CB2 Agonist (AM1241) Improving Effect on Ovalbumin-Induced Asthma in Rats

Document Type : Research article

Authors

1 University of Adiyaman, Faculty of Medicine, Department of Pharmacology, Adiyaman, Turkey.

2 Pharmacology Department, Faculty of Medicine, Yildirim Beyazit University, Ankara, Turkey.

Abstract

Asthma is a disease characterized by spontaneous contraction of the airways in response to a wide variety of endogenous and exogenous stimuli. Many asthma models are used to mimic the human asthma model in the literature. In order to better understand the role of the cannabinoid (CB) 2 receptor in the ovalbumin (OVA)-induced asthma model, a combination of both selective CB2 agonist (AM1241) and antagonist (AM630) was used to improve inflammatory hypersensitivity and edema in rats. In the present study, it was found that OVA decreased body weight (p<0.05), increased lung weights (p<0.05), increased diastolic and systolic blood pressure (p<0.001), and caused to irregularity in pulmonary functions (p<0.001). Moreover, CB2 agonist was found not to reduce body weight, cause blood pressure and respiratory irregularities (p< 0.05). OVA led to increase in IgE, TNF-α, IL-4, MDA level (p<0.001) and total WBC count (p<0.05). CB2 treatment caused to reduce the number of total WBC and the level of total protein in BALF, to hinder to increase level of MDA, IgE, TNF-α and IL-4 (p<0.05) in BALF or serum or lung tissue. But CB2-antagonist treatment prevented the protective effect of CB2 agonist. The aim of this study was to study the role of the CB2 receptor in the OVA induced asthma model, for improve inflammatory hypersensitivity, and edema in rats. The results suggested that CB2 agonist administration to OVA induced asthmatic rats via anti-asthmatic potential through inhibition of parameters such as IgE, IL-4, TNF-α, microvascular escape, and oxidative stress.

