Die Blockade des Endocannabinoidsystems - Gewichtsreduktion und kardiovaskuläres Risikomanagement

Zusammenfassung

Eine Blockade des Endocannabinoidsystems stellt eine neue Möglichkeit dar, über eine Gewichtsreduktion hinaus eine deutliche Reduktion kardiovaskulärer Risikofaktoren zu erreichen. Endocannabinoide sowie deren Rezeptoren sind sowohl im zentralen Nervensystem als auch in der Peripherie in verschiedenen Organen exprimiert und regulieren die zentrale Steuerung der Nahrungsaufnahme und die peripheren metabolischen Regelkreise. Im Kontext einer Steuerung der Nahrungsaufnahme ist der Cannabinoid-Rezeptor 1 (CB₁-Rezeptor) von zentraler Bedeutung. Seine Stimulation mit Δ⁹-Tetrahydrocannabiol (Δ⁹-THC) oder die Blockade mit Rimonabant sind klinisch bedeutsame therapeutische Ansätze zur Steuerung des Körpergewichts. Rimonabant ist der erste Vertreter einer neuen Gruppe von Medikamenten, die über eine Blockade des CB₁-Rezeptors in das Endocannabinoidsystem eingreifen. Mit der in klinischen Studien gefundenen deutlichen Reduktion des Körpergewichts und des Taillenumfangs geht eine Verbesserung des kardiovaskulären Risikoprofils einher, die durch einen Anstieg des HDL-Cholesterins, einem Absinken der Serumtriglyzeride und eine verbesserte Insulinsensitivität gekennzeichnet ist.

Summary

Blocking the endocannabinoid system is an option that substantially reduces cardiovascular risk beyond reducing body weight. Endocannabinoids and their receptors are expressed in the central nervous system as well as in the peripheral organs and regulate the central circuits for food uptake and peripheral metabolic circuits. Within the context of food uptake the cannabinoid receptors 1 (CB₁-receptor) is of crucial importance. Its stimulation with Δ⁹-tetrahydrocannabiol (Δ⁹-THC) or its blockade with rimonabant are clinically relevant therapeutic means to maintain body weight. Rimonabant is the first of a new class of drugs, that interferes with the endocannabinoid system by blocking the CB₁-Receptor. In recent clinical studies a substantial reduction of body weight and waist circumference was associated with an improvement of the cardiovascular risk profile, which was marked by increased HDL-cholesterol, serum triglycerides and improved insulin sensivity.

