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Parastouei K, Aarabi M H, Hamidi G A, Nasehi Z, Kabiri Arani S, Jozi F et al . A CB2 Receptor Agonist Reduces the Production of Inflammatory Mediators and Improves Locomotor Activity in Experimental Autoimmune Encephalomyelitis. rbmb.net 2022; 11 (1) :1-9
URL: http://rbmb.net/article-1-819-en.html
Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran.
Abstract:   (2370 Views)
Background: Cannabinoids (CBs) have been found to regulate the immune system, affect innate and adaptive immune responses, and reduce inflammatory reactions. This study assessed the therapeutic effects of GW-405833 synthetic CB2 agonist on inflammatory factors as well as locomotor activity in experimental autoimmune encephalomyelitis (EAE).

Methods: In this experimental study, 48 adult male C57BL/6 mice were randomly and equally assigned to eight groups. By injecting 250 mg of MOG35-55 peptide, EAE was induced. Every other day for 17 days after EAE onset, EAE-afflicted mice in groups 1–3 received an intraperitoneal injection of GW-405833 at a dose of 3, 10, and 30 mg/kg, respectively. Clinical status and locomotor activity, measured using the beam walking assay, were assessed every other day during the first 17 days after EAE onset. Mice were euthanized in day 17th of treatment and the serum levels of the IL-1ß, IL-12, CRP, and TNF-α proinflammatory cytokines as well as IL-4 and TGF-ß anti-inflammatory cytokines were measured by ELISA method.

Results: Clinical manifestations of EAE in groups 2 and 3 were significantly milder than group 4 and locomotor activity in groups 1–3 was significantly better than group 4 in days 5–17 (p< 0.05). GW-405833 also significantly decreased the levels of IL-12, TNF-α, and CRP and significantly increased the levels of IL-4 and TGF-ß but had no significant effects on the level of IL-1ß. GW-405833 was not associated with significant side effects.

Conclusions: The CB2 receptor agonist GW-405833, improves clinical conditions and reduces inflammation in mice with EAE.
Full-Text [PDF 223 kb]   (771 Downloads)    
Type of Article: Original Article | Subject: Biochemistry
Received: 2021/11/15 | Accepted: 2021/11/21 | Published: 2022/05/26

