TRO40303, a New Cardioprotective Compound, Inhibits Mitochondrial Permeability Transition

  • Schaller S
  • Paradis S
  • Ngoh G
 et al. 
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Abstract

3,5-Seco-4-nor-cholestan-5-one oxime-3-ol (TRO40303) is a new cardioprotective compound coming from a chemical series identified initially for neuroprotective properties. TRO40303 binds specifically to the mitochondrial translocator protein 18 kDa (TSPO) at the cholesterol site. After intravenous administration, TRO40303 tissue distribution was comparable to that of TSPO, and, in particular, the drug accumulated rapidly in the heart. In a model of 35 min of myocardial ischemia/24 h of reperfusion in rats, TRO40303 (2.5 mg/kg) reduced infarct size by 38% (p < 0.01 versus control), when administered 10 min before reperfusion, which was correlated with reduced release of apoptosis-inducing factor from mitochondria to the cytoplasm in the ischemic area at risk. Although TRO40303 had no effect on the calcium retention capacity of isolated mitochondria, unlike cyclosporine A, the drug delayed mitochondrial permeability transition pore (mPTP) opening and cell death in isolated adult rat cardiomyocytes subjected to 2 h of hypoxia followed by 2 h of reoxygenation and inhibited mPTP opening in neonatal rat cardiomyocytes treated with hydrogen peroxide. The effects of TRO40303 on mPTP in cell models of oxidative stress are correlated with a significant reduction in reactive oxygen species production and subsequent calcium overload. TRO40303 is a new mitochondrial-targeted drug and inhibits mPTP triggered by oxidative stress. Its mode of action differs from that of other mPTP inhibitors such as cyclosporine A, thus providing a new pharmacological approach to study mPTP regulation. Its efficacy in an animal model of myocardial infarctions makes TRO40303 a promising new drug for the reduction of cardiac ischemia-reperfusion injury.

Author-supplied keywords

  • Animals
  • Blotting
  • Calcium
  • Calcium: metabolism
  • Cardiac
  • Cardiac: drug effects
  • Cardiac: metabolism
  • Cardiotonic Agents
  • Cardiotonic Agents: metabolism
  • Cardiotonic Agents: pharmacokinetics
  • Cardiotonic Agents: pharmacology
  • Cell Death
  • Cell Death: drug effects
  • Cells
  • Cultured
  • Cytosol
  • Cytosol: drug effects
  • Cytosol: metabolism
  • Heart
  • Heart: drug effects
  • Heart: metabolism
  • Hydrogen Peroxide
  • Hydrogen Peroxide: toxicity
  • Injections
  • Intravenous
  • Male
  • Membrane Potentials
  • Membrane Potentials: drug effects
  • Mitochondria
  • Mitochondrial Membranes
  • Mitochondrial Membranes: drug effects
  • Myocardial Infarction
  • Myocardial Infarction: pathology
  • Myocytes
  • Newborn
  • Oxidants
  • Oxidants: toxicity
  • Oxidative Stress
  • Oxidative Stress: drug effects
  • Oximes
  • Oximes: metabolism
  • Oximes: pharmacokinetics
  • Oximes: pharmacology
  • Permeability
  • Permeability: drug effects
  • Rats
  • Reactive Oxygen Species
  • Reactive Oxygen Species: metabolism
  • Secosteroids
  • Secosteroids: metabolism
  • Secosteroids: pharmacokinetics
  • Secosteroids: pharmacology
  • Tissue Distribution
  • Western
  • Wistar

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Authors

  • Sophie Schaller

  • Stéphanie Paradis

  • Gladys A Ngoh

  • Rana Assaly

  • Bruno Buisson

  • Cyrille Drouot

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