title: Protective effects of hesperidin against amyloid-β (Aβ) induced neurotoxicity through the voltage dependent anion channel 1 (VDAC1)-mediated mitochondrial apoptotic pathway in PC12 cells.
abstract: Amyloid-β (Aβ) is known to exert cytotoxic effects by inducing mitochondrial dysfunction. Additionally, the mitochondrial voltage-dependent anion channel 1 (VDAC1), which is involved in the release of apoptotic proteins with possible relevance in Alzheimer's disease (AD) neuropathology, plays an important role in maintaining mitochondrial function and integrity. However, the application of therapeutic drugs, especially natural products in (AD) therapy via VDAC1-regulated mitochondrial apoptotic pathway has not aroused extensive attention. In the present study, we investigated neuroprotective effects of hesperidin, a bioactive flavonoid compound, on Aβ25-35-induced neurotoxicity in PC12 cells and also examined the potential cellular signalling mechanism. Our results showed that treatment with hesperidin significantly inhibited Aβ25-35-induced apoptosis by reversing Aβ-induced mitochondrial dysfunction, including the mitochondrial permeability transition pore opening, intracellular free calcium increase and reactive oxygen species production. Further study indicated that hesperidin can decrease the level ofVDAC1 phosphorylation through inhibiting the activity of the glycogen synthase kinase-3b and increase the level of hexokinaseI in mitochondria, preventing release of cytochrome c from mitochondria [corrected]. Furthermore, hesperidin inhibited mitochondria-dependent downstream caspase-mediated apoptotic pathway, such as that involving caspase-9 and caspase-3. These results demonstrate that hesperidin can protect Aβ-induced neurotoxicity via VDAC1-regulated mitochondrial apoptotic pathway, and they raise the possibility that hesperidin could be developed into a clinically valuable treatment for AD and other neuronal degenerative diseases associated with mitochondrial dysfunction.
authors.affiliation: Department of Pathogen Biology, Medical College, Henan University of Science and Technology, Building 6, Anhui, Jianxi District, Luoyang 471003, People's Republic of China. wdmzgadyx@163.com
authors.forename: Dong-Mei
authors.initials: DM
authors.lastname: Wang
authors.forename: San-Qiang
authors.initials: SQ
authors.lastname: Li
authors.forename: Xiao-Ying
authors.initials: XY
authors.lastname: Zhu
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Wen-Lan
authors.initials: WL
authors.lastname: Wu
authors.forename: Xiao-Juan
authors.initials: XJ
authors.lastname: Zhang
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D006569:Hesperidin / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects*; D016716:PC12 Cells; D010766:Phosphorylation; D051381:Rats; D050995:Voltage-Dependent Anion Channel 1 / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; C494764:Vdac1 protein, rat; D006569:Hesperidin; D050995:Voltage-Dependent Anion Channel 1; D053148:Caspase 3; D053453:Caspase 9