amyloid-beta-peptides and propentofylline

Apoptotic cell death has been implicated in Alzheimer's disease pathology and amyloid peptide induced neurotoxicity. We investigated the survival promoting effects of Propentofylline in two models of apoptotic cell death, nerve growth factor withdrawal and beta-amyloid mediated cell death in nerve growth factor differentiated rat pheochromocytoma cell lines. The increase in cell death as measured by lactate dehydrogenase release in response to nerve growth factor withdrawal was suppressed by nitric oxide donor S-nitroso-N-acetylpenicillamine (12.5 to 200 microM) and by 8-bromoguanosine-3',5'-cyclic monophosphate (1.25 to 10mM). Both agents decreased cell death mediated by 25 microM beta-amyloid, suggesting that the protective mechanism involves guanosine -3', 5'-cyclic monophosphate. In support of this hypothesis we can 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 protective effects in both nerve growth factor withdrawal and beta-amyloid mediated cell death. Lactate dehydrogenase release was significantly reduced and caspase-3-like activity was attenuated after cotreatment with Propentofylline. Furthermore Propentofylline dose responsively increases intracellular guanosine-3',5'-cyclic monophosphate levels over the same dose range that provided protection. We hypothesized that guanosine-3',5'-cyclic monophosphate is a key mediator of neuroprotection under these conditions.

Topics: 1-Methyl-3-isobutylxanthine; 4-(3-Butoxy-4-methoxybenzyl)-2-imidazolidinone; Amyloid beta-Peptides; Animals; Apoptosis; Caspase 3; Caspases; Cyclic GMP; Dose-Response Relationship, Drug; Nerve Growth Factor; Neurons; Neuroprotective Agents; Nitric Oxide; Nitric Oxide Donors; PC12 Cells; Penicillamine; Peptide Fragments; Phosphodiesterase Inhibitors; Rats; Rolipram; Xanthines

We have reported that continuous infusion of beta-amyloid protein-(1-40) into the cerebral ventricle produces learning and memory deficits in rats. Propentofylline has potent stimulatory effects on nerve growth factor (NGF) synthesis/secretion in mouse astrocytes in vitro and increases cerebral NGF content in aged rats. In the present study, we examined the effects of propentofylline on learning and memory deficits in beta-amyloid protein-infused rats. The rats were given propentofylline orally once a day throughout the period of behavioral examination. In the beta-amyloid protein-infused rats, spontaneous alternation behavior in a Y-maze, and performance in water maze and passive avoidance tasks were significantly impaired compared to sham-operated rats. Propentofylline prevented these behavioral deficits, but did not change the reduction of the activity of choline acetyltransferase in the hippocampus in the beta-amyloid protein-infused rats. These results suggest that propentofylline is useful for the treatment of patients with Alzheimer's disease.

Topics: Administration, Oral; Amyloid beta-Peptides; Animals; Avoidance Learning; Choline O-Acetyltransferase; Habituation, Psychophysiologic; Injections, Intraventricular; Learning; Male; Maze Learning; Memory; Nootropic Agents; Peptide Fragments; Rats; Rats, Wistar; Xanthines