Graphical Abstract

CB2 Agonist (AM1241) Improving Effect on Ovalbumin-Induced Asthma in Rats

Keywords

Main Subjects



(1) Aun M, Bonamichi-Santos R, Arantes-Costa FM,Kalil J and Giavina-Bianchi P. Animal models ofasthma: utility and limitations. J. Asthma Allergy(2017) Volume10: 293–301.
(2) Vuolo F, Petronilho F, Sonai B, Ritter C, Hallak JEC,Zuardi AW, Crippa JA and Dal-Pizzol F. Evaluationof Serum Cytokines Levels and the Role ofCannabidiol Treatment in Animal Model of Asthma.Mediators Inflamm. (2015) 2015: 538670.
(3) Beasley R, Roche WR, Roberts JA and Holgate ST.Cellular events in the bronchi in mild asthma andafter bronchial provocation. Am. Rev. Respir. Dis.
(1989) 139: 806–17.
(4) Kay AB. Pathology of Mild, Severe and FatalAsthma. Am. J. Respir. Crit. Care Med. (1996) 154:S66–S69.
(5) Hegele RG. The pathology of asthma: brief review.Immunopharmacology (2000) 48: 257–262.
(6) Shinagawa K and Kojima M. Mouse Model ofAirway Remodeling. Am. J. Respir. Crit. Care Med.(2003) 168: 959–967.
(7) Oktay ARSLAN S. Morphine modulatesmicrovascular leakage dose-dependently in theairway of ovalbumin-sensitized rats. Turk J Med Sci
(2010) 40: 279–286.
(8) Masini E, Bani D, Vannacci A, Pierpaoli S, MannaioniPF, Comhair SAA, Xu W, Muscoli C, Erzurum SCand Salvemini D. Reduction of antigen-inducedrespiratory abnormalities and airway inflammationin sensitized guinea pigs by a superoxide dismutase mimetic. Free Radic. Biol. Med. (2005) 39: 520–31.
(9) Mohammadpour F, Nasser Ostad S, Aliebrahimi S and Daman Z. Anti-invasion Effects of Cannabinoids Agonist and Antagonist on Human Breast CancerStem Cells. Vol. 16, Shaheed Beheshti University of Medical Sciences and Health Services Iranian
Journal of Pharmaceutical Research. (2017).
(10) Johnson MR, Rice KC, Howlett A, Melvin LS and Herkenham M. The cannabinoid receptorpharmacologic identification, anatomical 15AM1241 Effect on Ovalbumin-Induced Asthma localization and cloning. NIDA Res. Monogr. (1992) 119: 86–90.
(11) Gutierrez T, Farthing JN, Zvonok AM, Makriyannis A and Hohmann AG. Activation of peripheral cannabinoid CB1 and CB2 receptors suppresses the maintenance of inflammatory nociception: a comparative analysis. Br. J. Pharmacol. (2007) 150: 153–63.
(12) Nackley AG, Makriyannis A and Hohmann AG. Selective activation of cannabinoid CB(2) receptors suppresses spinal fos protein expression and pain behavior in a rat model of inflammation. Neuroscience (2003) 119: 747–57.
(13) Yu XH, Cao CQ, Martino G, Puma C, Morinville A, St-Onge S, Lessard E, Perkins MN and Laird JMA. A peripherally restricted cannabinoid receptor agonist produces robust anti-nociceptive effects in rodent models of inflammatory and neuropathic pain. Pain (2010) 151: 337–44.
(14) Clayton N, Marshall FH, Bountra C and O’Shaughnessy CT. CB1 and CB2 cannabinoid receptors are implicated in inflammatory pain. Pain (2002) 96: 253–60.
(15) Devane W, Hanus L, Breuer A, Pertwee R, Stevenson L, Griffin G, Gibson D, Mandelbaum A, Etinger A and Mechoulam R. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science (80-. ). (1992) 258: 1946–1949.
(16) Mechoulam R, Ben-Shabat S, Hanus L, Ligumsky M, Kaminski NE, Schatz AR, Gopher A, Almog S, Martin BR, Compton DR, Pertwee RG, Griffin G, Bayewitch M, Barg J and Vogel Z. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem. Pharmacol. (1995) 50: 83–90.
