Thymoquinone, the main constituent of Nigella sativa, affects adenosine receptors in asthmatic guinea pigs

Document Type: Original Article


1 Department of Physiology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran

2 Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran


Objective(s): For determining the mechanism of anti-asthmatic effect of thymoquinone, this investigation evaluated the effect of thymoquinone in the presence of selective A2A and A2B adenosine receptor antagonists (ZM241385 and MRS1706, respectively).
Materials and Methods: Seventy guinea pigs were randomly divided to 7 groups; control (C), sensitized with ovalbumin (S), sensitized groups pretreated with thymoquinone (S+TQ), ZM241385 (S+Anta A2A), MRS1706 (S+Anta A2B), thymoquinone and antagonists (S+Anta A2A+TQ and S+Anta A2B+TQ). Thymoquinone and each of these antagonists with 3 mg/kg dose were injected i.p. on 10th day of sensitization protocol. Tracheal responsiveness (TR) to methacholine and ovalbumin (OA), and total and differential cell count in lung lavage fluid (LLF) in different groups were measured.
Results: Increased EC50 and LLF neutrophil count and decreased TR to methacholine and OA, LLF eosinophil and basophil counts were observed in S+TQ group compared to S group (PP<0.05). Significant decrease in EC50 (P<0.01), LLF neutrophil, lymphocyte and monocyte count (PP<0.01), LLF total WBC (P<0.01) and eosinophil count (P<0.001) were observed in S+A2A group compared to S+TQ group. There was significant increase in LLF eosinophil and monocyte counts in S+Anta A2B group compared with S+TQ group (P2A group, there was significant increase in LLF eosinophil (P<0.001) and significant decrease in LLF neutrophil (P<0.01) and monocyte (P<0.001) counts compared with S+TQ group.
Conclusion: Thymoquinone affects adenosine receptors, which suggest that some of its anti-inflammatory effects may be mediated by these receptors.


1. Keir S, Page C. The rabbit a model to study asthma and other lung diseases. Pulm Pharmacol Ther 2008; 21:721–730.

2. Spicuzza L, Di Maria G, Polosa R. Adenosine in the airways: implications and applications. Eur J Pharm Biopharm 2006; 533:77-88.

3. Khan MA, Chen HC, Tania M, Zhang DZ. Anticancer activities of Nigella sativa (black cumin). Afr J Tradit Complement Altern Med 2011; 8:226-232.

4. Mansour M, Tornhamre S. Inhibition of 5-lipoxygenase and leukotriene C4 synthase in human blood cells by thymoquinone. J Enzyme Inhib Med Chem 2004; 19:431-436.

5. Keyhanmanesh R, Bagban H, Nazemiyeh H, Mirzaei Bavil F, Alipour MR, Ahmady M. The relaxant effects of different methanolic fractions of Nigella sativa on guinea pig tracheal chains. Iran J Basic Med Sci 2013; 16: 123-128.

6. Woo CC, Kumar AP, Sethi G, Tan KH. Thymoquinone: potential cure for inflammatory disorders and cancer. Biochem Pharmacol 2012; 83:443-451.

7. Kalus U, Pruss A, Bystron J, Jurecka M, Smekalova A, Lichius JJ, et al. Effect of Nigella sativa (black seed) on subjective feeling in patients with allergic diseases. Phytother Res 2003; 17:1209-1214.

8. Keyhanmanesh R, Boskabady MH, Khamneh S, Doostar Y. Effect of thymoquinone on the lung pathology and cytokine levels of ovalbumin-sensitized guinea pigs. Pharmacol Rep 2010; 62:910-916.

9. Ammar elSM, Gameil NM, Shawky NM, Nader MA. Comparative evaluation of anti-inflammatory properties of thymoquinone and curcumin using an asthmatic murine model. Int Immunopharmacol 2011; 11:2232-2236.

10. Kornerup KN, Page CP, Moffatt JD. Pharmacological characterisation of the adenosine receptor mediating increased ion transport in the mouse isolated trachea and the effect of allergen challenge. Br J Pharmacol 2005; 144:1011-1016.

