TNF-alpha induced PMN apoptosis in whole human blood: protective effect of SSR180575, a potent and selective peripheral benzodiazepine ligand.
The peripheral benzodiazepine receptor (PBR) has been shown to play a key role in the regulation of the mitochondrial process leading to apoptosis. Despite much controversy in the literature on this subject, PBR synthetic ligands (and specifically agonists such as Ro5-4864 and SSR180575) are described as presenting potent anti-apoptotic effect against oxidative stress, TNFalpha- and tamoxifen-induced apoptosis when the PBR ligand is administrated at a low dose, close to the affinity range of the ligand to its receptor. Such anti-apoptotic activity has already been correlated with a protective effect of PBR ligands against ischemia-reperfusion induced tissue dysfunction. Previously, we had shown that SSR180575 is a specific and high affinity PBR ligand of potential interest in pathological cardiovascular, renal and neurodegenerative indications. Beyond its expression in steroid-producing tissues, heart, liver and kidney, the PBR is also known to be highly expressed in blood cells. In this work, we demonstrate by flow cytometry experiments, that SSR180575, at low concentrations, is able to protect polymorphonuclear leukocytes (PMNs) against TNFalpha-induced apoptosis in whole blood. Thus, in a new context, SSR180575 again shows potent anti-apoptotic properties. Moreover, TNFalpha- induced PMN apoptosis appears to be a good surrogate marker for determining SSR180575 blood availability and activity in treated patients.
Leducq-Alet
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Sanofi-aventis Recherche and Développement, Toulouse, France. Nathalie.alet@sanofi-aventis.com
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Savi
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Bono
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D000081:Acetamides / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001569:Benzodiazepines / Q000494:pharmacology; D002478:Cells, Cultured; D019610:Cytoprotection; D058785:GABA-A Receptor Agonists; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D008024:Ligands; D009504:Neutrophils / Q000187:drug effects* / Q000502:physiology; D011963:Receptors, GABA-A / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D000081:Acetamides; D058785:GABA-A Receptor Agonists; D007211:Indoles; D008024:Ligands; D011963:Receptors, GABA-A; C456740:SSR180575; D014409:Tumor Necrosis Factor-alpha; D001569:Benzodiazepines