Renoprotective Effects of Edaravone in a Model of Acute kidney Injury Induced by Rhabdomyolysis in Rats, the Involvement of Nitric oxide

Document Type : Original Article

Authors

1 Department of Pharmacology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.

2 Nanomedicine and Nanobiology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

3 Nephrology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

4 Autoimmune Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.

5 Department of Immunology, Shiraz University of Medical Sciences, Shiraz, Iran.

Abstract

Edaravone is a free radical scavenger which is used as a drug for the treatment of cerebral infarction and amyotrophic lateral sclerosis. Edaravone is distributed widely in the body and its effects are not limited to the neural tissue. Many studies indicate that edaravone has some nitric oxide synthase (NOS) modulating properties. In this research we evaluated the effects of edaravone (1, 5 and 10 mg/kg) alone or in concombination with diphenyliodonium chloride (a specific endothelial NOS inhibitor) or aminoguanidine (a specific inducible NOS inhibitor) on oxidative stress, and renal tissue and function in a model of acute kidney injury induced by a single intramuscular injection of hypertonic glycerol solution. Effects of edaravone on gene expressions of eNOS and iNOS (by RT-PCR) were also investigated. Data were analyzed using one-way analysis of variance (ANOVA) followed by Tukey’s test. At the end of this study, edaravone attenuated oxidative stress and improved renal tissue damage and dysfunction. Aminoguanidine enhanced the renoprotective effects of edaravone. Edaravone showed no remarkable effect on the expression of eNOS gene but it reduced the induction of iNOS gene significantly. The results of this study showed that edaravone could protect against rhabdomyolysis-induced acute kidney injury using its antioxidant activity and inhibiting effect on iNOS gene expression.

