TERAPÖTİK HEDEF OLARAK ENDOKANNABİNOİD SİSTEM
Keywords:
Kannabinoid, THC, CBD, kenevir, kanserAbstract
Kenevir geçmişten günümüze içerdiği farmasötik öneme sahip bileşenleri nedeniyle yıllar boyunca ağrı kesici ve öfori verici olarak, zengin bir lif kaynağı olması nedeniyle de kumaş ve kâğıt üretiminde kullanılmıştır. Günümüzde de yine bu özellikleri nedeniyle tıp ve endüstride kullanılabilen önemli bir bitkidir. Kenevirin insanlar üzerindeki etkileri, içerdikleri fitokannabinoidler tarafından sağlanmaktadır. Fitokannabinoidler, kenevirden elde edilen ikincil metabolitlerin en önemli sınıfı olup psikoaktif özellik gösteren ve göstermeyen etken maddeler içermesine göre sınıflandırılabilmektedir. Bu bileşenlerin terapötik potansiyeli her geçen gün yapılan çalışmalarla ortaya konulmaktadır. Kenevir ile ilgili çalışmalar günümüzde hala tartışmalı ve bazen çelişkili olsa da tetrahidrokannabinol (THC) ve kannabidiol (CBD) başta olmak üzere çeşitli fitokannabinoidlerin kanser, epilepsi, iltihaplanma, bağımlılık gibi çeşitli patolojik durumlarda sağlık üzerinde olumlu etkileri olduğu belirtilmiştir. Yapılan bu çalışmaların çoğu, kenevirde üretilen iki ana kannabinoide odaklanmış olsa da kenevirde birçok benzersiz kannabinoid tanımlanmıştır. Kenevir bu etkisini, endokannabinoid sistem elemanlarıyla gerçekleştirmektedir. Bu sistem vücudun neredeyse tamamına yayılmıştır ve vücudun birçok farklı temel işlevini yerine getirmesinde düzenleyici rol oynamaktadır. Endokannabinoid sistemdeki terapötik hedeflerin belirlenmesi ve kenevirde daha az oranda bulunan fitokannabinoidlerin farmakolojik etkilerinin açığa kavuşturulması için yapılacak çalışmalar, kenevirin tıbbi kullanımını arttırabilecektir. Günümüzde kenevir bileşenlerinin terapötik potansiyellerinin tam olarak değerlendirilmesi için büyük ölçekli klinik çalışmalara ihtiyaç duyulmaktadır. Bu derlemede; fitokannabinoidler, endokannabinoid sistemin özellikleri ve etki mekanizmasına ek olarak bu bileşenlerin tedavi amaçlı kullanımları ayrıntılı bir şekilde irdelenmiştir.
References
Kaynaklar:
Howlett AC, Breivogel CS, Childers SR, Deadwyler SA, Hampson RE, Porrino LJ. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;47:345–58.
Tao R, Li C, Jaffe AE, Shin JH, Deep-Soboslay A, Yamin R, et al. Cannabinoid receptor CNR1 expression and DNA methylation in human prefrontal cortex, hippocampus and caudate in brain development and schizophrenia. Transl Psychiatry [Internet]. 2020;10(1):158. Available from: https://doi.org/10.1038/s41398-020-0832-8
LaFrance EM, Stueber A, Glodosky NC, Mauzay D, Cuttler C. Overbaked: assessing and predicting acute adverse reactions to Cannabis. J Cannabis Res. 2020;2:1–10.
Kano M. Control of synaptic function by endocannabinoid-mediated retrograde signaling. Proceedings of the Japan Academy, Series B. 2014;90(7):235–50.
Maccarrone M, Bab I, B’iró T, Cabral GA, Dey SK, Di Marzo V, et al. Endocannabinoid signaling at the periphery: 50 years after THC. Trends Pharmacol Sci. 2015;36(5):277–96.
Zou S, Kumar U. Cannabinoid receptors and the endocannabinoid system: signaling and function in the central nervous system. Int J Mol Sci. 2018;19(3):833.
Rozenfeld R. Type I cannabinoid receptor trafficking: all roads lead to lysosome. Traffic. 2011;12(1):12–8.
Bénard G, Massa F, Puente N, Lourenço J, Bellocchio L, Soria-Gómez E, et al. Mitochondrial CB1 receptors regulate neuronal energy metabolism. Nat Neurosci. 2012;15(4):558–64.
