期刊
EUROPEAN JOURNAL OF PHARMACOLOGY
卷 672, 期 1-3, 页码 45-55出版社
ELSEVIER
DOI: 10.1016/j.ejphar.2011.09.177
关键词
Neuroprotection; Amyloid beta-protein (A beta); Hyperoside; PI3K/Akt; Mitochondria
资金
- Korea Institute of Science and Technology, Republic of Korea [2Z03401, 2Z03380, 2U04150]
- National Natural Science Fund of China [30973813, 30672760]
- Ministry of Education, China [20070001707]
Amyloid beta-protein (A beta), which is deposited in neurons as neurofibrillary tangles, is known to exert cytotoxic effects by inducing mitochondrial dysfunction. Additionally, the PI3K/Akt-mediated interaction between Bad and Bcl(XL) plays an important role in maintaining mitochondrial integrity. However, the application of therapeutic drugs, especially natural products in Alzheimer's disease therapy via PI3K/Akt/Bad/Bcl(XL)-regulated mitochondrial apoptotic pathway has not aroused extensive attention. In the present study, we investigated the neuroprotective effects of hyperoside, a bioactive flavonoid compound from Hypericum perforatum, on A beta(25-35)-induced primary cultured cortical neurons, and also examined the potential cellular signaling mechanism for A beta detoxication. Our results showed that treatment with hyperoside significantly inhibited A beta(25-35)-induced cytotoxicity and apoptosis by reversing A beta-induced mitochondrial dysfunction, including mitochondrial membrane potential decrease, reactive oxygen species production, and mitochondrial release of cytochrome c. Further study indicated that hyperoside can activate the PI3K/Akt signaling pathway, resulting in inhibition of the interaction between Bad and Bcl(XL), without effects on the interaction between Bad and Bcl-2. Furthermore, hyperoside inhibited mitochondria-dependent downstream caspase-mediated apoptotic pathway, such as that involving caspase-9, caspase-3, and poly ADP-ribose polymerase (PARP). These results demonstrate that hyperoside can protect AB-induced primary cultured cortical neurons via PI3K/Akt/Bad/Bcl(XL)-regulated mitochondrial apoptotic pathway, and they raise the possibility that hyperoside could be developed into a clinically valuable treatment for Alzheimer's disease and other neuronal degenerative diseases associated with mitochondrial dysfunction. (C) 2011 Elsevier B.V. All rights reserved.
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