Wirtz-Brugger F, Giovanni A
Department of Neuroscience, Aventis Pharmaceuticals Inc., Bridgewater, New Jersey 08855, USA.
Neuroscience. 2000;99(4):737-50. doi: 10.1016/s0306-4522(00)00243-8.
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.
凋亡性细胞死亡与阿尔茨海默病病理学及淀粉样肽诱导的神经毒性有关。我们在两种凋亡性细胞死亡模型中研究了丙戊茶碱的促存活作用，这两种模型分别是神经生长因子撤除模型以及神经生长因子分化的大鼠嗜铬细胞瘤细胞系中β淀粉样蛋白介导的细胞死亡模型。通过乳酸脱氢酶释放来测定，对神经生长因子撤除反应所导致的细胞死亡增加，被一氧化氮供体S-亚硝基-N-乙酰青霉胺（12.5至200微摩尔）以及8-溴鸟苷-3',5'-环一磷酸（1.25至10毫摩尔）所抑制。这两种药物均降低了由25微摩尔β淀粉样蛋白介导的细胞死亡，提示保护机制涉及鸟苷-3',5'-环一磷酸。为支持这一假说，我们能够表明S-亚硝基-N-乙酰青霉胺使嗜铬细胞瘤细胞系中的鸟苷-3',5'-环一磷酸细胞内水平增加3至8倍。丙戊茶碱是一种磷酸二酯酶抑制剂，先前已在中风模型中证明具有神经保护活性，并且是神经退行性疾病治疗的潜在候选药物。本研究结果通过提供证据表明丙戊茶碱在神经生长因子撤除和β淀粉样蛋白介导的细胞死亡中均具有保护作用，支持了这一说法。与丙戊茶碱共同处理后，乳酸脱氢酶释放显著降低，且半胱天冬酶-3样活性减弱。此外，在提供保护的相同剂量范围内，丙戊茶碱剂量依赖性地增加细胞内鸟苷-3',5'-环一磷酸水平。我们推测在这些条件下鸟苷-3',5'-环一磷酸是神经保护的关键介质。
