Effects of thymoquinone in prevention of experimental contrast-induced nephropathy in rats

Document Type : Original Article

Authors

1 Department of Internal Medicine, Kayseri City Hospital, Kayseri, Turkey

2 Department of Nephrology, Erciyes University Medical Faculty, Kayseri, Turkey

3 Department of Medical Biochemistry, Ömer Halisdemir University School of Medicine, NiÄŸde, Turkey

4 Department of Pathology, Erciyes University Medical Faculty, Kayseri, Turkey

5 Department of Medical Genetics, Erciyes University Medical Faculty, Kayseri, Turkey

6 Department of Urology, Kayseri City Hospital, Kayseri, Turkey

7 Department of Biostatistics, Ä°zmir Katip Çelebi Üniversitesi Medical Faculty, Ä°zmir, Turkey

8 Department of Biochemistry, Erciyes University Medical Faculty, Kayseri, Turkey

Abstract

Objective(s): This study aimed to show the effects of thymoquinone, which is known for its antioxidant, anti-inflammatory, and renal protective effects in contrast-induced nephropathy.
Materials and Methods: This is an experimental study in rats. 7 groups were included within the scope of our study: sham-vehicle (n=3), premedication-control (n=6), model (n=6), isolated thymoquinone (n=3+3), low-dose thymoquinone (n=6), and high-dose thymoquinone (n=7). In addition to 48 hr of water deprivation, we pre-medicated the rats with intra-peritoneal indomethacin and L-NAME administration. After premedication, 12.5 ml/kg dose of a high osmolar contrast agent-diatrizoat (Urografin %76) was administrated. Thymoquinone was administrated in two different doses of 1 mg/kg and 1.75 mg/kg for four days intraperitoneally. Renal functions, histopathological differences, oxidative stress parameters, and inflammatory indicators of rats were evaluated at the end of the study.
Results: Significant decreases were observed in levels of serum creatinine and serum BUN with low-dose thymoquinone (1 mg/kg) administration. In light microscopy, significantly less histopathological damage was observed in the low-dose thymoquinone group compared to the contrast agent group. While high-dose thymoquinone is accepted as ineffective biochemically, toxic evidence was identified histopathologically. There were no significant differences between M and TA groups for serum MDA and SOD levels, which were compared to evaluate oxidative stress (P:0.99, P:0.98; respectively). TNF-α, iNOS, and NF-кB gene expressions were not significantly different between all groups (P:0.748, P:0.531, P:0.910; respectively).
Conclusion: This experimental study has demonstrated for the first time the protective effect of the TQ substance for CIN in 1 mg/kg dose, in the accompaniment of biochemical and histopathological data in rats.

Keywords


1. James M, Bouchard J, Ho J, Klarenbach S, LaFrance JP, Rigatto C, et al. Canadian Society of Nephrology commentary on the 2012 KDIGO clinical practice guideline for acute kidney injury. Am J Kidney Dis 2013; 61: 673-85.
2. Taylor AJ, Hotchkiss D, Morse RW, McCabe J. PREPARED: Preparation for angiography in renal dysfunction: a randomized trial of inpatient vs outpatient hydration protocols for cardiac catheterization in mild-to-moderate renal dysfunction. Chest 1998; 114: 1570-1574.
3. Persson PB, Tepel M. Contrast medium-induced nephropathy: the pathophysiology. Kidney Int Suppl 2006; 100: S8-10.
4. Romano G, Briguori C, Quintavalle C, Zanca C, Rivera NV, Colombo A, et al. Contrast agents and renal cell apoptosis. Eur Heart J 2008; 29: 2569-2576.
5. Kanter M. Protective effects of thymoquinone on streptozotocin-induced diabetic nephropathy. J Mol Histol 2009; 40: 107-115.
6. Gholamnezhad Z, Shakeri F, Saadat DS, Ghorani V, Boskabady MH. Clinical and experimental effects of Nigella Sativa and its constituents on respiratory and allergic disorders. Avicenna J Phytomed. 2019;9:195-212
7. Salem ML. Immunomodulatory and therapeutic properties of the Nigella sativa L. seed. Int Immunopharmacol 2005; 5: 1749-1770.
8. Sayed AA, Morcos M. Thymoquinone decreases AGE-induced NF-kappa B activation in proximal tubular epithelial cells. Phytother Res 2007; 21: 898-899.
9. Nagi MN, Mansour MA. Protective effect of thymoquinone against doxorubicin-induced cardiotoxicity in rats: a possible mechanism of protection. Pharmacol Res 2000; 41: 283-289.
10. Badary OA, Taha RA, Gamal el-Din AM, Abdel-Wahab MH. Thymoquinone is a potent superoxide anion scavenger. Drug Chem Toxicol 2003; 26: 87-98.
11. Agmon Y, Peleg H, Greenfeld Z, Rosen S, Brezis M, et al. Nitric oxide and prostanoids protect the renal outer medulla from radiocontrast toxicity in the rat. J Clin Invest 1994; 94: 1069-1075.
12. Kongkham S, Sriwong S, Tasanarong A. Protective effect of alpha tocopherol on contrast-induced nephropathy in rats. Nefrologia 2013; 33: 116-123.
13. Gong X, Wang Q, Tang X, Wang Y, Fu D, Lu H, et al. Tetramethylpyrazine prevents contrast-induced nephropathy by inhibiting p38 MAPK and FoxO1 signaling pathways. Am J Nephrol 2013; 37:199-207.
14. Jacob SW, Rosenbaum EE. The toxicology of dimethyl sulfoxide (DMSO). Headache. 1966; 6: 127-136.  
15. Hosseinzadeh H, Parvardeh S. Anticonvulsant effects of thymoquinone, the major constituent of Nigella sativa seeds, in mice. Phytomedicine 2004; 11: 56-64.
16. Bamosa AO, Ali BA, al Hawsawi ZA. The effect of thymoquinone on blood lipids in rats. Indian J Physiol Pharmacol 2002;46:195-201.
17. Fouda AM, Daba MH, Dahab GM, Sharaf El-Din OA. Thymoquinone ameliorates renal oxidative damage and proliferative response induced by mercuric chloride in rats. Basic Clin Pharmacol Toxicol 2008; 103: 109-118.
18. Colbay M, Yuksel S, Uslan I, Acarturk G, Karaman O, Bas O, et al. Novel approach for the prevention of contrast nephropathy. Exp Toxicol Pathol 2010; 62: 81-89.
19. Cikman O, Taysi S, Gulsen MT, Demir E, Akan M, Diril H, et al. The radio-protective effects of caffeic acid phenethyl ester and thymoquinone in rats exposed to total head irradiation. Wien Klin Wochenschr 2015;127:103-108.
20. Inal S, Koc E, Ulusal-Okyay G, Pasaoglu OT Isik-Gönül I, Oz-Oyar E, et al Protective effect of adrenomedullin on contrast induced nephropathy in rats. Nefrologia 2014; 34: 724-731.
21. Heyman SN, Rosen S, Rosenberger C. Renal parenchymal hypoxia, hypoxia adaptation, and the pathogenesis of radiocontrast nephropathy. Clin J Am Soc Nephrol 2008; 3: 288-296.
22. Ozkan G, Ulusoy S, Orem A, Ersoz S, Alkanat M, Yucesan FB, et al. Protective effect of the grape seed proanthocyanidin extract in a rat model of contrast-induced nephropathy. Kidney Blood Press Res 2012; 35: 445-453.
23. Toprak O, Cirit M, Tanrisev M, Yazici C, Canoz O, Sipahioglu M, et al. Preventive effect of nebivolol on contrast-induced nephropathy in rats. Nephrol Dial Transplant 2008; 23: 853-859.
24. Parvez Z, Rahman MA, Moncada R. Contrast media-induced lipid peroxidation in the rat kidney. Invest Radiol. 1989; 24: 697-702.
