetz M, Zimmer S, et al. Atheroprotection via cannabinoid receptor-2 is mediated by circulating and vascular cells in vivo. J Mol Cell Cardiol. 2011;51(6):1007−1014. doi: 10.1016/j.yjmcc.2011.08.008.
  46. Chiurchiu V, Lanuti M, Catanzaro G, et al. Detailed characterization of the endocannabinoid system in human macrophages and foam cells, and anti-inflammatory role of type-2 cannabinoid receptor. Atherosclerosis. 2014;233(1):55−63. doi: 10.1016/j.atherosclerosis.2013.12.042.
  47. Netherland-Van Dyke C, Rodgers W, Lahr Z, Thewke D. Cannabinoid receptor type 2 (CB2) dependent and independent effects of WIN55,212-2 on atherosclerosis in Ldlr-null mice. J Cardiol Ther. 2015;3(2):53−63. doi: 10.12970/2311-052X.2015.03.02.2.
  48. Netherland CD, Pickle TG, Bales A, Thewke DP. Cannabinoid receptor type 2 (CB2) deficiency alters atherosclerotic lesion formation in hyperlipidemic Ldlr-null mice. Atherosclerosis. 2010;213(1):102−108. doi: 10.1016/j.atherosclerosis.2010.07.060.
  49. Delsing DJ, Leijten FP, Arts K, et al. Cannabinoid receptor 2 deficiency in haematopoietic cells aggravates early atherosclerosis in LDL receptor deficient mice. Open Cardiovasc Med J. 2011;5:15−21. doi: 10.2174/1874192401105010015.

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