Mitochondrial respiratory chain as a new target for anti-ischemic molecules.
Vascular diseases like thrombosis, myocardial infarction, cerebral ischemia or chronic venous insufficiency affect a high proportion of the population. They are all associated with more or less pronounced ischemic conditions. We have previously shown that some venotropic drugs display an anti-ischemic activity, i.e. they prevent the hypoxia-induced decrease in ATP content in cultured cells. The effect is due to the fact that these molecules maintain mitochondrial respiratory activity during hypoxia. Among them is bilobalide. Starting from the 3D structure of bilobalide, we designed new molecules presenting the same chemical features. They were synthesized and tested for their biological activity. As the parent compound, two of them, malonic acid dicyclopent-2-enyl ester (MRC2P119) and 2-oxo-3-oxa-bicyclo[3.1.0]hexane-1-carboxylic acid allyl ester (MRC2P57), were able to markedly increase the respiratory control ratio of isolated mitochondria. They are able to prevent the inhibition of complex I by amytal and of complex III by myxothiazol, but not the uncoupling of the respiration by carbonylcyanide m-chlorophenyl hydrazone (m-CCP). Moreover, MRC2P119 and MRCP2P57 inhibit, in a dose-dependent way, the hypoxia-induced decrease in ATP content in endothelial cells as well as the subsequent activation of these cells as evidenced by an inhibition of the increase in neutrophil adherence to the endothelial cells induced by hypoxia. Finally, MRC2P119 prevent the hypoxia- and the hypoxia-reoxygenation-induced decrease in viability of SH-SY5Y neuroblastoma cells. In conclusion, we identified two new molecules, which display anti-ischemic properties when tested in vitro on endothelial and neuronal cell types. This anti-ischemic activity is probably due to a protection of complexes I and III of the mitochondrial respiratory chain.
Bouaziz
Najat
N
Laboratoire de Biochimie et Biologie Cellulaire, University of Namur, 61 rue de Bruxelles, 5000 Namur, Belgium.
Redon
Martine
M
Quéré
Luc
L
Remacle
José
J
Michiels
Carine
C
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000737:chemistry / Q000494:pharmacology*; D002317:Cardiovascular Agents / Q000737:chemistry / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D015687:Cell Hypoxia; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003517:Cyclopentanes / Q000737:chemistry / Q000494:pharmacology; D004224:Diterpenes; D004305:Dose-Response Relationship, Drug; D004579:Electron Transport / Q000187:drug effects*; D004952:Esters / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D005663:Furans / Q000737:chemistry / Q000494:pharmacology; D046934:Ginkgolides; D006801:Humans; D007511:Ischemia / Q000517:prevention & control; D008314:Malonates / Q000737:chemistry / Q000494:pharmacology*; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
C461019:2-oxo-3-oxa-bicyclo(3.1.0)hexane-1-carboxylic acid allyl ester; D001643:Bridged Bicyclo Compounds; D002317:Cardiovascular Agents; D003517:Cyclopentanes; D004224:Diterpenes; D004952:Esters; D005663:Furans; D046934:Ginkgolides; D008314:Malonates; C461020:malonic acid dicyclopent-2-enyl ester; D000255:Adenosine Triphosphate; C073710:bilobalide