1. Asouri M, Alinejad Rokni H, Sahraian MA, Fattahi S, Motamed N, Doosti R, et al. Association of HLA-DRA and IL2RA Polymorphisms with the Severity and Relapses Rate of Multiple Sclerosis in an Iranian Population. Rep Biochem Mol Biol. 2020;9(2):129-139. [DOI:10.29252/rbmb.9.2.129] [PMID] [PMCID]
2. Elliott DM, Singh N, Nagarkatti M, Nagarkatti PS. Cannabidiol Attenuates Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis Through Induction of Myeloid-Derived Suppressor Cells. Front Immunol. 2018;9:1782. [DOI:10.3389/fimmu.2018.01782] [PMID] [PMCID]
3. Wallin M, Culpepper W, Nichols E, Bhutta Z, Gebrehiwot T, Hay S, et al. Global, regional, and national burden of multiple sclerosis 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet Neurology. 2019;18:269-85. [DOI:10.1016/S1474-4422(18)30443-5]
4. Schwartz CE, Laitin E, Brotman S, LaRocca N. Utilization of unconventional treatments by persons with MS: Is it alternative or complementary?. Neurology. 1999;52(3):626-9. [DOI:10.1212/WNL.52.3.626] [PMID]
5. Zajicek JP, Hobart JC, Slade A, Barnes D, Mattison PG. MUltiple Sclerosis and Extract of Cannabis: results of the MUSEC trial. J Neurol Neurosurg Psychiatry. 2012;83(11):1125-32. [DOI:10.1136/jnnp-2012-302468] [PMID]
6. Manzanares J, Julian M, Carrascosa A. Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes. Curr Neuropharmacol. 2006;4(3):239-257. [DOI:10.2174/157015906778019527] [PMID] [PMCID]
7. Valenzano KJ, Tafesse L, Lee G, Harrison JE, Boulet JM, Gottshall SL, et al. Pharmacological and pharmacokinetic characterization of the cannabinoid receptor 2 agonist, GW405833, utilizing rodent models of acute and chronic pain, anxiety, ataxia and catalepsy. Neuropharmacology. 2005;48(5):658-72. [DOI:10.1016/j.neuropharm.2004.12.008] [PMID]
8. Bie B, Wu J, Foss JF, Naguib M. An overview of the cannabinoid type 2 receptor system and its therapeutic potential. Curr Opin Anaesthesiol. 2018;31(4):407-414. [DOI:10.1097/ACO.0000000000000616] [PMID] [PMCID]
9. Pan H-L, Wu Z-Z, Zhou H-Y, Chen S-R, Zhang H-M, Li D-P. Modulation of pain transmission by G-protein-coupled receptors. Pharmacol Ther. 2008;117(1):141-161. [DOI:10.1016/j.pharmthera.2007.09.003] [PMID] [PMCID]
10. Reggio PH. Endocannabinoid binding to the cannabinoid receptors: what is known and what remains unknown. Curr Med Chem. 2010;17(14):1468-1486. [DOI:10.2174/092986710790980005] [PMID] [PMCID]
11. Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol. 2008;153(2):199-215. [DOI:10.1038/sj.bjp.0707442] [PMID] [PMCID]
12. Gonçalves J, Rosado T, Soares S, Simão AY, Caramelo D, Luís Â, et al. Cannabis and Its Secondary Metabolites: Their Use as Therapeutic Drugs, Toxicological Aspects, and Analytical Determination. Medicines (Basel). 2019;6(1):31. [DOI:10.3390/medicines6010031] [PMID] [PMCID]
13. Ashton JC, Glass M. The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration. Curr Neuropharmacol. 2007;5(2):73-80. [DOI:10.2174/157015907780866884] [PMID] [PMCID]
14. Clayton N, Marshall FH, Bountra C, O'Shaughnessy CT. CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain. Pain. 2002;96(3):253-260. [DOI:10.1016/S0304-3959(01)00454-7]
15. Ibrahim MM, Deng H, Zvonok A, Cockayne DA, Kwan J, Mata HP, et al. Activation of CB2 cannabinoid receptors by AM1241 inhibits experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc Natl Acad Sci U S A. 2003;100(18):10529-33. [DOI:10.1073/pnas.1834309100] [PMID] [PMCID]
16. Malan Jr TP, Ibrahim MM, Deng H, Liu Q, Mata HP, Vanderah T, et al. CB2 cannabinoid receptor-mediated peripheral antinociception. Pain. 2001;93(3):239-245. [DOI:10.1016/S0304-3959(01)00321-9]
17. Malan T, Ibrahim M, Lai J, Vanderah T, Makriyannis A, Porreca F. CB2 cannabinoid receptor agonists: Pain relief without psychoactive effects?. Curr Opin Pharmacol. 2003;3(1):62-7. [DOI:10.1016/S1471-4892(02)00004-8]
18. Parlar A, Arslan SO, Doğan MF, Çam SA, Yalçin A, Elibol E, et al. The exogenous administration of CB2 specific agonist, GW405833, inhibits inflammation by reducing cytokine production and oxidative stress. Exp Ther Med. 2018;16(6):4900-4908. [DOI:10.3892/etm.2018.6753] [PMID] [PMCID]
19. Aarabi MH, Shahaboddin ME, Parastouei K, Motallebi M, Jafarnejad A, Mirhashemi M, et al. Evaluation of 11-hydroxy-8-THC-dimethylheptyl effects on cytokines profile and locomotor tests in experimental autoimmune encephalomyelitis. Journal of Medicinal Plants Research. 2011;5(17):4244-50. [DOI:10.1016/j.clinbiochem.2011.08.142]
