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J. Biol. Chem. 276 (7): 5287-5295

© 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

The Neuroprotective Effects of Phytoestrogens on Amyloid beta  Protein-induced Toxicity Are Mediated by Abrogating the Activation of Caspase Cascade in Rat Cortical Neurons*

Chuen-Neu WangDagger , Chih-Wen Chi§, Yun-Lian LinDagger , Chieh-Fu ChenDagger , and Young-Ji ShiaoDagger

From the Dagger  National Research Institute of Chinese Medicine, Republic of China and the § Institute of Pharmacology, National Yang-Ming University, Taipei 112, Taiwan, Republic of China

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 µM Abeta -(25-35) for 40 h decreased the cell viability by 45.5 ± 4.6% concomitant with the appearance of apoptotic morphology. 50 µM 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.

* This study was supported by the National Science Council (Grants NSC88-2314-B-077-014 and NSC89-2314-B-077-007), Taiwan, Republic of China.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: National Research Institute of Chinese Medicine, No. 155-1 Sec. 2, LiNung St., Peitou, Taipei 112, Taiwan, Republic of China. Tel.: 886-2-2820-1999 (ext. 4212); Fax: 886-2-2826-4266; E-mail:

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.

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