Koch M, Varela L, Kim JG, Kim JD, Hernández-Nuño F, Simonds SE, et al. Hypothalamic POMC neurons promote cannabinoid-induced feeding. Nature. 2015;519(7541):45–50.
Ma L, Jia J, Niu W, Jiang T, Zhai Q, Yang L, et al. Mitochondrial CB1 receptor is involved in ACEA-induced protective effects on neurons and mitochondrial functions. Sci Rep. 2015;5(1):12440.
Hebert-Chatelain E, Desprez T, Serrat R, Bellocchio L, Soria-Gomez E, Busquets-Garcia A, et al. A cannabinoid link between mitochondria and memory. Nature. 2016;539(7630):555–9.
Atwood BK, Mackie K. CB2: a cannabinoid receptor with an identity crisis. Br J Pharmacol. 2010;160(3):467–79.
Brailoiu GC, Deliu E, Marcu J, Hoffman NE, Console-Bram L, Zhao P, et al. Differential activation of intracellular versus plasmalemmal CB2 cannabinoid receptors. Biochemistry. 2014;53(30):4990–9.
De Petrocellis L, Ligresti A, Moriello AS, Allarà M, Bisogno T, Petrosino S, et al. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol [Internet]. 2011 Aug [cited 2023 Nov 7];163(7):1479–94. Available from: https://pubmed.ncbi.nlm.nih.gov/21175579/
Felder CC, Joyce KE, Briley EM, Mansouri J, Mackie K, Blond O, et al. Comparison of the pharmacology and signal transduction of the human cannabinoid CB1 and CB2 receptors. Mol Pharmacol. 1995;48(3):443–50.
Basavarajappa BS. Critical enzymes involved in endocannabinoid metabolism. Protein Pept Lett. 2007;14(3):237–46.
Chapman KD. Emerging physiological roles for N-acylphosphatidylethanolamine metabolism in plants: signal transduction and membrane protection. Chem Phys Lipids. 2000 Nov 1;108(1–2):221–9.
Ueda N, Okamoto Y, Tsuboi K. Endocannabinoid-Related Enzymes as Drug Targets with Special Reference to N-Acylphosphatidylethanolamine-Hydrolyzing Phospholipase D. Curr Med Chem. 2005 May 28;12(12):1413–22.
Ueda N. Endocannabinoid hydrolases. Prostaglandins Other Lipid Mediat. 2002 Aug 1;68–69:521–34.
Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995;50(1):83–90.
Sugiura T, Kodaka T, Kondo S, Tonegawa T, Nakane S, Kishimoto S, et al. 2-Arachidonoylglycerol, a putative endogenous cannabinoid receptor ligand, induces rapid, transient elevation of intracellular free Ca2+ in neuroblastoma glioma hybrid NG108-15 cells. Biochem Biophys Res Commun. 1996;229(1):58–64.
Sugiura T, Kondo S, Sukagawa A, Nakane S, Shinoda A, Itoh K, et al. 2-Arachidonoylgylcerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun. 1995;215(1):89–97.
Bisogno T, Berrendero F, Ambrosino G, Cebeira M, Ramos JA, Fernandez-Ruiz JJ, et al. Brain regional distribution of endocannabinoids: implications for their biosynthesis and biological function. Biochem Biophys Res Commun. 1999;256(2):377–80.
Sugiura T, Kobayashi Y, Oka S, Waku K. Biosynthesis and degradation of anandamide and 2-arachidonoylglycerol and their possible physiological significance. Prostaglandins, Leukotrienes and Essential Fatty Acids (PLEFA). 2002;66(2–3):173–92.
Van Egmond N, Straub VM, Van Der Stelt M. Targeting Endocannabinoid Signaling: FAAH and MAG Lipase Inhibitors. https://doi.org/101146/annurev-pharmtox-030220-112741 [Internet]. 2021 Jan 7 [cited 2023 Nov 14];61:441–63. Available from: https://www.annualreviews.org/doi/abs/10.1146/annurev-pharmtox-030220-112741
Narouze SN. Cannabinoids and pain: mechanisms of action. In: Cannabinoids and Pain. Springer; 2021. p. 191–204.
MacLennan SJ, Reynen PH, Kwan J, Bonhaus DW. Evidence for inverse agonism of SR141716A at human recombinant cannabinoid CB1 and CB2 receptors. Br J Pharmacol. 1998;124(4):619–22.
de Almeida DL, Devi LA. Diversity of molecular targets and signaling pathways for CBD. Pharmacol Res Perspect. 2020;8(6):e00682.
