Glucose deprivation and chemical hypoxia: neuroprotection by P2 receptor antagonists

In this work we investigate cell survival after glucose deprivation and/or chemical hypoxia and we analyse the neuroprotective properties of selected antagonists of P2 ATP receptors. We find that in rat cerebellar granule neu rones, the antagonist basilen blue prevents neuronal death under hypoglycae mia. Basilen blue acts through a wide temporal range and it retains its eff icacy under chemically induced hypoxic conditions, in the presence of the r espiratory inhibitors of mitochondria electron transport chain complexes II (3-nitropropionic acid) and III (antimycin A). In spite of the presence of these compounds, basilen blue maintains normal intracellular ATP levels. I t furthermore prevents neuronal death caused by agents blocking the mitocho ndrial calcium uptake (ruthenium red) or discharging the mitochondrial memb rane potential (carbonyl cyanide m-chlorophenylhydrazone). Inhibition of po ly (ADP-ribose) polymerase, modulation of the enzyme GAPDH and mitochondria l transport of mono-carboxylic acids are not conceivable targets for the ac tion of basilen blue. Survival is sustained by basilen blue also in CNS pri mary cultures from hippocampus and in PNS sympathetic-like neurones. Partia l neuroprotection is furthermore provided by three additional P2 receptor a ntagonists: suramin, pyridoxal-phosphate-6-azophenyl-2',4'-disulphonic acid 4-sodium and 4,4'-diisothiocyanatostilbene-2,2'disulphonic acid. Our data suggest the exploitation of selected P2 receptor antagonists as potential n europrotective agents. (C) 2001 Elsevier Science Ltd. All rights reserved.