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Journal of Basic and Clinical Physiology and Pharmacology

Editor-in-Chief: Horowitz, Michal

Editorial Board: Das, Kusal K. / Epstein, Yoram / S. Gershon MD, Elliot / Kodesh , Einat / Kohen, Ron / Lichtstein, David / Maloyan, Alina / Mechoulam, Raphael / Roth, Joachim / Schneider, Suzanne / Shohami, Esther / Sohmer, Haim / Yoshikawa, Toshikazu / Tam, Joseph


CiteScore 2016: 1.01

SCImago Journal Rank (SJR) 2016: 0.349
Source Normalized Impact per Paper (SNIP) 2016: 0.495

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2191-0286
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Volume 28, Issue 3

Issues

Aminoguanidine pretreatment prevents methotrexate-induced small intestinal injury in the rat by attenuating nitrosative stress and restoring the activities of vital mitochondrial enzymes

Kasthuri Natarajan / Premila Abraham
  • Corresponding author
  • Department of Biochemistry, Christian Medical College, Bagayam, Vellore 632002, Tamil Nadu, India, Phone: +914162284267, Mobile: +919894746285, Fax: +91-416-2262788
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/ Rekha Kota / Dhayakani Selvakumar
Published Online: 2017-01-18 | DOI: https://doi.org/10.1515/jbcpp-2016-0099

Abstract

Background:

One of the major toxic side effects of methotrexate (MTX) is enterocolitis, for which there is no efficient standard treatment. Nitric oxide overproduction has been reported to play an important role in MTX-induced mucositis. This study was designed to investigate whether pretreatment with aminoguanidine (AG) – a selective iNOS inhibitor – prevents MTX-induced mucositis in rats.

Methods:

Rats were pretreated with AG (30 and 50 mg/kg body weight) i.p. daily 1 h before MTX (7 mg/kg body weight) administration for 3 consecutive days. After the final dose of MTX, the rats were killed, and the small intestines were used for analysis.

Results:

The small intestines of MTX-treated rats showed moderate to severe injury. Pretreatment with AG had a dose-dependent protective effect on MTX-induced mucositis. AG pretreatment reduced iNOS protein levels, mucosal nitric oxide levels, and protein tyrosine nitration. AG pretreatment also restored the activities of electron transport chain (ETC) complexes, vital tricarboxylic acid (TCA cycle) enzymes, and mitochondrial antioxidant enzymes.

Conclusions:

These findings suggest that AG is beneficial in ameliorating MTX-induced enteritis in rats.

Keywords: aminoguanidine; antioxidant enzymes; ETC activity; methotrexate; nitrosative stress; small intestinal injury; TCA cycle enzymes

References

  • 1.

    Doan T, Massarotti E. Rheumatoid arthritis, an overview of new and emerging therapies. J Clin Pharmacol 2004;45:751–62.Google Scholar

  • 2.

    Xu P, He Y, Chen Y, Chao K, Chen B, Mao R, et al. The efficacy and safety of methotrexate in refractory Crohn’s disease. Zhonghua Nei Ke Za Zhi 2014;53:188–92. Chinese.Google Scholar

  • 3.

    Saibeni S, Bollani S, Losco A, Michielan A, Sostegni R, Devani M, et al. The use of methotrexate for treatment of inflammatory bowel disease in clinical practice. Dig Liver Dis 2012;44:123–27.Google Scholar

  • 4.

    Tsukada T, Nakano T, Miyata T, Sasaki S. Life-threatening gastrointestinal mucosal necrosis during methotrexate treatment for rheumatoid arthritis. Case Rep Gastroenterol 2013;7:470–5.Google Scholar

  • 5.

    Sezer A, Usta U, Cicin I. The effect of Saccharomyces boulardii on reducing irinotecan-induced intestinal mucositis and diarrhea. Med Oncol 2009;26:350–57.Google Scholar

  • 6.

    Kolli VK, Abraham P, Rabi S. Methotrexate-induced nitrosative stress may play a critical role in small intestinal damage in the rat. Arch Toxicol 2008;82:763–70.Google Scholar

  • 7.