Keywords

References

1.    Lameire N, Van Biesen W, Vanholder R. The changing epidemiology of acute renal failure. Nat Clin Pract Nephrol. 2006 Jul;2(7):364-77. doi: 10.1038/ncpneph0218. Erratum in: Nat Clin Pract Nephrol. 2010 Aug;6(8):446. PMID: 16932465.
2.    Waikar SS, Curhan GC, Wald R, McCarthy EP, Chertow GM. Declining mortality in patients with acute renal failure, 1988 to 2002. J Am Soc Nephrol. 2006 Apr;17(4):1143-50. doi: 10.1681/ASN.2005091017. Epub 2006 Feb 22. PMID: 16495376.
3.    Vanholder R, Sever MS, Erek E, Lameire N. Rhabdomyolysis. J Am Soc Nephrol. 2000 Aug;11(8):1553-1561. doi: 10.1681/ASN.V1181553. PMID: 10906171.
4.    Nath KA, Balla G, Vercellotti GM, Balla J, Jacob HS, Levitt MD, Rosenberg ME. Induction of heme oxygenase is a rapid, protective response in rhabdomyolysis in the rat. J Clin Invest. 1992 Jul;90(1):267-70. doi: 10.1172/JCI115847. PMID: 1634613; PMCID: PMC443091.
5.    Tamamura M, Saito M, Kinoshita Y, Shimizu S, Satoh I, Shomori K, Dimitriadis F, Satoh K. Protective effect of edaravone, a free-radical scavenger, on ischaemia-reperfusion injury in the rat testis. BJU Int. 2010 Mar;105(6):870-6. doi: 10.1111/j.1464-410X.2009.08798.x. Epub 2009 Aug 19. PMID: 19694712.
6.    Anggård E. Nitric oxide: mediator, murderer, and medicine. Lancet. 1994 May 14;343(8907):1199-206. doi: 10.1016/s0140-6736(94)92405-8. PMID: 7909873.
7.    Bobadilla NA, Tapia E, Franco M, López P, Mendoza S, García-Torres R, Alvarado JA, Herrera-Acosta J. Role of nitric oxide in renal hemodynamic abnormalities of cyclosporin nephrotoxicity. Kidney Int. 1994 Sep;46(3):773-9. doi: 10.1038/ki.1994.332. PMID: 7996799.
8.    Misko TP, Moore WM, Kasten TP, Nickols GA, Corbett JA, Tilton RG, McDaniel ML, Williamson JR, Currie MG. Selective inhibition of the inducible nitric oxide synthase by aminoguanidine. Eur J Pharmacol. 1993 Mar 16;233(1):119-25. doi: 10.1016/0014-2999(93)90357-n. PMID: 7682510.
9.    Watanabe T, Tanaka M, Watanabe K, Takamatsu Y, Tobe A. [Research and development of the free radical scavenger edaravone as a neuroprotectant]. Yakugaku Zasshi. 2004 Mar;124(3):99-111. Japanese. doi: 10.1248/yakushi.124.99. PMID: 15049127.
10.    Watanabe T, Tahara M, Todo S. The novel antioxidant edaravone: from bench to bedside. Cardiovasc Ther. 2008 Summer;26(2):101-14. doi: 10.1111/j.1527-3466.2008.00041.x. PMID: 18485133.
11.    YYamashita T, Sakamoto K, Yamanishi H, Totani N, Yamamoto J. Effect of a free radical scavenger on nitric oxide release in microvessels. Vascul Pharmacol. 2013 Jan;58(1-2):134-9. doi: 10.1016/j.vph.2012.10.006. Epub 2012 Oct 26. PMID: 23107619.
12.    Yoshida H, Kwon AH, Habara K, Yamada M, Kaibori M, Kamiyama Y, Nishizawa M, Ito S, Okumura T. Edaravone inhibits the induction of iNOS gene expression at transcriptional and posttranscriptional steps in murine macrophages. Shock. 2008 Dec;30(6):734-9. doi: 10.1097/SHK.0b013e318173ea0b. PMID: 18496239.
13.    Heitzer T, Schlinzig T, Krohn K, Meinertz T, Münzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation. 2001 Nov 27;104(22):2673-8. doi: 10.1161/hc4601.099485. Erratum in: Circulation. 2003 Jul 29;108(4):500. PMID: 11723017.
14.    Yoshida H, Sasaki K, Namiki Y, Sato N, Tada N. Edaravone, a novel radical scavenger, inhibits oxidative modification of low-density lipoprotein (LDL) and reverses oxidized LDL-mediated reduction in the expression of endothelial nitric oxide synthase. Atherosclerosis. 2005 Mar;179(1):97-102. doi: 10.1016/j.atherosclerosis.2004.10.037. Epub 2004 Dec 19. PMID: 15721014.
15.    Zhang XH, Matsuda N, Jesmin S, Sakuraya F, Gando S, Kemmotsu O, Hattori Y. Normalization by edaravone, a free radical scavenger, of irradiation-reduced endothelial nitric oxide synthase expression. Eur J Pharmacol. 2003 Aug 22;476(1-2):131-7. doi: 10.1016/s0014-2999(03)02151-4. PMID: 12969758.
16.    Sattarinezhad E, Panjehshahin MR, Torabinezhad S, Kamali-Sarvestani E, Farjadian S, Pirsalami F, Moezi L. Protective Effect of Edaravone Against Cyclosporine-Induced Chronic Nephropathy Through Antioxidant and Nitric Oxide Modulating Pathways in Rats. Iran J Med Sci. 2017 Mar;42(2):170-178. PMID: 28360443; PMCID: PMC5366365.
