The neuroprotective effects of phytoestrogens on amyloid beta protein-induced toxicity are mediated by abrogating the activation of caspase cascade in rat cortical neurons

Amyloid beta protein (Abeta) elicits a toxic effect on neurons in vitro and in vivo. In present study we attempt to elucidate the mechanism by which Abeta confers its neurotoxicity. The neuroprotective effects of phytoestrogens on Abeta-mediated toxicity were also investigated. Cortical neurons treated with 5 microm Abeta-(25-35) for 40 h decreased the cell viability by 45.5 +/- 4.6% concomitant with the appearance of apoptotic morphology. 50 microm kaempferol and apigenin decreased the Abeta-induced cell death by 81.5 +/- 9.4% and 49.2 +/- 9.9%, respectively. Abeta increased the activity of caspase 3 by 10.6-fold and to a lesser extent for caspase 2, 8, and 9. The Abeta-induced activation of caspase 3 and release of cytochrome c showed a biphasic pattern. Apigenin abrogated Abeta-induced cytochrome c release, and the activation of caspase cascade. Kaempferol showed a similar effect but to a less extent. Kaempferol was also capable of eliminating Abeta-induced accumulation of reactive oxygen species. These two events accounted for the remarkable effect of kaempferol on neuroprotection. Quercetin and probucol did not affect the Abeta-mediated neurotoxicity. However, they potentiated the protective effect of apigenin. Therefore, these results demonstrate that Abeta elicited activation of caspase cascades and reactive oxygen species accumulation, thereby causing neuronal death. The blockade of caspase activation conferred the major neuroprotective effect of phytoestrogens. The antioxidative activity of phytoestrogens also modulated their neuroprotective effects on Abeta-mediated toxicity.