(17) Liu Y-J, Fan H-B, Jin Y, Ren C-G, Jia X-E, Wang L, Chen Y, Dong M, Zhu K-Y, Dong Z-W, Ye B-X, Zhong Z, Deng M, Liu TX and Ren R. Cannabinoid receptor 2 suppresses leukocyte inflammatory migration by modulating the JNK/c-Jun/Alox5 pathway. J. Biol. Chem. (2013) 288: 13551–62.
(18) Guan R, Zhao X, Wang X, Song N, Guo Y, Yan X, Jiang L, Cheng W and Shen L. Emodin alleviates bleomycin-induced pulmonary fibrosis in rats. Toxicol. Lett. (2016) 262: 161–172.
(19) Wang P-F, Jiang L-S, Bu J, Huang X-J, Song W, Du Y-P and He B. Cannabinoid-2 receptor activation protects against infarct and ischemia-reperfusion
heart injury. J. Cardiovasc. Pharmacol. (2012) 59: 301–7.
(20) Comelli F, Giagnoni G, Bettoni I, Colleoni M and Costa B. The inhibition of monoacylglycerol lipase by URB602 showed an anti-inflammatory and anti-nociceptive effect in a murine model of acute inflammation. Br. J. Pharmacol. (2007) 152: 787–94.
(21) Gallant M, Dufresne C, Gareau Y, Guay D, Leblanc Y, Prasit P, Rochette C, Sawyer N, Slipetz DM, Tremblay N, Metters KM and Labelle M. New class of potent ligands for the human peripheral cannabinoid receptor. Bioorg. Med. Chem. Lett. (1996) 6: 2263–2268.
(22) Eftekhar N, Moghimi A, Hossein Boskabady M, Kaveh M and Shakeri F. Ocimum basilicum affects tracheal responsiveness, lung inflammatory cells and oxidant–antioxidant biomarkers in sensitized rats. Drug Chem. Toxicol. (2018) 1–9.
(23) Kaveh M, Eidi A, Nemati A and Boskabady MH. The Extract of Portulaca oleracea and Its Constituent, Alpha Linolenic Acid Affects Serum Oxidant Levels and Inflammatory Cells in
Sensitized Rats. Iran. J. Allergy. Asthma. Immunol. (2017) 16: 256–270.
(24) Kianmeher M, Ghorani V and Boskabady MH. Animal Model of Asthma, Various Methods and Measured Parameters: A Methodological Review. Iran. J. Allergy. Asthma. Immunol.(2016) 15: 445–465.
(25) Pacher P, Bátkai S and Kunos G. Theendocannabinoid system as an emerging targetof pharmacotherapy. Pharmacol. Rev. (2006) 58:389–462.
(26) Bartlett D and Tenney SM. Control of breathing inexperimental anemia. Respir. Physiol. (1970) 10:384–95.
(27) Mukherjee AA, Kandhare AD, Rojatkar SR andBodhankar SL. Ameliorative effects of Artemisiapallens in a murine model of ovalbumin-inducedallergic asthma via modulation ofbiochemical perturbations. Biomed. Pharmacother. (2017) 94:
880–889.
(28) Mortazavi N, Esmaeilzadeh H, Abbasinazari M, Babaie D, Alyasin S, Nabavizadeh H and Esmailzadeh E. Clinical and Immunological
Efficacy of Aspirin Desensitization in Nasal Polyp Patients with Aspirin-Exacerbated Respiratory Disease. Vol. 16, Shaheed Beheshti University of Medical Sciences and Health Services Iranian Journal of Pharmaceutical Research. (2017).
(29) Ghorani V, Marefati N, Shakeri F, Rezaee R, Boskabady M and Boskabady MH. The Effects of
Allium Cepa Extract on Tracheal Responsiveness, Lung Inflammatory Cells and Phospholipase A2 Level in Asthmatic Rats. Iran. J. Allergy. Asthma.
Immunol. (2018) 17: 221–231.
(30) Dong F, Wang C, Duan J, Zhang W, Xiang D andLi M. Puerarin attenuates ovalbumin-induced lung 16 Parlar A et al. / IJPR (2020), 19 (1): 3-17 inflammation and hemostatic unbalance in rat asthma model. Evid. Based. Complement. Alternat. Med. (2014) 2014: 726740.
(31) Woerly G, Honda K, Loyens M, Papin J-P, Auwerx J, Staels B, Capron M. and Dombrowicz D. Peroxisome Proliferator–activated Receptors α and γ Down-regulate Allergic Inflammation and Eosinophil Activation. J. Exp. Med. (2003) 198: 411–421.
(32) Marefati N, Eftekhar N, Kaveh M, Boskabadi J, Beheshti F and Boskabady MH. The Effect of &lt;b&gt;&lt;i&gt;Allium cepa&lt;/i&gt;&lt;/ b&gt; Extract on Lung Oxidant, Antioxidant, and Immunological Biomarkers in Ovalbumin- Sensitized Rats. Med. Princ. Pract. (2018) 27:122–128.
(33) Casini AF, Ferrali M, Pompella A, Maellaro Eand Comporti M. Lipid peroxidation and cellulardamage in extrahepatic tissues of bromobenzeneintoxicated mice. Am. J. Pathol. (1986) 123: 520–31.
(34) Sedlak J and Lindsay RH. Estimation of total,protein-bound and nonprotein sulfhydryl groupsin tissue with Ellman’s reagent. Anal. Biochem.
(1968) 25: 192–205.
(35) Kasahara K, Shiba K, Ozawa T, Okuda K andAdachi M. Correlation between the bronchialsubepithelial layer and whole airway wall thicknessin patients with asthma.
(36) Paniagua N, Lopez R, Muñoz N, Tames M,Mojica E, Arana-Arri E, Mintegi S and BenitoJ. Randomized Trial of Dexamethasone VersusPrednisone for Children with Acute Asthma Exacerbations. J. Pediatr. (2017) 191: 190-196.e1.
(37) Warrell DA, Robertson DG, Howes JN, Conolly ME, Paterson JW, Beilin LJ and Dollery CT. Comparison of cardiorespiratory effects of
isoprenaline and salbutamol in patients withbronchial asthma. Br. Med. J. (1970) 1: 65–70.
(38) Zhang HP, Jia CE, Lv Y, Gibson PG and WangG. Montelukast for prevention and treatment ofasthma exacerbations in adults: Systematic review
and meta-analysis. Allergy Asthma Proc. (2014) 35: 278–287.
(39) Hon K-LE, Leung TF and Leung AKC. Clinical effectiveness and safety of montelukast in asthma. What are the conclusions from clinical trials and meta-analyses? Drug Des. Devel. Ther. (2014) 8:839.
(40) Liu C, Yang N, Chen X, Tversky J, Zhan J, Chehade M, Miller RL and Li X-M. The Flavonoid 7,4′-Dihydroxyflavone Prevents Dexamethasone
Paradoxical Adverse Effect on Eotaxin Productionby Human Fibroblasts. Phyther. Res. (2017) 31:449–458.
(41) Arcaro I, Fischer BL, Lascola KM and Clark-Price SC. Effects of intravenous terbutaline on heart rate, arterial pressure and blood gases in anesthetized horses breathing air. Vet. Anaesth. Analg. (2017) 44: 70–76.
(42) Arslan SO, Zerin M, Vural H and Coskun A. The effect of melatonin on bleomycin-induced pulmonary fibrosis in rats. J. Pineal Res. (2002) 32: 21–5.
(43) Thakur VR, Beladiya J V., Chaudagar KK and Mehta AA. An anti-asthmatic activity of natural Toll-like receptor-4 antagonist in OVA-LPSinduced asthmatic rats. Clin. Exp. Pharmacol. Physiol. (2018) 45: 1187–1197.
(44) Parlar A, Arslan SO, Doğan MF, Çam SA, Yalçin A, Elibol E, Özer MK, Üçkardeş F and Kara H. The exogenous administration of CB2 specific agonist, GW405833, inhibits inflammation by reducing cytokine production and oxidative stress. Exp. Ther. Med. (2018) 16: 4900–4908.
(45) Pertwee RG and Ross RA. Cannabinoid receptors and their ligands. Prostaglandins, Leukot. Essent. Fat. Acids (2002) 66: 101–121.
(46) Eftekhar N, Moghimi A and Boskabady MH. The Effects of Ocimum basilicum Extract and Its Constituent, Rosmarinic Acid on Total and Differential Blood WBC, Serum Levels of NO, MDA, Thiol, SOD, and CAT in Ovalbumin Sensitized Rats. Iran. J. Pharm. Res. IJPR (2018) 17: 1371–1385.
(47) Al-Shammari B, Khalifa M, Bakheet SA and Yasser M. A Mechanistic Study on the AmiodaroneInduced Pulmonary Toxicity. Oxid. Med. Cell. Longev. (2016) 2016: 1–10.
(48) Winsauer PJ, Molina PE, Amedee AM, Filipeanu CM, McGoey RR, Troxclair DA, Walker EM, Birke LL, Stouwe C Vande, Howard JM, Leonard ST, Moerschbaecher JM and Lewis PB.
Tolerance to chronic delta-9-tetrahydrocannabinol(Δ9-THC) in rhesus macaques infected withsimian immunodeficiency virus. Exp. Clin.
