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Protective effect of peroxisome proliferator activator receptor (PPAR)-α and -γ ligands against methotrexate-induced

Mohamed A Ibrahim1, Azza A K El-Sheikh, Hanaa M Khalaf

  • 1Department of Pharmacology, Faculty of Medicine, Minia University , Minia , Egypt.

Immunopharmacology and Immunotoxicology
|February 14, 2014
PubMed
Abstract

Insights

Pioglitazone (PIO) and fenofibrate (FEN) protected against methotrexate (MTX)-induced nephrotoxicity in rats by reducing oxidative stress. PIO demonstrated superior protection by also inhibiting inflammatory pathways, unlike FEN.

Area of Science:

  • Pharmacology
  • Toxicology
  • Renal Medicine

Background:

  • Methotrexate (MTX), an anticancer drug, can induce multi-organ toxicities, notably nephrotoxicity.
  • Understanding protective mechanisms against MTX-induced kidney damage is crucial for patient safety.

Purpose of the Study:

  • To evaluate the protective effects of peroxisome proliferator activator receptor (PPAR)-α and -γ agonists, fenofibrate (FEN) and pioglitazone (PIO), against MTX-induced nephrotoxicity in a rat model.
  • To compare the efficacy of FEN and PIO in mitigating MTX-induced kidney damage.

Main Methods:

  • Rats were administered FEN (150 mg/kg/day) or PIO (5 mg/kg/day) orally for 15 days.
  • MTX (20 mg/kg, i.p.) was administered as a single dose on day 11, with or without prior PPAR agonist treatment.
  • Renal function, oxidative/nitrosative stress markers, inflammatory cytokines, and apoptosis markers were assessed.

Main Results:

  • MTX induced significant nephrotoxicity, evidenced by elevated serum urea and creatinine, and histopathological damage.
  • MTX increased renal oxidative/nitrosative stress (decreased GSH and catalase, increased MDA and NOx) and inflammation (increased TNF-α, NF-κB, and caspase 3).
  • Both FEN and PIO improved renal function and reversed oxidative/nitrosative stress. PIO, but not FEN, significantly reduced TNF-α and NF-κB expression and showed greater improvement in reversing caspase 3 expression.

Conclusions:

  • Both FEN and PIO offer protection against MTX-induced nephrotoxicity, primarily through ameliorating oxidative/nitrosative stress.
  • PIO exhibits superior renoprotective effects compared to FEN, attributed to its additional inhibitory action on the TNF-α/NF-κB inflammatory pathway.
  • These findings highlight the potential of PPAR-γ agonists like PIO in managing MTX-related kidney toxicity.

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