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.
Footnotes
This work was supported in part by the French Agence Nationale pour la Recherche [Grant ANR-07-RIB-IRI stop]. S.P. and R.A. were supported by doctoral grants from the Ministère de la Recherche et de la Technologie and the Région Ile de France, respectively. A.B. has served as a consultant and received an honorarium from Trophos. S.P.J. and A.B. received research grants from TROPHOS to support this project.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
doi:10.1124/jpet.110.167486.
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ABBREVIATIONS:
- mPTP
- mitochondrial permeability transition pore
- I/R
- ischemia-reperfusion
- ROS
- reactive oxygen species
- CsA
- cyclosporine A [(2S,5S,8S,11S,14R,17S,20S,23S,26S,32S)-32-ethyl-2-[(E,1R,2R)-1-hydroxy-2-methylpent-3-enyl]-3,6,9,12,14,17,21,27,30-nonamethyl-5,8, 11,20,26-pentakis(2-methylpropyl)-23-propan-2-yl-3,6,9,12,15,18,21,24,27,30,33-undecazacyclotritriacontane-1,4,7,10,13,16,19,22,25,28, 31-undecone]
- VDAC
- voltage-dependent anion channel
- TSPO
- translocator protein 18 kDa
- Ro5-4864
- 7-chloro-5-(4-chlorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepine-2-one
- SSR180575
- 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide
- TRO40303
- 3,5-seco-4-nor-cholestan-5-one oxime-3-ol
- DMSO
- dimethyl sulfoxide
- HPBCD
- hydroxypropyl-β-cyclodextrin
- calcein-AM
- calcein acetoxymethyl ester
- DCF
- 5(and 6-)-chloromethyl-2′,7′-dichlorodihydrofluorescein diacetate, acyl ester
- TMRM
- tetramethylrhodamine methyl ester
- PK11195
- 1-(2-chlorophenyl)-N-methyl-N-(1-methyl-propyl)-3-isoquinoline carboxamide
- CAO
- coronary artery occlusion
- CAR
- coronary artery reperfusion
- AAR
- area at risk
- AIF
- apoptosis inducing factor
- CRC
- calcium retention capacity
- NRCM
- neonatal rat cardiomyocyte
- BAPTA-AM
- 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid
- ANOVA
- one-way analysis of variance
- TRO19622
- cholest-4-en-3-one, oxime.
- Received February 19, 2010.
- Accepted March 9, 2010.
- Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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