17.    Dunnill MS. Manual of Histopathological Staining Methods. J Clin Pathol. 1973;26(9):728. 
18.    Wilson DR, Thiel G, Arce ML, Oken DE. Glycerol induced hemoglobinuric acute renal failure in the rat. 3. Micropuncture study of the effects of mannitol and isotonic saline on individual nephron function. Nephron. 1967;4(6):337-55. doi: 10.1159/000179594. PMID: 6065553.
19.    Zager RA, Gamelin LM. Pathogenetic mechanisms in experimental hemoglobinuric acute renal failure. Am J Physiol. 1989 Mar;256(3 Pt 2):F446-55. doi: 10.1152/ajprenal.1989.256.3.F446. PMID: 2923223.
20.    Zager RA. Studies of mechanisms and protective maneuvers in myoglobinuric acute renal injury. Lab Invest. 1989 May;60(5):619-29. PMID: 2716281.
21.    Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. N Engl J Med. 2009 Jul 2;361(1):62-72. doi: 10.1056/NEJMra0801327. Erratum in: N Engl J Med. 2011 May 19;364(20):1982. PMID: 19571284.
22.    Bagley WH, Yang H, Shah KH. Rhabdomyolysis. Intern Emerg Med. 2007 Oct;2(3):210-8. doi: 10.1007/s11739-007-0060-8. Epub 2007 Oct 1. PMID: 17909702.
23.    Khan FY. Rhabdomyolysis: a review of the literature. Neth J Med. 2009 Oct;67(9):272-83. PMID: 19841484.
24.    Noiri E, Nakao A, Uchida K, Tsukahara H, Ohno M, Fujita T, Brodsky S, Goligorsky MS. Oxidative and nitrosative stress in acute renal ischemia. Am J Physiol Renal Physiol. 2001 Nov;281(5):F948-57. doi: 10.1152/ajprenal.2001.281.5.F948. PMID: 11592952.
25.    Reeder BJ, Wilson MT. Hemoglobin and myoglobin associated oxidative stress: from molecular mechanisms to disease States. Curr Med Chem. 2005;12(23):2741-51. doi: 10.2174/092986705774463021. PMID: 16305469.
26.    Kikuchi K, Tancharoen S, Takeshige N, Yoshitomi M, Morioka M, Murai Y, Tanaka E. The efficacy of edaravone (radicut), a free radical scavenger, for cardiovascular disease. Int J Mol Sci. 2013 Jul 4;14(7):13909-30. doi: 10.3390/ijms140713909. PMID: 23880849; PMCID: PMC3742225.
27.    Mount PF, Power DA. Nitric oxide in the kidney: functions and regulation of synthesis. Acta Physiol (Oxf). 2006 Aug;187(4):433-46. doi: 10.1111/j.1748-1716.2006.01582.x. PMID: 16866775.
28.    Alderton WK, Cooper CE, Knowles RG. Nitric oxide synthases: structure, function and inhibition. Biochem J. 2001 Aug 1;357(Pt 3):593-615. doi: 10.1042/0264-6021:3570593. PMID: 11463332; PMCID: PMC1221991.
29.    Aktan F. iNOS-mediated nitric oxide production and its regulation. Life Sci. 2004 Jun 25;75(6):639-53. doi: 10.1016/j.lfs.2003.10.042. PMID: 15172174.
30.    Hori K, Tsujii M, Iino T, Satonaka H, Uemura T, Akeda K, Hasegawa M, Uchida A, Sudo A. Protective effect of edaravone for tourniquet-induced ischemia-reperfusion injury on skeletal muscle in murine hindlimb. BMC Musculoskelet Disord. 2013 Mar 27;14:113. doi: 10.1186/1471-2474-14-113. PMID: 23530927; PMCID: PMC3614524.
31.    Takahashi G, Sakurai M, Abe K, Itoyama Y, Tabayashi K. MCI-186 prevents spinal cord damage and affects enzyme levels of nitric oxide synthase and Cu/Zn superoxide dismutase after transient ischemia in rabbits. J Thorac Cardiovasc Surg. 2003 Nov;126(5):1461-6. doi: 10.1016/s0022-5223(03)00693-7. PMID: 14666020.
32.    Chiazza F, Chegaev K, Rogazzo M, Cutrin JC, Benetti E, Lazzarato L, Fruttero R, Collino M. A nitric oxide-donor furoxan moiety improves the efficacy of edaravone against early renal dysfunction and injury evoked by ischemia/reperfusion. Oxid Med Cell Longev. 2015;2015:804659. doi: 10.1155/2015/804659. Epub 2015 Mar 5. PMID: 25834700; PMCID: PMC4365375.
33.    Doi K, Suzuki Y, Nakao A, Fujita T, Noiri E. Radical scavenger edaravone developed for clinical use ameliorates ischemia/reperfusion injury in rat kidney. Kidney Int. 2004 May;65(5):1714-23. doi: 10.1111/j.1523-1755.2004.00567.x. PMID: 15086910.
Trends in Pharmaceutical Sciences
Volume 8, Issue 2
June 2022
Pages 85-94

Files

Share

How to cite

Statistics