بررسی اثر پروفیلاکسی و درمانی ال- آرژنین در پیش‌گیری از نفروتوکسیسیتی ناشی از سیس‌پلاتین در رت: نقش تفاوت جنسیت

نوع مقاله : مقاله های پژوهشی

نویسندگان

1 دانشجوی پزشکی، مرکز تحقیقات آب و الکترولیت و دانشکده‌ی پزشکی و کمیته‌ی تحقیقات دانشجویی، دانشگاه علوم پزشکی اصفهان، اصفهان، ایران

2 دانشیار، مرکز تحقیقات آب و الکترولیت و گروه آسیب شناسی، دانشکده‌ی پزشکی، دانشگاه علوم پزشکی اصفهان، اصفهان، ایران

3 استاد، مرکز تحقیقات آب و الکترولیت و گروه فیزیولوژی، دانشکده‌ی پزشکی، دانشگاه علوم پزشکی اصفهان و موسسه‌ی تحقیقاتی اصفهان، اصفهان، ایران

چکیده

مقدمه: نفروتوکسیسیتی از عوارض مهم درمان با سیس‌پلاتین است که ناشی از ایجاد استرس اکسیداتیو می‌باشد. نفروتوکسیسیتی ناشی از سیس‌پلاتین از یک طرف وابسته به جنس است و از طرفی، عامل اصلی برای محدود نمودن درمان با سیس‌پلاتین می‌باشد. از این رو، استفاده از مکمل‌ها برای پیش‌گیری و یا کاهش نفروتوکسیسیتی ناشی از سیس‌پلاتین ضروری است. این مطالعه، با هدف بررسی اثر پروفیلاکسی و درمانی ال- آرژنین در نفروتوکسیسیتی ناشی از سیس‌پلاتین در رت‌های نر و ماده طراحی گردید.روش‌ها: 16 سر رت نر و 20 سر رت ماده از نژاد ویستار به طور تصادفی در 8 گروه قرار گرفتند. گروه‌های 1 و 5 به عنوان گروه‌های شاهد مثبت نر و ماده، سیس‌پلاتین را با دوز روزانه 5/2 میلی‌گرم به ازای هر کیلوگرم وزن بدن به مدت یک هفته دریافت نمودند. گروه‌های 2 و 6 به عنوان گروه‌های پروفیلاکسی نر و ماده، ال- آرژنین را با دوز روزانه‌ 150 میلی‌گرم به ازای هر کیلوگرم وزن بدن به مدت سه روز دریافت کردند و سپس از روز سوم، سیس‌پلاتین به مدت یک هفته تجویز شد. گروه‌های 3 و 7 به عنوان گروه‌های پروفیلاکسی همراه با درمان تحت دریافت ال- آرژنین به مدت سه روز قرار گرفتند و سپس بدون این که تزریق روزانه‌‌ی ال- آرژنین قطع شود، از روز سوم سیس‌پلاتین به مدت یک هفته تزریق شد.گروه‌های 4 و 8 به عنوان گروه‌های درمان دریافت روزانه و هم‌زمان سیس‌پلاتین و ال- آرژنین را داشتند. در روز دهم، خون‌گیری انجام شد و کلیه‌ها جهت فرایند بافت‌شناسی آماده گردیدند.یافته‌ها: هیچ یک از روش‌های تجویز ال- آرژنین در جنس ماده تفاوتی را با گروه شاهد مثبت ایجاد نکرد. اما همرا ه شدن ال- آرژنین با سیس‌پلاتین بدون پروفیلاکسی در جنس نر (گروه 4) موجب کاهش معنی‌دار سطح سرمی ازت اوره‌ی خون و کراتینین و شدت آسیب بافت کلیوی گردید (05/0 > P). وزن کلیه، همچنین در گروه 4 نسبت به گروه شاهد کاهش داشت؛ هر چند معنی‌دار نبود (20/0 = P) که نشانگر کاهش شدت آسیب است. تفاوت معنی‌داری در سطح بافتی نیتریت در بین گروه‌های نر دیده نشد، اما کاهش وزن در بین این گروه‌ها متفاوت بود و گروه‌های دریافت کننده‌ی ال- آرژنین کاهش وزن بیشتری را نسبت به گروه شاهد مثبت نشان دادند (05/0 > P).نتیجه‌گیری: تجویز ال- آرژنین به عنوان پیش‌ساز نیتریک اکسید، هم‌زمان با سیس‌پلاتین می‌تواند موجب کاهش نفروتوکسیسیتی ناشی از سیس‌پلاتین در جنس نر باشد که احتمال می‌رود از طریق اصلاح عملکرد آندوتلیوم که به وسیله‌ی سیس‌پلاتین مختل شده است، می‌باشد.