Ribeiro A, Ferraz-de-Paula V, Pinheiro ML, Vitoretti LB, Mariano-Souza DP, Quinteiro-Filho WM, et al. Cannabidiol, a non-psychotropic plant-derived cannabinoid, decreases inflammation in a murine model of acute lung injury: Role for the adenosine A2A receptor. Eur J Pharmacol. 2012;678(1–3):78–85.
Clarke H, Roychoudhury P, Narouze SN. Other Phytocannabinoids. Cannabinoids and Pain [Internet]. 2021 Jan 1 [cited 2023 Nov 16];87–92. Available from: https://link.springer.com/chapter/10.1007/978-3-030-69186-8_12
Marzo V Di, Petrocellis L De. Plant, synthetic, and endogenous cannabinoids in medicine. Annu Rev Med. 2006;57:553–74.
Rinaldi-Carmona M, Barth F, Héaulme M, Shire D, Calandra B, Congy C, et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 1994;350(2–3):240–4.
Anthony AT, Rahmat S, Sangle P, Sandhu O, Khan S. Cannabinoid receptors and their relationship with chronic pain: a narrative review. Cureus. 2020;12(9).
Katsuyama S, Mizoguchi H, Kuwahata H, Komatsu T, Nagaoka K, Nakamura H, et al. Involvement of peripheral cannabinoid and opioid receptors in β-caryophyllene-induced antinociception. European journal of pain. 2013;17(5):664–75.
Kuster JE, Stevenson JI, Ward SJ, D’Ambra TE, Haycock DA. Aminoalkylindole binding in rat cerebellum: selective displacement by natural and synthetic cannabinoids. Journal of Pharmacology and Experimental Therapeutics. 1993;264(3):1352–63.
Ferraro L, Tomasini MC, Gessa GL, Bebe BW, Tanganelli S, Antonelli T. The cannabinoid receptor agonist WIN 55,212-2 regulates glutamate transmission in rat cerebral cortex: an in vivo and in vitro study. Cerebral Cortex. 2001;11(8):728–33.
Compton DR, Gold LH, Ward SJ, Balster RL, Martin BR. Aminoalkylindole analogs: cannabimimetic activity of a class of compounds structurally distinct from delta 9-tetrahydrocannabinol. Journal of Pharmacology and Experimental Therapeutics. 1992;263(3):1118–26.
Zhang Q, Ma P, Iszard M, Cole RB, Wang W, Wang G. In Vitro Metabolism ofR (+)-[2, 3-Dihydro-5-methyl-3-[(morpholinyl) methyl] pyrrolo [1, 2, 3-de] 1, 4-benzoxazinyl]-(1-naphthalenyl) methanone mesylate, a Cannabinoid Receptor Agonist. Drug metabolism and disposition. 2002;30(10):1077–86.
Chelliah MP, Zinn Z, Khuu P, Teng JMC. Self-initiated use of topical cannabidiol oil for epidermolysis bullosa. Pediatr Dermatol. 2018 Jul 1;35(4):e224–7.
Phan NQ, Siepmann D, Gralow I, Ständer S. Adjuvante topische Therapie mit einem Cannabinoid-Rezeptor-Agonisten bei postzosterischer Neuralgie im Gesicht. JDDG: Journal der Deutschen Dermatologischen Gesellschaft [Internet]. 2010 Feb 1 [cited 2023 Sep 26];8(2):88–91. Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/j.1610-0387.2009.07213_supp.x
Maida V, Corban J. Topical Medical Cannabis: A New Treatment for Wound Pain—Three Cases of Pyoderma Gangrenosum. J Pain Symptom Manage. 2017 Nov 1;54(5):732–6.
Andersen HH, Elberling J, Arendt-Nielsen L. Human Surrogate Models of Histaminergic and Non-histaminergic Itch. Acta Derm Venereol [Internet]. 2015 Jun 8 [cited 2023 Sep 26];95(7):771–7. Available from: https://medicaljournalssweden.se/actadv/article/view/5863
Leonti M, Casu L, Raduner S, Cottiglia F, Floris C, Altmann KH, et al. Falcarinol is a covalent cannabinoid CB1 receptor antagonist and induces pro-allergic effects in skin. Biochem Pharmacol. 2010 Jun 15;79(12):1815–26.
