O Sistema Endocanabinóide – uma perspetiva terapêutica.
Abstract
Although the medicinal use of Cannabis sativa derivatives is well known since antiquity, the study of their properties expanded recently with the discovery of an endogenous cannabinoid system, which comprises the endogenous cannabis-like ligands (endocannabinoids), the cannabinoid receptors (CB1 and CB2) and the enzymes involved in their metabolism. Since the discovery of the endocannabinoid system (ECS), the scientific community focused on research of its clinical use and achieved important findings during the last decade. In some countries, cannabis derivatives are a pharmacological option for appetite stimulation and pain treatment. However, the first ECS-based drug rimonabant (a CB1 antagonist), approved for the treatment obesity with associated risk factors, was withdrawn due to safety concerns. Nowadays, based on the growing evidences resulting from preclinical and clinical studies of ECS modulators, these drugs are currently pointed out as novel therapeutic approaches for several pathophysiological conditions. Here, we review the potential role of (endo)cannabinoid system in therapeutics and the recent designed strategies for the development of drugs that target this system.
References
Robson PJ. Therapeutic potential of cannabinoid medicines. Drug Testing and Analysis. 2013 Sep 4, (Doi: 10.1002/dta.1529).
Mechoulam R, Gaoni Y. A Total Synthesis of Dl- Delta-1-Tetrahydrocannabinol, the Active Constit- uent of Hashish. J Am Chem Soc. 1965; 87:3273-5.
Pertwee RG. Targeting the endocannabinoid sys- tem with cannabinoid receptor agonists: phar- macological strategies and therapeutic possibili- ties. Philos Trans R Soc Lond B Biol Sci. 2012; 367(1607):3353-63.
Devane WA, Dysarz FA, 3rd, Johnson MR, Melvin LS, Howlett AC. Determination and characteriza- tion of a cannabinoid receptor in rat brain. Mol Pharmacol. 1988;34(5):605-13.
Devane WA, Hanus L, Breuer A, Pertwee RG, Ste- venson LA, Griffin G, et al. Isolation and structure of a brain constituent that binds to the cannabi- noid receptor. Science. 1992; 258(5090):1946-9.
Munro S, Thomas KL, Abu-Shaar M. Molecular characterization of a peripheral receptor for can- nabinoids. Nature. 1993; 365(6441):61-5.
Fonseca BM, Costa MA, Almada M, Correia-da- Silva G, Teixeira NA. Endogenous cannabinoids revisited: a biochemistry perspective. Prostaglan- dins Other Lipid Mediat. 2013; 102-103:13-30.
FowlerCJ.Transportofendocannabinoidsacross the plasma membrane and within the cell. FEBS J. 2013; 280(9):1895-904.
Pacher P, Kunos G. Modulating the endocannabi- noid system in human health and disease--suc- cesses and failures. FEBS J. 2013; 280(9):1918-43.
Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimaraes FS. Multiple mechanisms involved in the large-spectrum therapeutic potential of can- nabidiol in psychiatric disorders. Philos Trans R Soc Lond B Biol Sci. 2012; 367(1607):3364-78.
Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Batkai S, et al. Endocannabinoid ac- tivation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity. J Clin Invest. 2005; 115(5):1298-305.
Maresz K, Pryce G, Ponomarev ED, Marsicano G,Croxford JL, Shriver LP, et al. Direct suppression of CNS autoimmune inflammation via the canna- binoid receptor CB(1) on neurons and CB(2) on autoreactive T cells. Nat Med. 2007; 13(4):492-7.
Fonseca BM, Correia-da-Silva G, Taylor AH, Lam PM, Marczylo TH, Bell SC, et al. The endocan- nabinoid 2-arachidonoylglycerol (2-AG) and me- tabolizing enzymes during rat fetoplacental de- velopment: a role in uterine remodelling. Int J Biochem Cell Biol. 2010; 42(11):1884-92.
Talwar R, Potluri VK. Cannabinoid 1 (CB1) recep- tor--pharmacology, role in pain and recent devel- opments in emerging CB1 agonists. CNS Neurol Disord Drug Targets. 2011; 10(5):536-44.
Marco EM, Romero-Zerbo SY, Viveros MP, Bermu- dez-Silva FJ. The role of the endocannabinoid sys- tem in eating disorders: pharmacological implica- tions. Behav Pharmacol. 2012; 23(5-6):526-36.