کلیدواژه‌ها


عنوان مقاله [English]

The Evaluation of L-arginine Prophylaxis and Treatment on Preventing Nephrotoxicity Cisplatin-Induced in Rat: Role of Gender Difference

نویسندگان [English]

  • Moazzameh Meimandinia 1
  • Roya Amiri 1
  • Fatemeh Eshraghi-Jazi 1
  • Ardeshir Talebi 2
  • Mehdi Nematbakhsh 3
1 Student of Medicine, Water and Electrolytes Research Center AND School of Medicine AND Student Research Committee, Isfahan University of Medical Sciences, Isfahan, Iran
2 Associate Professor, Water and Electrolytes Research Center AND Department of Clinical Pathology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
3 Professor, Water and Electrolytes Research Center AND Department of Physiology, School of Medicine, Isfahan University of Medical Sciences AND Institute of Basic and Applied Sciences Research, Isfahan, Iran
چکیده [English]

Background: Nephrotoxicity is the main side effect of cisplatin (CP)-therapy which is induced by oxidative stress. Nephrotoxicity is gender related and limits the cisplatin treatment. Therefore, it is essential to prevent or to ameliorate cisplatin-induced nephrotoxicity via administration of supplementations. This study was designed to investigate the effect of L-arginine (L-Arg) prophylaxis and treatment on preventing cisplatin-induced nephrotoxicity in male and female rats.Methods: Sixteen male and twenty female Wistar rats were divided into eight groups. Groups 1 (male) and 5(female), as positive control groups, received cisplatin (2.5 mg/kg/day; Intraperitoneally) for a week. Groups 2 (male) and 6 (female) received L-arginine (150 mg/kg/day; Intraperitoneally) as prophylaxis for 3 days, and cisplatin was administered from the day 3 for a week. Groups 3 (male) and 7 (female) received L-arginine, as prophylaxis for 3 days; and cisplatin was administered from the day 3, for a week, without withdrawal of daily L-arginine administration. Groups 4 (male) and 8 (female) received cisplatin and L-arginine simultaneously for a week. On the day 10, blood samples were taken and kidneys were prepared for histopathological investigation.Findings: L-arginine administration did not changed the measured parameters from positive control group in females. Simultaneous administration of cisplatin and L-arginine decreased serum levels of blood urea nitrogen and creatinine as well as intensity of renal tissue damage in comparison with positive control group in males (P < 0.05). In addition, it ameliorated kidney weight in comparison with positive control group in male, insignificantly (P = 0.20). No significant difference was observed in tissue nitrite level among male groups and L-arginine treated male groups had body weight loss more than positive control group (P < 0.05).Conclusion: Simultaneous administration of L-arginine, as nitric oxide precursor, and cisplatin could ameliorate cisplatin-induced nephrotoxicity in male gender through improving endothelium function.

کلیدواژه‌ها [English]

