Evaluation of Δ9-tetrahydrocannabinol metabolites and oxidative stress in type 2 diabetic rats

Document Type: Original Article

Authors

1 Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Istanbul Bilim University, Istanbul, Turkey

2 Department of Medical Biology, Faculty of Cerrahpasa Medicine, Istanbul University, Istanbul, Turkey

Abstract

Objective(s): The object of the study is to examine the effects of Δ9-tetrahydrocannabinol (THC) against oxidative stress in the blood and excretion of THC metabolites in urine of type 2 diabetic rats.

Materials and Methods:
The control (n=8), THC control (n=6), diabetes (n=8) and diabetes + THC (n=7) groups were created. Type 2 diabetes was induced by nicotinamide (NA, 85 mg/kg) + streptozotocin (STZ, 65 mg/kg). THC was administered intraperitoneally for seven days. The glutathione (GSH) level in erythrocytes and malondialdehyde (MDA) level, superoxide dismutase (SOD) and catalase (CAT) enzyme activities in plasma were measured. THC metabolites were analyzed in urine.

Results:
The results showed that the erythrocyte GSH levels were significantly increased (P<0.05), but plasma MDA levels were non-significantly decreased in diabetes group treated with THC when compared with the diabetes group. The CAT activity was non-significantly reduced and SOD was significantly increased (P<0.01) in the plasma of diabetes induced by THC in comparison with the diabetic group. The excretion of THC metabolites was higher in the urine of diabetes + THC rats as compared to the THC control rats.

Conclusion:
These findings highlight that THC treatment may attenuate slightly the oxidative stress in diabetic rats. The excretion rate of THC may vary in the type 2 diabetes mellitus status.    

Keywords


1. Hillig KW, Mahlberg PG. A chemotaxonomic analysis of cannabinoid variation in Cannabis (Cannabaceae). Am J Bot 2004; 91:961-975.

2. Kochanowski M, Kała M. Tetrahydrocannabinols in clinical and forensic toxicology. Przegl Lek 2005; 62:576-580.

3. Gieringer D, Rosenthal E, Carter GT. Marijuana medical handbook: Practical guide to the therapeutic uses of marijuana. Berkley, CA, USA: 2008.

4. ElSohly MA, Slade D. Chemical constituents of marijuana: The complex mixture of natural cannabinoids. Life Sci 2005; 78:539-548.

5. Borgelt LM, Franson KL, Nussbaum AM, Wang GS. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy 2013; 33:195-209.

6. Lutge EE, Gray A, Siegfried N. The medical use of cannabis for reducing morbidity and mortality in patients with HIV/AIDS. Cochrane Database Syst Rev 2013; 4:CD005175.

7. Reynolds TD, Osborn HL. The use of cannabinoids in chronic pain. BMJ Case Rep 2013; bcr2013010417.

8. Carroll CB, Zeissler ML, Hanemann CO, Zajicek JP. Δ⁹-tetrahydrocannabinol (Δ⁹-THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson's disease. Neuropathol Appl Neurobiol 2012; 38:535-547.

9. Chen J, Errico SL, Freed WJ. Reactive oxygen species and p38 phosphorylation regulate the protective effect of delta9-tetrahydrocannabinol in the apoptotic response to NMDA. Neurosci Lett 2005; 389:99-103.

10. Li X, Kaminski NE, Fischer LJ. Examination of the immunosuppressive effect of delta9-tetrahydro-cannabinol in streptozotocin-induced autoimmune diabetes. Int Immunopharmacol 2001; 1:699-712.

11. Moldzio R, Pacher T, Krewenka C, Kranner B, Novak J. Effects of cannabinoids Δ(9)-tetrahydrocannabinol, Δ(9)-tetrahydrocannabinolic acid and cannabidiol in MPP+ affected murine mesencephalic cultures. Phytomedicine 2012; 19:819-824.

12. Sagredo O, Pazos MR, Satta V, Ramos JA, Pertwee RG, Fernández-Ruiz J. Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington's disease. J Neurosci Res 2011; 89:1509-1518.

13. Shinde SN, Dhadke VN, Suryakar AN. Evaluation of oxidative stress in type 2 diabetes mellitus and follow-up along with vitamin E supplementation. Indian J Clin Biochem 2011; 26:74-77.