11. Huszar E, Vass G, Vizi E, Csoma Z, Barat E, Vilagos G M, et al. Adenosine in exhaled breath condensate in healthy volunteers and in patients with asthma. Eur Respir J 2002; 20:1393-1398.

12. Brown RA, Spina D, Page CP. Adenosine receptors and asthma. Br J Pharm 2008; 153:S446–S456.

13. Boskabady MH, Keyhanmansh R, Khamneh                     S, Doostar Y, Khakhzad MR. Potential immuno-modulation effect of the extract of Nigella sativa on ovalbumin sensitized guinea pigs. J Zhejiang Univ-Sci B 2011; 12:201-209.

14. Boskabady MH, Keyhanmanesh R, Ebrahimi Saadatlou MA. Relaxant effect of different fractions from Nigella sativa L. on guinea pig tracheal chains and its possible mechanism(s). Indian J Experimental Biology 2008; 46:805-810.

15. Boskabady MH, Keyhanmanesh R, Khamneh S, Ebrahimi Saadatlou MA. The effect of Nigella sativa extract on tracheal responsiveness and lung inflammation in ovalbumin sensitized guinea pigs. Clinics (Sao Paulo) 2011; 66:879-887.

16. Boskabady MH, Kiani S, Jandaghi P. Antitussive effect of Nigella sativa. Pakistan J Med Sci 2004; 20:224–228.

17. Keyhanmanesh R, Boskabady MH, Eslamizadeh MJ, Khamneh S, Ebrahimi MA. The effect of thymoquinone, the main constituent of Nigella sativa on tracheal responsiveness and white blood cell count in lung lavage of sensitized guinea pigs. Planta Med 2010; 76:218-222.

18. Anderson SE, Franko J, Kashon ML, Anderson KL, Hubbs AF, Lukomska E, et al. Exposure to triclosan augments the allergic response to ovalbumin in a mouse model of asthma. Toxicol Sci 2013; 132:96-106.

19. Hajhashemi V, Ghannadi A, Jafarabadi H. Black cumin seed essential oil, as a potent analgesic and anti-inflammatory drug. Phytother Res 2004; 18:195–199.

20. Spicuzza L, Bonfiglio C, Polosa R. Research applications and implications of adenosine in diseased airways. J Trends Pharmacol Sci 2003; 24:409-413.

21. Polosa R, Rorke S, Holgate ST. Evolving concepts on the value of adenosine hyperresponsiveness in asthma and chronic obstructive pulmonary disease. J Thorax 2002; 57:649-654.

22. Lappas CM, Sullivan GW, Linden J. Adenosine A2A agonists in development for the treatment of inflammation. Expert Opin Investig Drugs 2005; 14:797-806.

23. Thiel M, Chouker A, Ohta A, Jackson E, Caldwell C, Smith P, et al. Oxygenation inhibits the physiological tissue-protecting mechanism and thereby exacerbates acute inflammatory lung injury. PLOS Biol 2005; 3:174.

24. Wilson CN, Mustafa SJ. Adenosine receptors in health and disease (handbook of experimental
pharmacology). Berlin: Springer; 2009:193.

25. Mustafa SJ, Nadeem A, Fan M, Zhong H, Belardinelli L, Zeng D. Effect of a specific and selective a2b adenosine receptor antagonist on adenosine agonist amp and allergen-induced airway responsiveness and cellular influx in a mouse model of asthma. J Pharm Exp Ther 2007; 320:1246-1251.

26. Zhou Y, Mohsenin A, Morschl E, Young HW, Molina JG, Ma W, et al. Enhanced airway inflammation and remodeling in adenosine deaminase-deficient mice lacking the a2b adenosine receptor. J Immunol 2009; 182:8037-8046.

27. Zhong H, Belardinelli L, Maa T, Zeng D. Synergy between A2B adenosine receptors and hypoxia in activating human lung fibroblasts. Am J Respir Cell Mol Biol 2005; 32:2-8.

28. Holgate ST. The quintiles prize lecture 2004. The identification of the adenosine a2b receptor as a novel therapeutic target in asthma. Br J Pharmacol 2005; 145:1009-1015