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 centra
l role in cell death, we have determined the effects of various PER agonist
s and antagonists on the apoptosis of the human lymphoblastoid cell line U9
37. On this cell type, the PER agonist Ro5-4864 was found to strongly prote
ct the cells against apoptosis induced by TNF alpha. The antiapoptotic effe
ct of PER agonists was due to a selective interaction with the PER as demon
strated by: (1) a close correlation between the antiapoptotic activity of v
arious PER agonists and their respective affinity for the PER determined on
the same cells, (2) a lack of effect of central benzodiazepine receptors a
gonists such as clonazepam on cell survival, (3) the lack of an antiapoptot
ic 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 a
re potent antiapoptotic compounds and show that this effect might represent
a major function for this enigmatic receptor. (C) 1999 Academic Press.