Dvorak M, Watkinson A, McGlone F, Rukwied R. Histamine induced responses are attenuated by a cannabinoid receptor agonist in human skin. Inflammation Research [Internet]. 2003 Jun 1 [cited 2023 Sep 26];52(6):238–45. Available from: https://link.springer.com/article/10.1007/s00011-003-1162-z
Muller C, Morales P, Reggio PH. Cannabinoid ligands targeting TRP channels. Front Mol Neurosci. 2019;11:487.
Ambrosino P, Soldovieri MV, Russo C, Taglialatela M. Activation and desensitization of TRPV1 channels in sensory neurons by the PPARα agonist palmitoylethanolamide. Br J Pharmacol [Internet]. 2013 Mar 1 [cited 2023 Sep 26];168(6):1430–44. Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/bph.12029
Schlosburg JE, O’Neal ST, Conrad DH, Lichtman AH. CB1 receptors mediate rimonabant-induced pruritic responses in mice: Investigation of locus of action. Psychopharmacology (Berl) [Internet]. 2011 Aug 22 [cited 2023 Sep 26];216(3):323–31. Available from: https://link.springer.com/article/10.1007/s00213-011-2224-5
Schlosburg JE, Boger DL, Cravatt BF, Lichtman AH. Endocannabinoid Modulation of Scratching Response in an Acute Allergenic Model: A New Prospective Neural Therapeutic Target for Pruritus. Journal of Pharmacology and Experimental Therapeutics [Internet]. 2009 Apr 1 [cited 2023 Sep 26];329(1):314–23. Available from: https://jpet.aspetjournals.org/content/329/1/314
Odan M, Ishizuka N, Hiramatsu Y, Inagaki M, Hashizume H, Fujii Y, et al. Discovery of S-777469: An orally available CB2 agonist as an antipruritic agent. Bioorg Med Chem Lett. 2012 Apr 15;22(8):2803–6.
Maekawa T, Nojima H, Kuraishi Y, Aisaka K. The cannabinoid CB2 receptor inverse agonist JTE-907 suppresses spontaneous itch-associated responses of NC mice, a model of atopic dermatitis. Eur J Pharmacol. 2006 Aug 7;542(1–3):179–83.
Devane WA, Breuer A, Sheskin T, Jaerbe TUC, Eisen MS, Mechoulam R. A novel probe for the cannabinoid receptor. J Med Chem. 1992;35(11):2065–9.
Eberlein B, Eicke C, Reinhardt HW, Ring J. Adjuvant treatment of atopic eczema: Assessment of an emollient containing N-palmitoylethanolamine (ATOPA study). Journal of the European Academy of Dermatology and Venereology. 2008 Jan;22(1):73–82.
Ständer S, Reinhardt HW, Luger TA. Topische cannabinoidagonisten. Eine effektive, neue möglichkeit zur behandlung von chronischem pruritus. Hautarzt [Internet]. 2006 Sep [cited 2023 Sep 27];57(9):801–7. Available from: https://link.springer.com/article/10.1007/s00105-006-1180-1
Yuan C, Wang XM, Guichard A, Tan YM, Qian CY, Yang LJ, et al. N-palmitoylethanolamine and N-acetylethanolamine are effective in asteatotic eczema: Results of a randomized, double-blind, controlled study in 60 patients. Clin Interv Aging. 2014 Jul 17;9:1163–9.
Szepietowski JC, Szepietowski T, Reich A. Efficacy and tolerance of the cream containing structured physiological lipids with endocannabinoids in the treatment of uremic pruritus: A preliminary study. Acta Dermatovenerologica Croatica. 2005;13(2):97–103.
Gaston TE, Szaflarski JP. Cannabis for the treatment of epilepsy: an update. Curr Neurol Neurosci Rep. 2018;18:1–9.
Cannabis (Marijuana) and Cannabinoids: What You Need To Know | NCCIH [Internet]. [cited 2023 Sep 27]. Available from: https://www.nccih.nih.gov/health/cannabis-marijuana-and-cannabinoids-what-you-need-to-know
Camilleri M. Cannabinoids and gastrointestinal motility: pharmacology, clinical effects, and potential therapeutics in humans. Neurogastroenterology & Motility. 2018;30(9):e13370.
