Protection of Hesperidin against Methotrexate-Induced Nephrotoxicity may be Mediated by Nrf2/HO-1 Pathway

Indian Journal of Pharmaceutical Education and Research

  • Mohamed Aly Morsy1Department of Pharmaceutical Sciences, College of Clinical Pharmacy, King Faisal University, Al-Ahsa, SAUDI ARABIA., 2Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia, EGYPT.
  • Azza Ali Kamel El-Sheikh2Department of Pharmacology, Faculty of Medicine, Minia University, El-Minia, EGYPT., 3Basic Health Sciences Department, Faculty of Medicine, Princess Nourah bint Abdulrahman University, Riyadh, SAUDI ARABIA.
  • Ahmed Ragaa Nour Ibrahim4Department of Clinical Pharmacy, College of Pharmacy, King Khalid University, Abha, SAUDI ARABIA., 5Department of Biochemistry, Faculty of Pharmacy, Minia University, El-Minia, EGYPT.
  • Mahmoud El-Daly6Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, EGYPT.

Volume 55 Issue 4 Pages 1066-1073

DOI: 10.5530/ijper.55.4.207

Abstract

Background: Methotrexate (MTX), a successfully used chemotherapeutic in the treatment of various malignancies and autoimmune diseases, might cause severe nephrotoxicity. Here, we aimed at investigating possible nephroprotective effects of hesperidin (HES), a flavanone present in citrus fruits, against MTX-induced toxicity. Methods: Rats were divided into control, HES, MTX, and MTX/HES groups, where HES was administered in a dose of 100 mg/kg/day orally for 8 days and MTX in a single i.p. dose of 20 mg/kg on day 5 of the experiment. Results: Pretreatment with HES significantly improved MTX-induced deteriorated kidney function and structure, as well as reversed MTX effects on renal tumor necrosis factor (TNF)-α level and caspase 3 expression. MTX upregulated renal breast cancer resistance protein (BCRP); an efflux transporter that extrudes MTX from the kidney. Unfortunately, MTX/HES did not show a further increase in BCRP expression but rather showed downregulation. MTX also caused downregulation of renal nuclear factor erythroid 2-related factor 2 (Nrf2) and hemeoxygenase-1 (HO-1) expressions, whereas HES reversed the MTX effect and upregulated renal Nrf2/HO-1. Conclusion: HES conferred protection against MTX-mediated nephrotoxicity, at least in part via anti-inflammatory and anti-apoptotic mechanisms. Nrf2/HO-1 pathway, but not BCRP, may have a role in HES-induced nephroprotection against MTX toxicity.

Keywords

  • Methotrexate
  • Hesperidin
  • Nrf2
  • HO-1
  • TNF-α
  • Caspase 3
  • BCRP
IJOPP

Loading…