Peripheral benzodiazepine receptor agonists exhibit potent antiapoptotic activities

The peripheral benzodiazepine receptor (PBR) has been implicated in several mitochondrial functions but the exact physiological role of this receptor is still under debate. Since the mitochondria have been attributed a central role in cell death, we have determined the effects of various PBR agonists and antagonists on the apoptosis of the human lymphoblastoid cell line U937. On this cell type, the PBR agonist Ro5-4864 was found to strongly protect the cells against apoptosis induced by TNFalpha. The antiapoptotic effect of PBR agonists was due to a selective interaction with the PBR as demonstrated by: (1) a close correlation between the antiapoptotic activity of various PBR agonists and their respective affinity for the PBR determined on the same cells, (2) a lack of effect of central benzodiazepine receptors agonists such as clonazepam on cell survival, (3) the lack of an antiapoptotic activity of Ro5-4864 on wild-type Jurkat cells (lacking the PBR receptor) and the reappearance of this effect on PBR-transfected Jurkat cells, and (4) the blockade of the antiapoptotic effect of PBR agonists by a selective PBR antagonist. The present results therefore indicate that PBR agonists are potent antiapoptotic compounds and show that this effect might represent a major function for this enigmatic receptor.