  • Cisplatin
  • Nephrotoxicity
  • L-arginine
  • Gender
  1. Schilsky RL, Anderson T. Hypomagnesemia and renal magnesium wasting in patients receiving cisplatin. Ann Intern Med 1979; 90(6): 929-31.
  2. Vogelzang NJ, Torkelson JL, Kennedy BJ. Hypomagnesemia, renal dysfunction, and Raynaud's phenomenon in patients treated with cisplatin, vinblastine, and bleomycin. Cancer 1985; 56(12): 2765-70.
  3. Tezcan S, Izzettin FV, Sancar M, Yumuk PF, Turhal S. Nephrotoxicity evaluation in outpatients treated with cisplatin-based chemotherapy using a short hydration method. Pharmacology and Pharmacy 2013; 4(3): 293-302.
  4. Logothetis CJ, Assikis V, Sarriera JE. Diagnosis, treatment, and prevention of nephrotoxicity of cancer therapeutic agents. In: Kufe DW, Pollock RE, Ralph R Weichselbaum RR, Bast RC, Gansler TS, editors. Holland-Frei Cancer Medicine; 6th ed. Hamilton, ON: BC Decker; 2003.
  5. Santoso JT, Lucci JA, III, Coleman RL, Schafer I, Hannigan EV. Saline, mannitol, and furosemide hydration in acute cisplatin nephrotoxicity: a randomized trial. Cancer Chemother Pharmacol 2003; 52(1): 13-8.
  6. Stewart DJ, Mikhael NZ, Nanji AA, Nair RC, Kacew S, Howard K, et al. Renal and hepatic concentrations of platinum: relationship to cisplatin time, dose, and nephrotoxicity. J Clin Oncol 1985; 3(9): 1251-6.
  7. Dobyan DC, Levi J, Jacobs C, Kosek J, Weiner MW. Mechanism of cis-platinum nephrotoxicity: II. Morphologic observations. J Pharmacol Exp Ther 1980; 213(3): 551-6.
  8. Atessahin A, Yilmaz S, Karahan I, Ceribasi AO, Karaoglu A. Effects of lycopene against cisplatin-induced nephrotoxicity and oxidative stress in rats. Toxicology 2005; 212(2-3): 116-23.
  9. Chirino YI, Pedraza-Chaverri J. Role of oxidative and nitrosative stress in cisplatin-induced nephrotoxicity. Exp Toxicol Pathol 2009; 61(3): 223-42.
  10. Nematbakhsh M, Ashrafi F, Safari T, Talebi A, Nasri H, Mortazavi M, et al. Administration of vitamin E and losartan as prophylaxes in cisplatin-induced nephrotoxicity model in rats. J Nephrol 2012; 25(3): 410-7.
  11. Antunes LM, Darin JD, Bianchi MD. Protective effects of vitamin c against cisplatin-induced nephrotoxicity and lipid peroxidation in adult rats: a dose-dependent study. Pharmacol Res 2000; 41(4): 405-11.
  12. Motamedi F, Nematbakhsh M, Monajemi R, Pezeshki Z, Talebi A, Zolfaghari B, et al. Effect of pomegranate flower extract on cisplatin-induced nephrotoxicity in rats. J Nephropathol 2014; 3(4): 133-8.
  13. Nematbakhsh M, Hajhashemi V, Ghannadi A, Talebi A, Nikahd M. Protective effects of the Morus alba L. leaf extracts on cisplatin-induced nephrotoxicity in rat. Res Pharm Sci 2013; 8(2): 71-7.
  14. Deegan PM, Nolan C, Ryan MP, Basinger MA, Jones MM, Hande KR. The role of the renin-angiotensin system in cisplatin nephrotoxicity. Ren Fail 1995; 17(6): 665-74.
  15. Kamper M, Tsimpoukidi O, Chatzigeorgiou A, Lymberi M, Kamper EF. The antioxidant effect of angiotensin II receptor blocker, losartan, in streptozotocin-induced diabetic rats. Transl Res 2010; 156(1): 26-36.
  16. Haghighi M, Nematbakhsh M, Talebi A, Nasri H, Ashrafi F, Roshanaei K, et al. The role of angiotensin II receptor 1 (AT1) blockade in cisplatin-induced nephrotoxicity in rats: gender-related differences. Ren Fail 2012; 34(8): 1046-51.
  17. Nematbakhsh M, Ebrahimian S, Tooyserkani M, Eshraghi-Jazi F, Talebi A, Ashrafi F. Gender difference in Cisplatin-induced nephrotoxicity in a rat model: greater intensity of damage in male than female. Nephrourol Mon 2013; 5(3): 818-21.
  18. Pinches M, Betts C, Bickerton S, Burdett L, Thomas H, Derbyshire N, et al. Evaluation of novel renal biomarkers with a cisplatin model of kidney injury: gender and dosage differences. Toxicol Pathol 2012; 40(3): 522-33.