    Kolli VK, Kanakasabapathy I, Faith M, Ramamoorthy H, Isaac B, Natarajan K, et al. A preclinical study on the protective effect of melatonin against methotrexate-induced small intestinal damage: effect mediated by attenuation of nitrosative stress, protein tyrosine nitration, and PARP activation. Cancer Chemother Pharmacol 2013;71:1209–18.Google Scholar

  • 8.

    Leitão RF, Brito GA, Oriá RB, Braga-Neto MB, Bellaguarda EA, Silva JV, et al. Role of inducible nitric oxide synthase pathway on methotrexate-induced intestinal mucositis in rodents. BMC Gastroenterol 2011;11:90–111.Google Scholar

  • 9.

    El-Boghdady NA. Protective effect of ellagic acid and pumpkin seed oil against methotrexate-induced small intestine damage in rats. Indian J Biochem Biophys 2011;48:380–87.Google Scholar

  • 10.

    Corbett JA, McDaniel ML. The Use of Aminoguanidine, a Selective iNOS Inhibitor, to evaluate the role of nitric oxide in the development of autoimmune diabetes. Methods 1996;10:21–30.Google Scholar

  • 11.

    Takizawa Y, Kishimoto H, Kitazato T, Tomita M, Hayashi M. Effects of nitric oxide on mucosal barrier dysfunction during early phase of intestinal ischemia/reperfusion. Eur J Pharm Sci 2011;42:246–52.Google Scholar

  • 12.

    Chiu CJ, McArdle AH, Brown R, Scott HJ, Gurd FN. Intestinal mucosal lesion in low-flow states. I. A morphological, hemodynamic, and metabolic reappraisal. Arch Surg 1970;101:478–83.Google Scholar

  • 13.

    Cuzzocrea S, Zingarelli B, Costantino G. Beneficial effects of 3-aminobenzamide, an inhibitor of poly (ADP-ribose) synthetase in a rat model of splanchnic artery occlusion and reperfusion. Br J Pharmacol 1997;121:1065–74.Google Scholar

  • 14.

    Young SL, Lessey BA, Fritz MA, Meyer WR, Murray MJ, Speckman PL, et al. In vivo and in vitro evidence suggest that HB-EGF regulates endometrial expression of human decay-accelerating factor. J Clin Endocrinol Metab 2002;87:1368–75.Google Scholar

  • 15.

    Sastry KV, Moudgal RP, Mohan J, Tyagi JS, Rao GS. Spectrophotometric determination of serum nitrite and nitrate by copper–cadmium alloy. Anal Biochem 2002;306:79–82.Google Scholar

  • 16.

    Darley-Usmar VM. The molecular etiology of human mitochondrial myopathies. Biochem Soc Trans 1987;15:102–03.Google Scholar

  • 17.

    Soper JW, Pedersen PL. Isolation of an oligomycin sensitive ATPase complex from rat liver mitochondria. Methods Enzymol 1979;55:328–33.Google Scholar

  • 18.

    Morton RL, Ikle D, White CW. Loss of lung mitochondrial aconitase activity due to hyperoxia in bronchopulmonary dysplasia in primates. Am J Physiol 1998;274:L127–33.Google Scholar

  • 19.

    Kolli VK, Abraham P, Isaac B. Alteration in antioxidant defense mechanisms in the small intestines of methotrexate treated rat may contribute to its gastrointestinal toxicity. Cancer therapy 2007;5B:501–510.Google Scholar

  • 20.

    Shapira E, Ben-Yoseph Y, Eyal FG, Russell A. Enzymatically inactive red cell carbonic anhydrase B in a family with renal tubular acidosis. J Clin Invest 1974;53:59–63.Google Scholar

  • 21.

    Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193: 265–75.Google Scholar

  • 22.

    Hafez HM, Ibrahim MA, Ibrahim SA, Amin EF, Goma W, Abdelrahman AM. Potential protective effect of etanercept and aminoguanidine in methotrexate-induced hepatotoxicity and nephrotoxicity in rats. Eur J Pharmacol 2015;768:1–12.Google Scholar

  • 23.

