Nicorandil mitigates arsenic trioxide-induced lung injury via modulating vital signalling pathways SIRT1/PGC-1α/TFAM, JAK1/STAT3, and miRNA-132 expression

Br J Pharmacol. 2024 Sep;181(17):3215-3231. doi: 10.1111/bph.16414. Epub 2024 May 13.

Abstract

Background and purpose: Nicorandil, a selective opener of potassium channels, used to treat angina, has drawn attention for its potential in mitigating lung injury, positioning it as a promising therapeutic approach to treat drug-induced lung toxicity. This study aimed to explore the protective role of nicorandil in arsenic trioxide (ATO)-induced lung injury and to elucidate the underlying mechanistic pathways.

Experimental approach: We assessed the effects of nicorandil (15 mg·kg-1, p.o.) in a rat model of pulmonary injury induced by ATO (5 mg·kg-1, i.p.). The assessment included oxidative stress biomarkers, inflammatory cytokine levels, and other biomarkers, including sirtuin-1, sirtuin-3, STAT3, TFAM, and JAK in lung tissue. Histological examination using H&E staining and molecular investigations using western blotting and PCR techniques were conducted.

Key results: In our model of lung injury, treatment with nicorandil ameliorated pathological changes as seen with H&E staining, reduced tissue levels of toxicity markers, and exerted significant antioxidant and anti-inflammatory actions. On a molecular level, treatment with nicorandil down-regulated JAK, STAT3, PPARγ, Nrf2, VEGF, p53, and micro-RNA 132 while up-regulating Sirt1, 3, TFAM, AMPK, and ERR-α in lung tissue.

Conclusions and implications: The results presented here show nicorandil as a significant agent in attenuating lung injury induced by ATO in a rodent model. Nonetheless, further clinical studies are warranted to strengthen these findings.

Keywords: AMPK/SIRT1/PGC‐1α/TFAM, JAK1/STAT3 pathway; arsenic trioxide; miRNA‐132; nicorandil; oxidative stress; pulmonary injury.

MeSH terms

  • Animals
  • Arsenic Trioxide* / pharmacology
  • Arsenic Trioxide* / toxicity
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Janus Kinase 1* / metabolism
  • Lung Injury* / chemically induced
  • Lung Injury* / drug therapy
  • Lung Injury* / metabolism
  • Lung Injury* / pathology
  • Lung Injury* / prevention & control
  • Male
  • MicroRNAs* / genetics
  • MicroRNAs* / metabolism
  • Nicorandil* / pharmacology
  • Oxidative Stress / drug effects
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha* / genetics
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha* / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • STAT3 Transcription Factor* / metabolism
  • Signal Transduction* / drug effects
  • Sirtuin 1* / genetics
  • Sirtuin 1* / metabolism
  • Transcription Factors / metabolism

Substances

  • Nicorandil
  • STAT3 Transcription Factor
  • Sirtuin 1
  • Arsenic Trioxide
  • MicroRNAs
  • Sirt1 protein, rat
  • Janus Kinase 1
  • Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
  • Ppargc1a protein, rat
  • Stat3 protein, rat
  • Jak1 protein, rat
  • Tfam protein, rat
  • Transcription Factors
  • DNA-Binding Proteins