  19. Nematbakhsh M, Talebi A, Nasri H, Safari T, Dolatkhah Sh, Ashrafi F. Some evidence for sex-based differences in cisplatin-induced nephrotoxicity in rats. Med Sci Tech 2012; 53(1): RA29-32.
  20. Pezeshki Z, Nematbakhsh M, Nasri H, Talebi A, Pilehvarian AA, Safari T, et al. Evidence against protective role of sex hormone estrogen in Cisplatin-induced nephrotoxicity in ovarectomized rat model. Toxicol Int 2013; 20(1): 43-7.
  21. Nematbakhsh M, Sorooshzadeh SMA, Pezeshki Z, Talebi A, Ashrafi F. Gender difference in the serum levels of total nitric oxide metabolites, nitrite, and nitrate in cisplatin-induced nephrotoxicity in rats. J Isfahan Med Sch 2013; 30(214): 1967-75. [In Persian].
  22. Saleh S, El-Demerdash E. Protective effects of L-arginine against cisplatin-induced renal oxidative stress and toxicity: role of nitric oxide. Basic Clin Pharmacol Toxicol 2005; 97(2): 91-7.
  23. Eshraghi-Jazi F, Nematbakhsh M, Nasri H, Talebi A, Haghighi M, Pezeshki Z, et al. The protective role of endogenous nitric oxide donor (L-arginine) in cisplatin-induced nephrotoxicity: Gender related differences in rat model. J Res Med Sci 2011; 16(11): 1389-96.
  24. Kohli R, Meininger CJ, Haynes TE, Yan W, Self JT, Wu G. Dietary L-arginine supplementation enhances endothelial nitric oxide synthesis in streptozotocin-induced diabetic rats. J Nutr 2004; 134(3): 600-8.
  25. Moslemi F, Nematbakhsh M, Eshraghi-Jazi F, Talebi A, Nasri H, Ashrafi F, et al. Inhibition of Nitric Oxide Synthase by L-NAME Promotes Cisplatin-Induced Nephrotoxicity in Male Rats. ISRN Toxicol 2013; 2013: 242345.
  26. Razmjoo F, Soltani N, Nematbakhsh M. The role of losartan and oral magnesium sulfate in cisplatin induced nephrotoxicity in female rats. Br J Pharm Res 2014; 4(15): 1886-99.
  27. Ashrafi F, Haghshenas S, Nematbakhsh M, Nasri H, Talebi A, Eshraghi-Jazi F, et al. The Role of Magnesium Supplementation in Cisplatin-induced Nephrotoxicity in a Rat Model: No Nephroprotectant Effect. Int J Prev Med 2012; 3(9): 637-43.
  28. Rostami B, Nematbakhsh M, Pezeshki Z, Talebi A, Sharifi MR, Moslemi F, et al. Effect of testosterone on Cisplatin-induced nephrotoxicity in surgically castrated rats. Nephrourol Mon 2014; 6(5): e21546.
  29. Nematbakhsh M, Ashrafi F, Nasri H, Talebi A, Pezeshki Z, Eshraghi F, et al. A model for prediction of cisplatin induced nephrotoxicity by kidney weight in experimental rats. J Res Med Sci 2013; 18(5): 370-3.
  30. Ramesh G, Reeves WB. TNF-alpha mediates chemokine and cytokine expression and renal injury in cisplatin nephrotoxicity. J Clin Invest 2002; 110(6): 835-42.
  31. Santos NA, Catao CS, Martins NM, Curti C, Bianchi ML, Santos AC. Cisplatin-induced nephrotoxicity is associated with oxidative stress, redox state unbalance, impairment of energetic metabolism and apoptosis in rat kidney mitochondria. Arch Toxicol 2007; 81(7): 495-504.
  32. Mansour M, Daba MH, Gado A, Al-Rikabi A, Al-Majed A. Protective effect of L-arginine against nephrotoxicity induced by cyclosporine in normal rats. Pharmacol Res 2002; 45(6): 441-6.
  33. Can C, Sen S, Boztok N, Tuglular I. Protective effect of oral L-arginine administration on gentamicin-induced renal failure in rats. Eur J Pharmacol 2000; 390(3): 327-34.
  34. Bidadkosh A, Derakhshanfar A, Rastegar AM, Yazdani S. Antioxidant preserving effects of l -arginine at reducing the hemodynamic toxicity of gentamicin-induced rat nephrotoxicity: pathological and biochemical findings. Comparative Clinical Pathology 2012; 21(6): 1739-44.
