RT Journal Article
SR Electronic
T1 TRO40303, a New Cardioprotective Compound, Inhibits Mitochondrial Permeability Transition
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 696
OP 706
DO 10.1124/jpet.110.167486
VO 333
IS 3
A1 Sophie Schaller
A1 Stéphanie Paradis
A1 Gladys A. Ngoh
A1 Rana Assaly
A1 Bruno Buisson
A1 Cyrille Drouot
A1 Mariano A. Ostuni
A1 Jean-Jacques Lacapere
A1 Firas Bassissi
A1 Thierry Bordet
A1 Alain Berdeaux
A1 Steven P. Jones
A1 Didier Morin
A1 Rebecca M. Pruss
YR 2010
UL http://jpet.aspetjournals.org/content/333/3/696.abstract
AB 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. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics