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 PER agonists and antagonists on the apoptosis of the human lymphoblastoid cell line U937. On this cell type, the PER agonist Ro5-4864 was found to strongly protect the cells against apoptosis induced by TNF alpha. The antiapoptotic effect of PER agonists was due to a selective interaction with the PER as demonstrated by: (1) a close correlation between the antiapoptotic activity of various PER agonists and their respective affinity for the PER 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 PER receptor) and the reappearance of this effect on PBR-transfected Jurkat cells, and (4) the blockade of the antiapoptotic effect of PER agonists by a selective PER antagonist, The present results therefore indicate that PER agonists are potent antiapoptotic compounds and show that this effect might represent a major function for this enigmatic receptor. (C) 1999 Academic Press.