  35. Pezeshki Z, Nematbakhsh M. Nitric oxide metabolites change in cisplatin-induced nephrotoxicity: the effect of L-arginine and losartan. J Anal Oncol 2013; 2(2): 117-9.
  36. Kosaka H, Yoneyama H, Zhang L, Fujii S, Yamamoto A, Igarashi J. Induction of LOX-1 and iNOS expressions by ischemia-reperfusion of rat kidney and the opposing effect of L-arginine. FASEB J 2003; 17(6): 636-43.
  37. Nematbakhsh M, Pezeshki Z. Sex-Related Difference in Nitric Oxide Metabolites Levels after Nephroprotectant Supplementation Administration against Cisplatin-Induced Nephrotoxicity in Wistar Rat Model: The Role of Vitamin E, Erythropoietin, or N-Acetylcysteine. ISRN Nephrol 2013; 2013: 612675.
  38. Eshraghi-Jazi F, Nematbakhsh M, Pezeshki Z, Nasri H, Talebi A, Safari T, et al. Sex differences in protective effect of recombinant human erythropoietin against cisplatin-induced nephrotoxicity in rats. Iran J Kidney Dis 2013; 7(5): 383-9.
  39. Pezeshki Z, Nematbakhsh M, Mazaheri S, Eshraghi-Jazi F, Talebi A, Nasri H, et al. Estrogen Abolishes Protective Effect of Erythropoietin against Cisplatin-Induced Nephrotoxicity in Ovariectomized Rats. ISRN Oncol 2012; 2012: 890310.
  40. Nematbakhsh M, Pezeshki Z, Eshraghi-Jazi F, Ashrafi F, Nasri H, Talebi A, et al. Vitamin E, Vitamin C, or Losartan Is Not Nephroprotectant against Cisplatin-Induced Nephrotoxicity in Presence of Estrogen in Ovariectomized Rat Model. Int J Nephrol 2012; 2012: 284896.
  41. Xia Y, Krukoff TL. Estrogen induces nitric oxide production via activation of constitutive nitric oxide synthases in human neuroblastoma cells. Endocrinology 2004; 145(10): 4550-7.
  42. Ogando D, Farina M, Ribeiro ML, Perez MS, Cella M, Rettori V, et al. Steroid hormones augment nitric oxide synthase activity and expression in rat uterus. Reprod Fertil Dev 2003; 15(5): 269-74.
  43. Leung EL, Fraser M, Fiscus RR, Tsang BK. Cisplatin alters nitric oxide synthase levels in human ovarian cancer cells: involvement in p53 regulation and cisplatin resistance. Br J Cancer 2008; 98(11): 1803-9.
  44. Rajabi N, Nematbakhsh M, Pezeshki Z, Talebi A, Ashrafi F. N-acetylcysteine and cisplatin-induced nephrotoxicity: is it a suitable antioxidant supplementation to prevent nephrotoxicity in male or female rats? J Isfahan Med Sch 2013; 31(229): 294-304. [In Persian].
  45. Mazaheri S, Nematbakhsh M, Bahadorani M, Pezeshki Z, Talebi A, Ghannadi AR, et al. Effects of Fennel Essential Oil on Cisplatin-induced Nephrotoxicity in Ovariectomized Rats. Toxicol Int 2013; 20(2): 138-45.
  46. Rastghalam R, Nematbakhsh M, Bahadorani M, Eshraghi-Jazi F, Talebi A, Moeini M, et al. Angiotensin Type-1 Receptor Blockade May Not Protect Kidney against Cisplatin-Induced Nephrotoxicity in Rats. ISRN Nephrol 2014; 2014: 479645.
  47. Soltani N, Nematbakhsh M, Eshraghi-Jazi F, Talebi A, Ashrafi F. Effect of oral administration of magnesium on Cisplatin-induced nephrotoxicity in normal and streptozocin-induced diabetic rats. Nephrourol Mon 2013; 5(4): 884-90.
  48. Ohno T, Kato S, Wakatsuki M, Noda SE, Murakami C, Nakamura M, et al. Incidence and temporal pattern of anorexia, diarrhea, weight loss, and leukopenia in patients with cervical cancer treated with concurrent radiation therapy and weekly cisplatin: comparison with radiation therapy alone. Gynecol Oncol 2006; 103(1):
  49. -9.
  50. Fenster CP, Darley-Usmar VM, Landar AL, Gower BA, Weinsier RL, Hunter GR, et al. Weight loss and race modulate nitric oxide metabolism in overweight women. Free Radic Biol Med 2004; 37(5): 695-702.
دوره 33، شماره 339 - شماره پیاپی 339
مرداد و شهریور 1394
صفحه 932-944
  • تاریخ دریافت: 12 دی 1393
  • تاریخ بازنگری: 04 فروردین 1402
  • تاریخ پذیرش: 17 فروردین 1401
  • تاریخ اولین انتشار: 17 فروردین 1401