MicroRNA-188-3p is involved in sevoflurane anesthesia-induced neuroapoptosis by targeting MDM2

Mol Med Rep. 2018 Mar;17(3):4229-4236. doi: 10.3892/mmr.2018.8437. Epub 2018 Jan 16.

Abstract

Sevoflurane is a commonly used inhalation anesthetic. Sevoflurane-induced neuroapoptosis and cognitive impairments in animals are widely reported, however, the underlying molecular mechanisms remain largely unknown. The results of the present study demonstrated that sevoflurane anesthesia induced spatial memory impairments in rats, as determined by the Morris water maze test. Mechanistically, the current study demonstrated that sevoflurane administration significantly enhanced the expression of microRNA (miR)‑188‑3p. Furthermore, inhibition of miR‑188‑3p using lentiviral miR‑188‑3p inhibitors attenuated sevoflurane‑induced cognitive impairments in rats. The present study also demonstrated that miR‑188‑3p targeted MDM2 proto‑oncogene (MDM2) and negatively regulated the expression of MDM2, as determined by luciferase assays, reverse transcription‑quantitative polymerase chain reaction and western blot analysis. Furthermore, decreased abundance of MDM2 following transfection with miR‑188‑3p mimics was associated with increased stability of p53 protein. Suppression of p53 activity using the specific p53 inhibitor pifithrin‑α alleviated sevoflurane‑induced neuroapoptosis. These results indicate that the miR‑188‑3p‑MDM2‑p53 axis may have a critical role in sevoflurane‑induced cognitive dysfunction. Therefore, miR‑188‑3p may be a potential target for the treatment of sevoflurane‑induced cognitive impairment.

Keywords: sevoflurane; microRNA‑188‑3p; cognitive impairment; MDM2 proto‑oncogene; p53.

MeSH terms

  • Anesthetics, Inhalation / adverse effects*
  • Animals
  • Antagomirs / genetics
  • Antagomirs / metabolism
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Benzothiazoles / pharmacology
  • Cell Line, Tumor
  • Cognitive Dysfunction / chemically induced
  • Cognitive Dysfunction / genetics*
  • Cognitive Dysfunction / physiopathology
  • Cognitive Dysfunction / prevention & control
  • Gene Expression Regulation
  • Genes, Reporter
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • Hippocampus / physiopathology
  • Humans
  • Luciferases / genetics
  • Luciferases / metabolism
  • Male
  • Maze Learning / drug effects
  • Methyl Ethers / adverse effects*
  • MicroRNAs / agonists
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Molecular Mimicry
  • Neurons / drug effects
  • Neurons / metabolism
  • Neurons / pathology
  • Oligoribonucleotides / genetics
  • Oligoribonucleotides / metabolism
  • Proto-Oncogene Proteins c-mdm2 / genetics*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Sevoflurane
  • Signal Transduction
  • Toluene / analogs & derivatives
  • Toluene / pharmacology
  • Tumor Suppressor Protein p53 / antagonists & inhibitors
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Anesthetics, Inhalation
  • Antagomirs
  • Benzothiazoles
  • Methyl Ethers
  • MicroRNAs
  • Oligoribonucleotides
  • Tumor Suppressor Protein p53
  • Sevoflurane
  • Toluene
  • pifithrin
  • Luciferases
  • Mdm2 protein, rat
  • Proto-Oncogene Proteins c-mdm2