title: Protective effects of astragaloside IV against amyloid beta1-42 neurotoxicity by inhibiting the mitochondrial permeability transition pore opening.
abstract: Mitochondrial dysfunction caused by amyloid β-peptide (Aβ) plays an important role in the pathogenesis of Alzheimer disease (AD). Substantial evidence has indicated that the mitochondrial permeability transition pore (mPTP) opening is involved in Aβ-induced neuronal death and reactive oxygen species (ROS) generation. Astragaloside IV (AS-IV), one of the major active constituents of Astragalus membranaceus, has been reported as an effective anti-oxidant for treating neurodegenerative diseases. However, the molecular mechanisms still need to be clarified. In this study, we investigated whether AS-IV could prevent Aβ1-42-induced neurotoxicity in SK-N-SH cells via inhibiting the mPTP opening. The results showed that pretreatment of AS-IV significantly increased the viability of neuronal cells, reduced apoptosis, decreased the generation of intracellular reactive oxygen species (ROS) and decreased mitochondrial superoxide in the presence of Aβ1-42. In addition, pretreatment of AS-IV inhibited the mPTP opening, rescued mitochondrial membrane potential (ΔΨm), enhanced ATP generation, improved the activity of cytochrome c oxidase and blocked cytochrome c release from mitochondria in Aβ1-42 rich milieu. Moreover, pretreatment of AS-IV reduced the expression of Bax and cleaved caspase-3 and increased the expression of Bcl-2 in an Aβ1-42 rich environment. These data indicate that AS-IV prevents Aβ1-42-induced SK-N-SH cell apoptosis via inhibiting the mPTP opening and ROS generation. These results provide novel insights of AS-IV for the prevention and treatment of neurodegenerative disorders such as AD.
authors.affiliation: Department of Human Anatomy and Histo-Embryology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
authors.forename: Qinru
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Human Anatomy and Histo-Embryology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Jia
authors.affiliation: Department of Human Anatomy and Histo-Embryology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
authors.forename: Weixi
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Human Anatomy and Histo-Embryology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Jin
authors.affiliation: Department of Human Anatomy and Histo-Embryology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
authors.forename: Jiehua
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Human Anatomy and Histo-Embryology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Hu
mesh_terms: D016229:Amyloid beta-Peptides / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D045304:Cytochromes c / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism*; D000083162:Mitochondrial Permeability Transition Pore; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity*; D010446:Peptide Fragments / Q000633:toxicity*; D011487:Protein Conformation / Q000187:drug effects; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D012503:Saponins / Q000494:pharmacology*; D013481:Superoxides / Q000378:metabolism; D014315:Triterpenes / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010446:Peptide Fragments; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D012503:Saponins; D014315:Triterpenes; C075222:amyloid beta-protein (1-42); D051028:bcl-2-Associated X Protein; D013481:Superoxides; C052064:astragaloside A; D045304:Cytochromes c