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Apocynin abrogates methotrexate-induced nephrotoxicity: role of TLR4/NF-κB-p65/p38-MAPK, IL-6/STAT-3, PPAR-γ, and

Emad H M Hassanein1, Ahmed M Sayed2, Omnia A M Abd El-Ghafar3

  • 1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Al-Azhar University, 71524, Asyut, Egypt.

Archives of Pharmacal Research
|March 13, 2023
PubMed

Insights

Apocynin (APC) protects against methotrexate (MTX)-induced kidney damage by reducing oxidative stress and inflammation. This study demonstrates APC

Area of Science:

  • Pharmacology and Toxicology
  • Nephrology
  • Biochemistry

Background:

  • Methotrexate (MTX) is a chemotherapy agent known to induce nephrotoxicity.
  • Oxidative stress and inflammation are key mechanisms underlying MTX-induced kidney damage.
  • Apocynin (APC) is an inhibitor of NADPH oxidase with potential antioxidant and anti-inflammatory properties.

Purpose of the Study:

  • To evaluate the renoprotective effects of apocynin (APC) against methotrexate (MTX)-induced nephrotoxicity in a rat model.
  • To investigate the underlying molecular mechanisms of APC's protective action, including its impact on oxidative stress, inflammation, and specific signaling pathways.

Main Methods:

  • Rats were treated with APC, MTX, or a combination of both, with control groups included.
  • Kidney function biomarkers (urea, creatinine, KIM-1), oxidative stress markers (MDA, GSH, SOD, MPO), and inflammatory markers (iNOS, NO, NF-κB, TLR4, JAK/STAT pathway) were assessed.
  • In vitro studies using NRK-52E cells and computational pharmacology (molecular docking, network pharmacology) were employed to confirm findings.

Main Results:

  • APC treatment significantly reduced MTX-induced increases in urea, creatinine, and KIM-1 levels, improving kidney histology.
  • APC restored the oxidant/antioxidant balance and significantly reduced pro-inflammatory markers and expressions of iNOS, NF-κB, TLR4, p38-MAPK, JAK1, and STAT-3.
  • APC protected renal tubular epithelial cells in vitro by inhibiting the JAK/STAT3 pathway, with findings supported by computational analyses.

Conclusions:

  • Apocynin (APC) exhibits significant renoprotective effects against methotrexate (MTX)-induced nephrotoxicity.
  • APC's protective mechanisms involve strong antioxidative and anti-inflammatory activities, including the inhibition of the JAK/STAT3 pathway.
  • APC shows promise as a therapeutic candidate to mitigate MTX-induced renal damage.
Keywords:
ApocyninIL-6/STAT-3MethotrexateNephrotoxicityTLR4/NF-κB-p65/p38-MAPK

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