    Kubes P, Wallace JL. Nitric oxide as a mediator of gastrointestinal mucosal injury?-Say it ain’t so. Mediators Inflamm 1995;4:397–405.Google Scholar

  • 24.

    Nadler EP, Upperman JS, Dickinson EC, Ford HR. Nitric oxide and intestinal barrier failure. Semin Pediatr Surg 1999;8:148–54.Google Scholar

  • 25.

    Radi R, Peluffo G, Alvarez MN, Naviliat M, Cayota A. Unraveling peroxynitrite formation in biological systems. Free Radic Biol Med 2001;30:463–88.Google Scholar

  • 26.

    Greenacre SA, Ischiropoulos H. Tyrosine nitration: localization, quantitation, consequences for protein function and signal transduction. Free Radic Res 2001;34:541–81.Google Scholar

  • 27.

    Aulak KS, Miyagi M, Yan L, West KA, Massillon D, Crabb JW, et al. Proteomic method identifies proteins nitrated in vivo during inflammatory challenge. Proc Natl Acad Sci U S A 2001;98:12056–61.Google Scholar

  • 28.

    Fan X, Wang J, Soman KV, Ansari GA, Khan MF. Aniline-induced nitrosative stress in rat spleen: proteomic identification of nitrated proteins. Toxicol Appl Pharmacol 2011;255:103–12.Google Scholar

  • 29.

    Abdel-Zaher AO, Abdel-Rahman MM, Hafez MM, Omran FM. Role of nitric oxide and reduced glutathione in the protective effects of aminoguanidine, gadolinium chloride and oleanolic acid against acetaminophen-induced hepatic and renal damage. Toxicology 2007;234:124–34.Google Scholar

  • 30.

    Eroglu C, Yildiz OG, Saraymen R, Soyuer S, Kilic E, Ozcan S. Aminoguanidine ameliorates radiation-induced oxidative lung damage in rats. Clin Invest Med 2008;31:E182–8.Google Scholar

  • 31.

    Ara C, Karabulut AB, Kirimlioglu H, Yilmaz M, Kirimliglu V, Yilmaz S. Protective effect of aminoguanidine against oxidative stress in an experimental peritoneal adhesion model in rats. Cell Biochem Funct 2006;24:443–8.Google Scholar

  • 32.

    Abraham P, Rabi S, Selvakumar D. Protective effect of aminoguanidine against oxidative stress and bladder injury in cyclophosphamide-induced hemorrhagic cystitis in rat. Cell Biochem Funct 2009;27:56–62.Google Scholar

  • 33.

    Yuan Y, Liao YM, Hsueh CT, Mirshahidi HR. Novel targeted therapeutics: inhibitors of MDM2, ALK and PARP. J Hematol Oncol 2011;4:16–30.Google Scholar

  • 34.

    Brindicci C, Ito K, Torre O, Barnes PJ, Kharitonov SA. Effects of aminoguanidine, an inhibitor of inducible nitric oxide synthase, onnitric oxide production and its metabolites in healthy control subjects, healthy smokers, and COPD patients. Chest 2009;135:353–67.Google Scholar

  • 35.

    Brindicci C, Ito K, Barnes PJ, Kharitonov SA. Effect of an inducible nitric oxide synthase inhibitor on differential flow-exhaled nitric oxide in asthmatic patients and healthy volunteers. Chest 2007;132:581–88.Google Scholar

  • 36.

    Watanabe D, Takagi H. Potential pharmacological treatments for diabetic retinopathy. Nippon Rinsho 2005;63:244–49.Google Scholar

About the article

Received: 2016-06-29

Accepted: 2016-10-26

Published Online: 2017-01-18

Published in Print: 2017-05-01


Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: Center for scientific and Industrial research (CSIR) (No. 37/(1358)/09/EMR-II).

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


Citation Information: Journal of Basic and Clinical Physiology and Pharmacology, Volume 28, Issue 3, Pages 239–247, ISSN (Online) 2191-0286, ISSN (Print) 0792-6855, DOI: https://doi.org/10.1515/jbcpp-2016-0099.

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