14. Kassab A, Piwowar A. Cell oxidant stress delivery and cell dysfunction onset in type 2 diabetes. Biochimie 2012; 94:1837-1848.

15. Chen L, Magliano DJ, Zimmet PZ. The worldwide epidemiology of type 2 diabetes mellitus-present and future perspectives. Nat Rev Endocrinol 2011; 8:228-236.

16. Wolfsdorf J, Glaser N, Sperling MA. Diabetic ketoacidosis in infants, children, and adolescents. Diabetes Care 2006; 29:1150-1159.

17. Masiello P, Broca C, Gross R, Roye M, Manteghetti M, Hillaire-Buys D, et al. Experimental NIDDM: development of a new model inadult rats administered streptozotocin and nicotinamide. Diabetes 1998; 47:224–229.

18. Murugan P, Pari L. Influence of tetrahydrocurcumin on hepatic and renal functional markers and protein levels in experimental type 2 diabetic rats. Basic Clin Pharmacol Toxicol 2007; 101:241-245.

19. Beutler E, Duron O, Kelly BM. Improved method for  the determination of blood glutathione. J Lab Clin Med 1963; 51:882-888.

20. Crosby WN, Munn JI, Furth FW. Standardizing a method for clinical hemoglobinometry. U S Armed Forces Med J 1954; 5:693- 703.

21. Ledwozyw A, Michalak J, Stepień A, Kadziolka A. The relationship between plasma triglycerides, cholesterol, total lipids and lipid peroxidation products during human atherosclerosis. Clin Chim Acta 1986; 155:275-283.

22. Sun Y, Oberley LW, Li Y. A simple method for clinical assay of superoxide dismutase. Clin Chem 1988; 34:497-500.

23. Aebi H. Catalase in vitro. Methods Enzymol 1984; 105:121–126.

24. Coskun ZM, Bolkent S. Oxidative stress and cannabinoid receptor expression in type-2 diabetic rat pancreas following treatment with Δ(9) -THC. Cell Biochem Funct 2014; 32:612-619.

25. Chang YC, Chuang LM. The role of oxidative stress in the pathogenesis of type 2 diabetes: from molecular mechanism to clinical implication. Am J Transl Res 2010; 2:316-331.

26. Niedowicz DM, Daleke DL. The role of oxidative stress in diabetic complications. Cell Biochem Biophys 2005; 43:289-330.

27. Kopáni M, Celec P, Danisovic L, Michalka P, Biró C. Oxidative stress and electron spin resonance. Clin Chim Acta 2006; 364:61-66.

28. Koch JE. Delta (9)-THC stimulates food intake in Lewis rats: effects on chow, high-fat and sweet high-fat diets. Pharmacol Biochem Behav 2001; 68:539-543.

29. Robson P. Therapeutic aspects of cannabis and cannabinoids. Br J Psychiatry 2001; 178:107-115.

30. Hampson AJ, Grilmaldi M, Axelrod J, Wink D. Cannabidiol and (-)Δ9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci 1998; 95:8268-8273.

31. Nicotera P, Orrenius S. Role of thiols in protection against biological reactive intermediates. Adv Exp Med Biol 1986; 197:41–49.

32. Feillet-Coudray C, Rock E, Coudray C, Grzelkowska K, Azais-Braesco V, Dardavet D, et al.  Lipid peroxidation and antioxidant status in experimental diabetes. Clin Chim Acta 1999; 284:31-43.

33. Coskun ZM, Sacan O, Karatug A, Turk N, Yanardag R, Bolkent S, et al. Regulation of oxidative stress and somatostatin, cholecystokinin, apelin gene expressions by ghrelin in stomach of newborn diabetic rats. Acta Histochem 2013; 115:740-747.

34. Abdel-Salam OME, Nada SA, Salem NA, El-Sayed El-Shamarka M, Omara E. Effect of Cannabis sativa on oxidative stress and organ damage after systemic endotoxin administration in mice. Comp Clin Pathol 2013; 23:1069-1085.

35. Lowe RH, Abraham TT, Darwin WD, Herning R, Cadet JL, Huestis MA. Extended urinary Delta9-tetrahydrocannabinol excretion in chronic cannabis users precludes use as a biomarker of new drug exposure. Drug Alcohol Depend 2009; 105:24-32.

36. Kreuz DS, Axelrod J. Delta-9-tetrahydrocannabinol: localization in body fat. Science 1973; 179:391-393.