Duncan M, Mouihate A, Mackie K, Keenan CM, Buckley NE, Davison JS, et al. Cannabinoid CB2 receptors in the enteric nervous system modulate gastrointestinal contractility in lipopolysaccharide-treated rats. American Journal of Physiology-Gastrointestinal and Liver Physiology. 2008;295(1):G78–G87.
Wright KL, Duncan M, Sharkey KA. Cannabinoid CB2 receptors in the gastrointestinal tract: a regulatory system in states of inflammation. Br J Pharmacol. 2008;153(2):263–70.
Young-Wolff KC, Sarovar V, Tucker LY, Avalos LA, Alexeeff S, Conway A, et al. Trends in marijuana use among pregnant women with and without nausea and vomiting in pregnancy, 2009–2016. Drug Alcohol Depend. 2019;196:66–70.
Esfandyari T, Camilleri M, Ferber I, Burton D, Baxter K, Zinsmeister AR. Effect of a cannabinoid agonist on gastrointestinal transit and postprandial satiation in healthy human subjects: a randomized, placebo-controlled study. Neurogastroenterology & Motility. 2006;18(9):831–8.
Hornby PJ, Prouty SM. Involvement of cannabinoid receptors in gut motility and visceral perception. Br J Pharmacol. 2004;141(8):1335–45.
Juan-Picó P, Fuentes E, Bermudez-Silva FJ, D’iaz-Molina FJ, Ripoll C, de Fonseca FR, et al. Cannabinoid receptors regulate Ca2+ signals and insulin secretion in pancreatic β-cell. Cell Calcium. 2006;39(2):155–62.
Dembinski A, Warzecha Z, Ceranowicz P, Dembinski M, Cieszkowski J, Pawlik WW, et al. Cannabinoids in acute gastric damage and pancreatitis. Journal of Physiology and Pharmacology. 2006;57:137.
Michalski CW, Laukert T, Sauliunaite D, Pacher P, Bergmann F, Agarwal N, et al. Cannabinoids ameliorate pain and reduce disease pathology in cerulein-induced acute pancreatitis. Gastroenterology. 2007;132(5):1968–78.
Sharafi G, He H, Nikfarjam M. Potential use of cannabinoids for the treatment of pancreatic cancer. J Pancreat Cancer. 2019;5(1):1–7.
Caraceni P, Domenicali M, Bernardi M. The endocannabinoid system and liver diseases. J Neuroendocrinol. 2008;20:47–52.
Argemi J, Bataller R. Hepatocyte–stellate cell synapse in alcohol-induced steatosis: another role for endocannabinoids. Nat Rev Gastroenterol Hepatol. 2020;17(1):5–6.
Hézode C, Roudot-Thoraval F, Nguyen S, Grenard P, Julien B, Zafrani ES, et al. Daily cannabis smoking as a risk factor for progression of fibrosis in chronic hepatitis C. Hepatology. 2005;42(1):63–71.
Dai E, Zhang L, Ye L, Wan S, Feng L, Qi Q, et al. Hepatic expression of cannabinoid receptors CB1 and CB2 correlate with fibrogenesis in patients with chronic hepatitis B. International Journal of Infectious Diseases. 2017;59:124–30.
Carracedo A, Lorente M, Egia A, Blázquez C, Garc’ia S, Giroux V, et al. The stress-regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells. Cancer Cell. 2006;9(4):301–12.
McKallip RJ, Nagarkatti M, Nagarkatti PS. Δ-9-tetrahydrocannabinol enhances breast cancer growth and metastasis by suppression of the antitumor immune response. The Journal of Immunology. 2005;174(6):3281–9.
De Petrocellis L, Ligresti A, Schiano Moriello A, Iappelli M, Verde R, Stott CG, et al. Non-THC cannabinoids inhibit prostate carcinoma growth in vitro and in vivo: pro-apoptotic effects and underlying mechanisms. Br J Pharmacol. 2013;168(1):79–102.
Mangal N, Erridge S, Habib N, Sadanandam A, Reebye V, Sodergren MH. Cannabinoids in the landscape of cancer. J Cancer Res Clin Oncol. 2021;147:2507–34.
Fraguas-Sánchez AI, Fernández-Carballido A, Simancas-Herbada R, Martin-Sabroso C, Torres-Suárez AI. CBD loaded microparticles as a potential formulation to improve paclitaxel and doxorubicin-based chemotherapy in breast cancer. Int J Pharm. 2020;574:118916.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 Türk Bilimsel Derlemeler Dergisi
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
