title: 17-DMAG Protects Against Hypoxia-/Reoxygenation-Induced Cell Injury in HT22 Cells Through Akt/Nrf2/HO-1 Pathway.
abstract: Oxidative stress is well known to play a pivotal role in hypoxia/reoxygenation (H/R)-induced neuron injury. On the basis of this fact, antioxidative agents have been demonstrated to be neuroprotective. 17-DMAG (HSP90 inhibitor) is reported to have neuroprotective effects in vitro, which may interfere with oxidative stress through reduction in pro-oxidative factors. However, little is known about its effects on H/R-induced neuron injury and the underlying mechanisms. In this study, the effects of 17-DMAG on H/R-treated HT22 cells were investigated. MTT and lactate dehydrogenase (LDH) assays indicated that 17-DMAG led to a dose-dependent recovery of cell viability in H/R-treated HT22 cells. Flow cytometry demonstrated that 17-DMAG inhibited the cell apoptosis induced by H/R in HT22 cells. In addition, Western blot and real-time reverse transcription-polymerase chain reaction indicated that 17-DMAG inhibited the H/R-induced upregulation of Bax/Bcl-2 ratio and cleaved caspase-3 expression. Moreover, our results demonstrated that 17-DMAG promoted the expression of antioxidant enzymes, including manganese superoxide dismutase, catalase, and glutathione peroxidase. As a result, 17-DMAG might resist to H/R-induced oxidative stress. Furthermore, 17-DMAG increased the expression of phosphorylation of Akt (p-Akt) and the heme oxygenase-1 (HO-1), as well as the translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) in H/R-treated HT22 cells. However, the Akt inhibitor, LY294002, partially hampered the effects of 17-DMAG on the expression of p-Akt, nuclear Nrf2, and HO-1 and cell viability, as well as cell apoptosis induced by H/R in HT22 cells. In conclusion, the findings of our study thus demonstrate that 17-DMAG protects against H/R-induced HT22 cell injury through Akt/Nrf2/HO-1 pathway, which may be associated with its antiapoptotic and antioxidative stress effects.
authors.affiliation: 1 Department of Neurosurgery, The First Affiliated hospital of Xi'an Medical University , Xi'an, China .
authors.forename: Zhuopeng
authors.initials: Z
authors.lastname: Jia
authors.affiliation: 2 Department of Neurosurgery, Shaanxi Second Provincial People's Hospital , Xi'an, China .
authors.forename: Arui
authors.initials: A
authors.lastname: Dong
authors.affiliation: 1 Department of Neurosurgery, The First Affiliated hospital of Xi'an Medical University , Xi'an, China .
authors.forename: Hongmin
authors.initials: H
authors.lastname: Che
authors.affiliation: 3 Department of Neurosurgery, No. 215 Hospital of Shaanxi Nuclear Industry, Xianyang, China .
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D015687:Cell Hypoxia / Q000187:drug effects; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C448659:17-(dimethylaminoethylamino)-17-demethoxygeldanamycin; D051547:Heme Oxygenase-1; D051057:Proto-Oncogene Proteins c-akt; D010100:Oxygen
keywords: 17-DMAG; cell injury; hypoxia/reoxygenation; oxidative stress