1. TRO40303, a new cardioprotective compound, inhibits mitochondrial permeability transition
- Author
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Jean-Jacques Lacapère, Mariano A. Ostuni, Stéphanie Paradis, Alain Berdeaux, Rana Assaly, Firas Bassissi, Cyrille Drouot, Sophie Schaller, Bruno Buisson, Didier Morin, Steven P. Jones, Rebecca M. Pruss, Thierry Bordet, Gladys A. Ngoh, Trophos S.A., Institut Mondor de Recherche Biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Department of Physiology and Biophysics, and Diabetes and Obesity Center, University of Louisville-Institute of Molecular Cardiology, Centre de recherche biomédicale Bichat-Beaujon (CRB3), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Guellaen, Georges
- Subjects
Male ,MESH: Cell Death ,Myocardial Infarction ,MESH: Myocytes, Cardiac ,030204 cardiovascular system & hematology ,Pharmacology ,Mitochondrion ,medicine.disease_cause ,Mitochondria, Heart ,MESH: Animals, Newborn ,Membrane Potentials ,chemistry.chemical_compound ,Cytosol ,0302 clinical medicine ,MESH: Mitochondrial Membranes ,MESH: Cytosol ,MESH: Oxidants ,Oximes ,Myocytes, Cardiac ,Tissue Distribution ,MESH: Animals ,Cells, Cultured ,Heart metabolism ,chemistry.chemical_classification ,0303 health sciences ,MESH: Oxidative Stress ,Cell Death ,biology ,MPTP ,MESH: Reactive Oxygen Species ,Oxidants ,MESH: Oximes ,MESH: Myocardial Infarction ,MESH: Permeability ,MESH: Calcium ,Injections, Intravenous ,Mitochondrial Membranes ,Molecular Medicine ,MESH: Hydrogen Peroxide ,MESH: Mitochondria, Heart ,MESH: Cells, Cultured ,Cardiotonic Agents ,MESH: Rats ,Blotting, Western ,MESH: Secosteroids ,Neuroprotection ,Permeability ,03 medical and health sciences ,[SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,medicine ,Translocator protein ,Animals ,Secosteroids ,MESH: Membrane Potentials ,MESH: Blotting, Western ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Rats, Wistar ,MESH: Tissue Distribution ,030304 developmental biology ,Reactive oxygen species ,Hydrogen Peroxide ,MESH: Rats, Wistar ,MESH: Cardiotonic Agents ,MESH: Injections, Intravenous ,MESH: Male ,Rats ,Oxidative Stress ,Animals, Newborn ,Mitochondrial permeability transition pore ,chemistry ,biology.protein ,Calcium ,Reactive Oxygen Species ,Oxidative stress - Abstract
International audience; 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.
- Published
- 2010
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