TRO40303, a new cardioprotective compound, inhibits mitochondrial permeability transition.
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.
Schaller
Sophie
S
Trophos S.A., Luminy Biotech Entreprises, Marseille, France. sschaller@trophos.com
Paradis
Stéphanie
S
Ngoh
Gladys A
GA
Assaly
Rana
R
Buisson
Bruno
B
Drouot
Cyrille
C
Ostuni
Mariano A
MA
Lacapere
Jean-Jacques
JJ
Bassissi
Firas
F
Bordet
Thierry
T
Berdeaux
Alain
A
Jones
Steven P
SP
Morin
Didier
D
Pruss
Rebecca M
RM
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002316:Cardiotonic Agents / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D006861:Hydrogen Peroxide / Q000633:toxicity; D007275:Injections, Intravenous; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects; D009203:Myocardial Infarction / Q000473:pathology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D016877:Oxidants / Q000633:toxicity; D018384:Oxidative Stress / Q000187:drug effects; D010091:Oximes / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D010539:Permeability / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism; D012632:Secosteroids / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D014018:Tissue Distribution
D002316:Cardiotonic Agents; D016877:Oxidants; D010091:Oximes; D017382:Reactive Oxygen Species; D012632:Secosteroids; C549911:3,5-seco-4-norcholestan-5-one oxime-3-ol; D006861:Hydrogen Peroxide; D002118:Calcium