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Hyperoside protects primary rat cortical neurons from neurotoxicity induced by amyloid β-protein via the PI3K/Akt/Bad/Bcl(XL)-regulated mitochondrial apoptotic pathway.
Eur J Pharmacol 2011; 672(1-3):45-55EJ

Abstract

Amyloid β-protein (Aβ), 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 Aβ(25-35)-induced primary cultured cortical neurons, and also examined the potential cellular signaling mechanism for Aβ detoxication. Our results showed that treatment with hyperoside significantly inhibited Aβ(25-35)-induced cytotoxicity and apoptosis by reversing Aβ-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 Aβ-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.

Authors+Show Affiliations

Natural Products Research Center, Korea Institute of Science and Technology (KIST) Gangneung Institute, Gangneung 210-340, Republic of Korea.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21978835

Citation

Zeng, Ke-Wu, et al. "Hyperoside Protects Primary Rat Cortical Neurons From Neurotoxicity Induced By Amyloid Β-protein Via the PI3K/Akt/Bad/Bcl(XL)-regulated Mitochondrial Apoptotic Pathway." European Journal of Pharmacology, vol. 672, no. 1-3, 2011, pp. 45-55.
Zeng KW, Wang XM, Ko H, et al. Hyperoside protects primary rat cortical neurons from neurotoxicity induced by amyloid β-protein via the PI3K/Akt/Bad/Bcl(XL)-regulated mitochondrial apoptotic pathway. Eur J Pharmacol. 2011;672(1-3):45-55.
Zeng, K. W., Wang, X. M., Ko, H., Kwon, H. C., Cha, J. W., & Yang, H. O. (2011). Hyperoside protects primary rat cortical neurons from neurotoxicity induced by amyloid β-protein via the PI3K/Akt/Bad/Bcl(XL)-regulated mitochondrial apoptotic pathway. European Journal of Pharmacology, 672(1-3), pp. 45-55. doi:10.1016/j.ejphar.2011.09.177.
Zeng KW, et al. Hyperoside Protects Primary Rat Cortical Neurons From Neurotoxicity Induced By Amyloid Β-protein Via the PI3K/Akt/Bad/Bcl(XL)-regulated Mitochondrial Apoptotic Pathway. Eur J Pharmacol. 2011 Dec 15;672(1-3):45-55. PubMed PMID: 21978835.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hyperoside protects primary rat cortical neurons from neurotoxicity induced by amyloid β-protein via the PI3K/Akt/Bad/Bcl(XL)-regulated mitochondrial apoptotic pathway. AU - Zeng,Ke-Wu, AU - Wang,Xue-Mei, AU - Ko,Hyeonseok, AU - Kwon,Hak Cheol, AU - Cha,Jin Wook, AU - Yang,Hyun Ok, Y1 - 2011/09/29/ PY - 2011/05/12/received PY - 2011/09/14/revised PY - 2011/09/19/accepted PY - 2011/10/8/entrez PY - 2011/10/8/pubmed PY - 2012/3/8/medline SP - 45 EP - 55 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 672 IS - 1-3 N2 - Amyloid β-protein (Aβ), 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 Aβ(25-35)-induced primary cultured cortical neurons, and also examined the potential cellular signaling mechanism for Aβ detoxication. Our results showed that treatment with hyperoside significantly inhibited Aβ(25-35)-induced cytotoxicity and apoptosis by reversing Aβ-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 Aβ-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. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/21978835/Hyperoside_protects_primary_rat_cortical_neurons_from_neurotoxicity_induced_by_amyloid_β_protein_via_the_PI3K/Akt/Bad/Bcl_XL__regulated_mitochondrial_apoptotic_pathway_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(11)01160-5 DB - PRIME DP - Unbound Medicine ER -