25. Sun S, Zhang T, Nie P, Hu L, Yu Y, Cui M, et al. A novel rat model of contrast-induced acute kidney injury. Int J Cardiol 2014; 172: 48-50.
26. Nguyen MT, Devarajan P. Biomarkers for the early detection of acute kidney injury. Pediatr Nephrol. 2008; 23: 2151-2157.
27. Kjeldsen L, Johnsen AH, Sengeløv H, Borregaard N. Isolation and primary structure of NGAL, a novel protein associated with human neutrophil gelatinase. J Biol Chem 1993; 268: 10425-10432.
28. Bolignano D, Donato V, Coppolino G, Campo S, Buemi A, Lacquaniti A, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a marker of kidney damage. Am J Kidney Dis 2008; 52: 595-605.
29. Mishra J, Dent C, Tarabishi R, Mitsnefes MM, Ma Q, Kelly C, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet 2005; 365: 1231-1238.
30. Hirsch R, Dent C, Pfriem H, Allen J, Beekman RH 3rd, Ma Q, et al. NGAL is an early predictive biomarker of contrast-induced nephropathy in children. Pediatr Nephrol 2007; 22: 2089-2095.
31. Bachorzewska-Gajewska H, Malyszko J, Sitniewska E, Malyszko JS, Dobrzycki S. Neutrophil gelatinase-associated lipocalin (NGAL) correlations with cystatin C, serum creatinine and eGFR in patients with normal serum creatinine undergoing coronary angiography. Nephrol Dial Transplant 2007; 22: 295-296.
32. Bachorzewska-Gajewska H, Malyszko J, Sitniewska E, Malyszko JS, Pawlak K, Mysliwiec M, et al. Could neutrophil-gelatinase-associated lipocalin and cystatin C predict the development of contrast-induced nephropathy after percutaneous coronary interventions in patients with stable angina and normal serum creatinine values? Kidney Blood Press Res 2007; 30: 408-415.
33. Zappitelli M, Washburn KK, Arikan AA, Loftis L, Ma Q, Devarajan P, et al. Urine neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in critically ill children: a prospective cohort study. Crit Care. 2007; 11: 84.
34. Sayed-Ahmed MM, Nagi MN. Thymoquinone supplementation prevents the development of gentamicin-induced acute renal toxicity in rats. Clin Exp Pharmacol Physiol 2007; 34: 399-405.
35. Badary OA, Abdel-Naim AB, Abdel-Wahab MH, Hamada FM. The influence of thymoquinone on doxorubicin-induced hyperlipidemic nephropathy in rats. Toxicology 2000; 143: 219-226.
36. Badary OA. Thymoquinone attenuates ifosfamide-induced Fanconi syndrome in rats and enhances its antitumor activity in mice. J Ethnopharmacol 1999 ; 67:135-142.
37. Badary OA, Nagi MN, al-Shabanah OA, al-Sawaf HA, al-Sohaibani MO, al-Bekairi AM. Thymoquinone ameliorates the nephrotoxicity induced by cisplatin in rodents and potentiates its antitumor activity. Can J Physiol Pharmacol 1997; 75:1356-1361.
38. Ozer EK, Goktas MT, Toker A, Pehlivan S, Bariskaner H, Ugurluoglu C, et al. Thymoquinone protects against the sepsis induced mortality, mesenteric hypoperfusion, aortic dysfunction and multiple organ damage in rats. Pharmacol Rep 2017; 69:683-690.
39. Hosseinian S, Rad AK, Bideskan AE, Soukhtanloo M, Sadeghnia H, Shafei MN, et al. Thymoquinone ameliorates renal damage in unilateral ureteral obstruction in rats. Pharmacol Rep 2017; 69:648-657.
40. Faisal R, Ahmad N, Fahad YS, Chiragh S. Anti-arthritic effect of thymoquinone in comparison with methotrexate on pristane induced arthritis in female Sprague Dawley Rats. J Ayub Med Coll Abbottabad 2018; 30:3-7.
41. Aycan Ä°Ö, Tokgöz O, Tüfek A, Alabalık U, EvliyaoÄŸlu O, Turgut H, et al. The use of thymoquinone in nephrotoxicity related to acetaminophen. Int J Surg 2015; 13: 33-37.
42. Samarghandian S, Azimi-Nezhad M, Mehrad-Majd H, Mirhafez SR. Thymoquinone ameliorates acute renal failure in gentamicin-treated adult male rats. Pharmacology 2015; 96: 112-117.
43. Al-Malki AL, Sayed AA. Thymoquinone attenuates cisplatin-induced hepatotoxicity via nuclear factor kappa-B. BMC Complement Altern Med 2014; 14: 282.
44. Pisani A, Sabbatini M, Riccio E, Rossano R, Andreucci M, Capasso C, et al. Effect of a recombinant manganese superoxide dismutase on prevention of contrast-induced acute kidney injury. Clin Exp Nephrol 2014; 18: 424-431.