Literatur

• 1 RIO-EUROPE .Rimonabant impressive once more in obesity:. http://www.theheart.org > Heartwire > News > Aug 29, 2004
• 2 Third Report of the National Cholesterol Education Program (NCEP) . Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.  Circulation. 2002;  106 3143-3421
• 3 Two-year data for rimonabant „encouraging” once again for weight loss, CV risk factor reduction:. http://www.theheart.org > Heartwire > News > Nov 9, 2004
• 4 Bensaid M, Gary-Bobo M, Esclangon A. et al . The cannabinoid CB1 receptor antagonist SR141716 increases Acrp30 mRNA expression in adipose tissue of obese fa/fa rats and in cultured adipocyte cells.  Mol Pharmacol. 2003;  63 908-914
• 5 Bramlage P, Wittchen H U, Pittrow D. et al . Recognition and management of overweight and obesity in primary care in Germany.  Int J Obes Relat Metab Disord. 2004;  28 1299-1308
• 6 Christopoulos A, Coles P, Lay L, Lew M J, Angus J A. Pharmacological analysis of cannabinoid receptor activity in the rat vas deferens.  Br J Pharmacol. 2001;  132 1281-1291
• 7 Cleland J G, Ghosh J, Freemantle N. et al . Clinical trials update and cumulative meta-analyses from the American College of Cardiology: WATCH, SCD-HeFT, DINAMIT, CASINO, INSPIRE, STRATUS-US, RIO-Lipids and cardiac resynchronisation therapy in heart failure.  Eur J Heart Fail. 2004;  6 501-508
• 8 Cota D, Marsicano G, Lutz B. et al . Endogenous cannabinoid system as a modulator of food intake.  Int J Obes Relat Metab Disord. 2003;  27 289-301
• 9 Cota D, Marsicano G, Tschop M. et al . The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis.  J Clin Invest. 2003;  112 423-431
• 10 Devane W A, Hanus L, Breuer A. et al . Isolation and structure of a brain constituent that binds to the cannabinoid receptor.  Science. 1992;  258 1946-1949
• 11 Di Marzo V, Bifulco M, De Petrocellis L. The endocannabinoid system and its therapeutic exploitation.  Nat Rev Drug Discov. 2004;  3 771-784
• 12 Di Marzo V, Goparaju S K, Wang L. et al . Leptin-regulated endocannabinoids are involved in maintaining food intake.  Nature. 2001;  410 822-825
• 13 Gomez R, Navarro M, Ferrer B. et al . A peripheral mechanism for CB1 cannabinoid receptor-dependent modulation of feeding.  J Neurosci. 2002;  22 9612-9617
• 14 Guerre-Millo M. Adipose tissue hormones.  J Endocrinol Invest. 2002;  25 855-861
• 15 Hao S, Avraham Y, Mechoulam R, Berry E M. Low dose anandamide affects food intake, cognitive function, neurotransmitter and corticosterone levels in diet-restricted mice.  Eur J Pharmacol. 2000;  392 147-156
• 16 Harrold J A, Elliott J C, King P J, Widdowson P S, Williams G. Down-regulation of cannabinoid-1 (CB-1) receptors in specific extrahypothalamic regions of rats with dietary obesity: a role for endogenous cannabinoids in driving appetite for palatable food?.  Brain Res. 2002;  952 232-238
• 17 Hildebrandt A L, Kelly-Sullivan D M, Black S C. Antiobesity effects of chronic cannabinoid CB1 receptor antagonist treatment in diet-induced obese mice.  Eur J Pharmacol. 2003;  462 125-132
• 18 Hill J O, Wyatt H R, Reed G W, Peters J C. Obesity and the environment: where do we go from here?.  Science. 2003;  299 853-855
• 19 Kirkham T C, Williams C M. Endogenous cannabinoids and appetite.  Nutr Res Rev. 2001;  14 65-86
• 20 Kirkham T C, Williams C M, Fezza F, Di Marzo V. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol.  Br J Pharmacol. 2002;  136 550-557
• 21 Landi M, Croci T, Rinaldi-Carmona M, Maffrand J P, Le Fur G, Manara L. Modulation of gastric emptying and gastrointestinal transit in rats through intestinal cannabinoid CB(1) receptors.  Eur J Pharmacol. 2002;  450 77-83
• 22 Lange J H, Coolen H K, van Stuivenberg H H. et al . Synthesis, biological properties, and molecular modeling investigations of novel 3,4-diarylpyrazolines as potent and selective CB(1) cannabinoid receptor antagonists.  J Med Chem. 2004;  47 627-643
• 23 Matsuda L A, Lolait S J, Brownstein M J, Young A C, Bonner T I. Structure of a cannabinoid receptor and functional expression of the cloned cDNA.  Nature. 1990;  346 561-564
• 24 McAllister S D, Glass M. CB(1) and CB(2) receptor-mediated signalling: a focus on endocannabinoids.  Prostaglandins Leukot Essent Fatty Acids. 2002;  66 161-171
• 25 McPartland J M, Glass M. Functional mapping of cannabinoid receptor homologs in mammals, other vertebrates, and invertebrates.  Gene. 2003;  312 297-303
• 26 Mechoulam R. Cannabis as a therapeutic agent. Boca Raton: CRC Press In: Mechoulam R (Editor) 1986
• 27 Merker N, Wagner N, Kirch W, Muller M J. Frühzeitige Prävention von Adipositas und Herz-Kreislauferkrankungen.  Dtsch Med Wochenschr. 2002;  127 2661-2663
• 28 Peeters A, Barendregt J J, Willekens F, Mackenbach J P, Al Mamun A, Bonneux L. Obesity in adulthood and its consequences for life expectancy: a life-table analysis.  Ann Intern Med. 2003;  138 24-32
• 29 Pertwee R G. Pharmacology of cannabinoid CB1 and CB2 receptors.  Pharmacol Ther. 1997;  74 129-180
• 30 Plasse T F, Gorter R W, Krasnow S H, Lane M, Shepard K V, Wadleigh R G. Recent clinical experience with dronabinol.  Pharmacol Biochem Behav. 1991;  40 695-700
• 31 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 R345-353
• 32 Xie X Q, Pavlopoulos S, DiMeglio D M, Makriyannis A. Conformational studies on a diastereoisomeric pair of tricyclic nonclassical cannabinoids by NMR spectroscopy and computer molecular modeling.  J Med Chem. 1998;  41 167-174