Guanosine 3 ',5 '-cyclic monophosphate mediated inhibition of cell death induced by nerve growth factor withdrawal and beta-amyloid: Protective effects of propentofylline

Apoptotic cell death has been implicated in Alzheimer's disease pathology a nd amyloid peptide induced neurotoxicity. We investigated the survival prom oting effects of Propentofylline in two models of apoptotic cell death, ner ve growth factor withdrawal and beta-amyloid mediated cell death in nerve g rowth factor differentiated rat pheochromocytoma cell lines. The increase i n cell death as measured by lactate dehydrogenase release in response to ne rve growth factor withdrawal was suppressed by nitric oxide donor S-nitroso -N-acetylpenicillamine (12.5 to 200 mu M) and by 8-bromoguanosine-3',5'-cyc lic monophosphate (1.25 to 10 mM). Both agents decreased cell death mediate d by 25 mu M beta-amyloid, suggesting that the protective mechanism involve s guanosine -3',5'-cyclic monophosphate. In support of this hypothesis we c an show that S-nitroso-N-acetylpenicillamine increases intracellular levels of guanosine -3',5'-cyclic monophosphate in pheochromocytoma cell lines 3 to 8 fold. Propentofylline, a phosphodiesterase inhibitor, has previously demonstrated neuroprotective activity in stroke models and is a potential candidate for therapeutic treatment in neurodegenerative diseases. The present findings support this claim by providing evidence that Propentofylline has protectiv e effects in both nerve growth factor withdrawal and beta-amyloid mediated cell death. Lactate dehydrogenase release was significantly reduced and cas pase-3-like activity was attenuated after cotreatment with Propentofylline. Furthermore Propentofylline dose responsively increases intracellular guan osine 3',5'-cyclic monophosphate levels over the same dose range that provi ded protection. We hypothesized that guanosine-3',5'-cyclic monophosphate i s a key mediator of neuroprotection under these conditions. (C) 2000 IBRO. Published by Elsevier Science Ltd. All rights reserved.