20. Costa O, Divoux D, Ischenko A, Tron F, Fontaine M. Optimization of an animal model of experimental autoimmune encephalomyelitis achieved with a multiple MOG(35-55)peptide in C57BL6/J strain of mice. J Autoimmun. 2003;20(1):51-61. [DOI:10.1016/S0896-8411(02)00108-7]
21. Kerschensteiner M, Stadelmann C, Buddeberg BS, Merkler D, Bareyre FM, Anthony DC, et al. Targeting experimental autoimmune encephalomyelitis lesions to a predetermined axonal tract system allows for refined behavioral testing in an animal model of multiple sclerosis. Am J Pathol. 2004;164(4):1455-69. [DOI:10.1016/S0002-9440(10)63232-4]
22. Buddeberg BS, Kerschensteiner M, Merkler D, Stadelmann C, Schwab ME. Behavioral testing strategies in a localized animal model of multiple sclerosis. J Neuroimmunol. 2004;153(1-2):158-70. [DOI:10.1016/j.jneuroim.2004.05.006] [PMID]
23. Metz GA, Merkler D, Dietz V, Schwab ME, Fouad K. Efficient testing of motor function in spinal cord injured rats. Brain Research. 2000;883(2):165-177. [DOI:10.1016/S0006-8993(00)02778-5]
24. Buccellato E, Carretta D, Utan A, Cavina C, Speroni E, Grassi G, et al. Acute and chronic cannabinoid extracts administration affects motor function in a CREAE model of multiple sclerosis. J Ethnopharmacol. 2011;133(3):1033-8. [DOI:10.1016/j.jep.2010.11.035] [PMID]
25. Achiron A, Miron S, Lavie V, Margalit R, Biegon A. Dexanabinol (HU-211) effect on experimental autoimmune encephalomyelitis: implications for the treatment of acute relapses of multiple sclerosis. J Neuroimmunol. 2000;102(1):26-31. [DOI:10.1016/S0165-5728(99)00149-6]
26. Li A-L, Carey LM, Mackie K, Hohmann AG. Cannabinoid CB(2) Agonist GW405833 Suppresses Inflammatory and Neuropathic Pain through a CB(1) Mechanism that is Independent of CB(2) Receptors in Mice. J Pharmacol Exp Ther. 2017;362(2):296-305. [DOI:10.1124/jpet.117.241901] [PMID] [PMCID]
27. Zhang J, Hoffert C, Vu HK, Groblewski T, Ahmad S, O'Donnell D. Induction of CB2 receptor expression in the rat spinal cord of neuropathic but not inflammatory chronic pain models. Eur J Neurosci. 2003;17(12):2750-4. [DOI:10.1046/j.1460-9568.2003.02704.x] [PMID]
28. Tanasescu R, Constantinescu CS. Cannabinoids and the immune system: an overview. Immunobiology. 2010;215(8):588-97. [DOI:10.1016/j.imbio.2009.12.005] [PMID]
29. t Hart BA, Brok HP, Remarque E, Benson J, Treacy G, Amor S, et al. Suppression of ongoing disease in a nonhuman primate model of multiple sclerosis by a human-anti-human IL-12p40 antibody. J Immunol. 2005;175(7):4761-8. [DOI:10.4049/jimmunol.175.7.4761] [PMID]
30. t Hart BA, Hintzen RQ, Laman JD. Preclinical assessment of therapeutic antibodies against human CD40 and human interleukin-12/23p40 in a nonhuman primate model of multiple sclerosis. Neurodegener Dis. 2008;5(1):38-52. [DOI:10.1159/000109937] [PMID]
31. Liu J, Cao S, Kim S, Chung EY, Homma Y, Guan X, et al. Interleukin-12: an update on its immunological activities, signaling and regulation of gene expression. Curr Immunol Rev. 2005;1(2):119-137. [DOI:10.2174/1573395054065115] [PMID] [PMCID]
32. Klein TW, Newton CA, Nakachi N, Friedman H. Delta 9-tetrahydrocannabinol treatment suppresses immunity and early IFN-gamma, IL-12, and IL-12 receptor beta 2 responses to Legionella pneumophila infection. J Immunol. 2000;164(12):6461-6. [DOI:10.4049/jimmunol.164.12.6461] [PMID]
33. Visser J, van Boxel-Dezaire A, Methorst D, Brunt T, de Kloet ER, Nagelkerken L. Differential regulation of interleukin-10 (IL-10) and IL-12 by glucocorticoids in vitro. Blood. 1998;91(11):4255-64. https://doi.org/10.1182/blood.V91.11.4255 [DOI:10.1182/blood.V91.11.4255.411a03_4255_4264] [PMID]
34. Guindon J, Hohmann AG. Cannabinoid CB2 receptors: a therapeutic target for the treatment of inflammatory and neuropathic pain. Br J Pharmacol. 2008;153(2):319-34. [DOI:10.1038/sj.bjp.0707531] [PMID] [PMCID]
35. Nagarkatti P, Pandey R, Rieder SA, Hegde VL, Nagarkatti M. Cannabinoids as novel anti-inflammatory drugs. Future Med Chem. 2009;1(7):1333-1349. [DOI:10.4155/fmc.09.93] [PMID] [PMCID]
36. Rieder SA, Chauhan A, Singh U, Nagarkatti M, Nagarkatti P. Cannabinoid-induced apoptosis in immune cells as a pathway to immunosuppression. Immunobiology. 2010;215(8):598-605. [DOI:10.1016/j.imbio.2009.04.001] [PMID] [PMCID]

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