Zeng, Ke-Wu Wang, Xue-Mei Ko, Hyeonseok Kwon, Hak Cheol Cha, Jin Wook Yang, Hyun Ok 2024-01-20T15:34:53Z 2024-01-20T15:34:53Z 2021-09-05 2011-12-15 0014-2999 https://pubs.kist.re.kr/handle/201004/129717 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. English ELSEVIER SCIENCE BV TERT-BUTYL HYDROPEROXIDE ALZHEIMERS-DISEASE HIPPOCAMPAL-NEURONS HYDROGEN-PEROXIDE CELL-SURVIVAL DYSFUNCTION AKT ACTIVATION TOXICITY INJURY Hyperoside protects primary rat cortical neurons from neurotoxicity induced by amyloid beta-protein via the PI3K/Akt/Bad/Bcl(XL)-regulated mitochondrial apoptotic pathway Article 10.1016/j.ejphar.2011.09.177 1 EUROPEAN JOURNAL OF PHARMACOLOGY, v.672, no.1-3, pp.45 - 55 EUROPEAN JOURNAL OF PHARMACOLOGY 672 1-3 45 55 scie scopus 000298202700006 2-s2.0-81255135741 Pharmacology & Pharmacy Pharmacology & Pharmacy Article TERT-BUTYL HYDROPEROXIDE ALZHEIMERS-DISEASE HIPPOCAMPAL-NEURONS HYDROGEN-PEROXIDE CELL-SURVIVAL DYSFUNCTION AKT ACTIVATION TOXICITY INJURY Neuroprotection Amyloid beta-protein (A beta) Hyperoside PI3K/Akt Mitochondria