Bilkei-Gorzo A. The endocannabinoid system in normal and pathological brain ageing. Philos Trans R Soc Lond B Biol Sci. 2012; 367(1607):3326-41.
Montecucco F, Di Marzo V. At the heart of the mat- ter: the endocannabinoid system in cardiovascu- lar function and dysfunction. Trends Pharmacol Sci. 2012; 33(6):331-40.
Zogopoulos P, Vasileiou I, Patsouris E, Theocharis SE. The role of endocannabinoids in pain modula- tion. Fundam Clin Pharmacol. 2013; 27(1):64-80.
Lederer CM. The use of marijuana to treat glau- coma. Missouri Medicine. 2012; 109(2):95.
Ashton CH, Moore PB. Endocannabinoid system dysfunction in mood and related disorders. Acta Psychiatr Scand. 2011; 124(4):250-61.
Parker LA, Rock EM, Limebeer CL. Regulation of nausea and vomiting by cannabinoids. Br J Phar- macol. 2011; 163(7):1411-22.
Hall W, Degenhardt L. The adverse health effects of chronic cannabis use. Drug Testing and Analy- sis. 2013, (Doi: 10.1002/dta.1506).
Hall W, Degenhardt L. Adverse health effects of non-medical cannabis use. Lancet. 2009; 374(9698):1383-91.
Buys YM, Rafuse PE. Canadian Ophthalmological Society policy statement on the medical use of marijuana for glaucoma. Can J Ophthalmol. 2010; 45(4):324-6.
Elsohly MA, Slade D. Chemical constituents of marijuana: the complex mixture of natural can- nabinoids. Life Sci. 2005; 78(5):539-48.
Russo EB, Burnett A, Hall B, Parker KK. Agonis- tic properties of cannabidiol at 5-HT1a receptors. Neurochem Res. 2005; 30(8):1037-43.
Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and car- diovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet. 2005; 365(9468):1389-97.
Tam J, Vemuri VK, Liu J, Batkai S, Mukhopadhyay B, Godlewski G, et al. Peripheral CB1 cannabi- noid receptor blockade improves cardiometabol- ic risk in mouse models of obesity. J Clin Invest. 2010; 120(8):2953-66.
Ravinet Trillou C, Delgorge C, Menet C, Arnone M, Soubrie P. CB1 cannabinoid receptor knock- out in mice leads to leanness, resistance to diet- induced obesity and enhanced leptin sensitivity. Int J Obes Relat Metab Disord. 2004; 28(4):640-8.
Sam AH, Salem V, Ghatei MA. Rimonabant: From RIO to Ban. J Obes. 2011;2011:432607.
Moreira FA, Crippa JA. The psychiatric side- effects of rimonabant. Rev Bras Psiquiatr. 2009; 31(2):145-53.
Alonso M, Serrano A, Vida M, Crespillo A, Her- nandez-Folgado L, Jagerovic N, et al. Anti-obesity efficacy of LH-21, a cannabinoid CB(1) recep- tor antagonist with poor brain penetration, in diet-induced obese rats. Br J Pharmacol. 2012; 165(7):2274-91.
Engeli S, Bohnke J, Feldpausch M, Gorzelniak K, Janke J, Batkai S, et al. Activation of the periph- eral endocannabinoid system in human obesity. Diabetes. 2005; 54(10):2838-43.
Boger DL, Miyauchi H, Du W, Hardouin C, Fecik RA, Cheng H, et al. Discovery of a potent, selec- tive, and efficacious class of reversible alpha- ketoheterocycle inhibitors of fatty acid amide hydrolase effective as analgesics. J Med Chem. 2005; 48(6):1849-56.
De Petrocellis L, Bisogno T, Davis JB, Pertwee RG, Di Marzo V. Overlap between the ligand recog- nition properties of the anandamide transport- er and the VR1 vanilloid receptor: inhibitors of anandamide uptake with negligible capsaicin-like activity. FEBS letters. [Research Support, Non- U.S. Gov’t]. 2000; 483(1):52-6.
Tambaro S, Bortolato M. Cannabinoid-related agents in the treatment of anxiety disorders: cur- rent knowledge and future perspectives. Recent Pat CNS Drug Discov. 2012; 7(1):25-40.
[cited 2013 22/02/2013]; Available from: http:// clinicaltrials.gov/ct2/show/NCT01618656.