Psychopharmacol. (2011) 19: 154–72.
(49) Kasvis P, Vigano M and Vigano A. Health-related quality of life across cancer cachexia stages. Ann.
Palliat. Med. (2018) 0.
(50) Ben Amar M. Cannabinoids in medicine: A review of their therapeutic potential. J. Ethnopharmacol.
(2006) 105: 1–25.
(51) Drevytska T, Morhachov R, Tumanovska L, Portnichenko G, Nagibin V, Boldyriev O, Lapikova-Bryhinska T, Gurianova V, Dons’koi B, Freidin M, Ivanisenko V, Bragina EY, Hofestädt
R and Dosenko V. shRNA-Induced Knockdown 17AM1241 Effect on Ovalbumin-Induced Asthmaof a Bioinformatically Predicted Target IL10Influences Functional Parameters in Spontaneously Hypertensive Rats with Asthma. J. Integr. Bioinform. (2018) 0.
(52) Jacono FJ, Peng Y-J, Nethery D, Faress JA, Lee Z, Kern JA and Prabhakar NR. HIGHLIGHTED TOPIC Reflexes from the Lungs and Airways Acute lung injury augments hypoxic ventilatory response in the absence of systemic hypoxemia. J Appl Physiol (2006) 101: 1795–1802.
(53) Yu X, Zhang Y, Yang X, Zhang X, Wang X, Liu X and Yan Y. The Influence of BuqiHuoxueTongluo Formula on Histopathology and Pulmonary
Function Test in Bleomycin-Induced Idiopathic Pulmonary Fibrosis in Rats. Evidence-Based Complement. Altern. Med. (2018) 2018: 1–13.
(54) Collins J-A, Rudenski A, Gibson J, Howard L and O’Driscoll R. Relating oxygen partial pressure, saturation and content: the haemoglobin-oxygen dissociation curve. Breathe (Sheffield, England) (2015) 11: 194–201.
(55) Ho WSV and Kelly MEM. Cannabinoids in the Cardiovascular System. Adv. Pharmacol. (2017) 80: 329–366.
(56) Savill J and Fadok V. Corpse clearance defines themeaning of cell death. Nature (2000) 407: 784–788.
(57) Kandhare AD, Bodhankar SL, Mohan V and Thakurdesai PA. Effect of glycosides based
standardized fenugreek seed extract in bleomycininduced pulmonary fibrosis in rats: Decisive role of Bax, Nrf2, NF-ÎoB, Muc5ac, TNF-α and IL-1Î2.Chem. Biol. Interact. (2015) 237: 151–165.
(58) Varin A, Mukhopadhyay S, Herbein G and Gordon S. Alternative activation of macrophages by IL-4 impairs phagocytosis of pathogens but potentiates
microbial-induced signalling and cytokinesecretion. Blood (2010) 115: 353–362.
(59) Zemmouri H, Sekiou O, Ammar S, El Feki A, Bouaziz M, Messarah M and Boumendjel A. Urtica dioica attenuates ovalbumin-induced inflammation and lipid peroxidation of lung tissues in rat asthma model. Pharm. Biol. (2017) 55: 1561–1568.
(60) Shakeri F and Boskabady MH. Anti-inflammatory, antioxidant, and immunomodulatory effects ofcurcumin in ovalbumin-sensitized rat. BioFactors
(2017) 43: 567–576.
(61) Wu W, Li Y, Jiao Z, Zhang L, Wang X and Qin R. Phyllanthin and hypophyllanthin from Phyllanthus amarus ameliorates immune-inflammatory response in ovalbumin-induced asthma: role of IgE, Nrf2, iNOs, TNF-α, and IL’s. Immunopharmacol. Immunotoxicol. (2018) 1–13.
(62) Shamri R, Xenakis JJ and Spencer LA. Eosinophils in innate immunity: an evolving story. Cell Tissue Res. (2011) 343: 57–83.
(63) Shin I-S, Shin N-R, Jeon C-M, Kwon O-K, Hong J-M, Kim H-S, Oh S-R and Ahn K-S. Thuja orientalis reduces airway inflammation in ovalbumin-induced allergic asthma. Mol. Med.Rep. (2015) 12: 4640–4646.
(64) Pope SM, Brandt EB, Mishra A, Hogan SP, Zimmermann N, Matthaei KI, Foster PS and Rothenberg ME. IL-13 induces eosinophil recruitment into the lung by an IL-5- and eotaxindependent mechanism. J. Allergy Clin. Immunol. (2001) 108: 594–601.