title: Edaravone protects against glutamate-induced PERK/EIF2α/ATF4 integrated stress response and activation of caspase-12.
abstract: As a potent novel free radical scavenger, edaravone has been reported to have neuroprotective effects in both animals and humans, although the underlying mechanisms remain unclear. In our study, we generated a culture of almost pure neurons, which were either left untreated or prophylactically treated with edaravone, then exposed to 50 μM glutamate for 10 min. Flow Cytometry analysis was performed to quantify the percentage of apoptotic cells. Ultrastructural changes in the endoplasmic reticulum were observed by electron microscopy. Immunofluorescence and western blotting for activation of selected related molecules, including PERK (pancreatic ER stress kinase, PERK), eIF2α (eukaryotic initiation factor 2 alpha, eIF2α), activating ATF4 (transcription factor 4, ATF4), and caspase-12 were examined. In Glutamate-treated group, the sequential activation of PERK, eIF2α, ATF4 and caspase-12 could be observed at 2h, and peaked at 24h. However, treatment with edaravone was able to prevent these changes. In addition, the morphology of the endoplasmic reticulum was better preserved and the percentage of apoptotic cells was lower in cells treated with edaravone. In summary, our results indicate that ISR (PERK/eIF2/ATF4 integrated stress response, ISR) plays an important role in glutamate-induced nerve cells death, and that edaravone could protect neurons against glutamate-induced endoplasmic reticulum stress.
authors: The First Affiliated Hospital of Nanjing Medical University, Jiangsu 210029, China.
authors: Jin
authors: J
authors: Fan
authors: Hao
authors: H
authors: Long
authors: Yiming
authors: Y
authors: Li
authors: Yuwen
authors: Y
authors: Liu
authors: Wei
authors: W
authors: Zhou
authors: Qingqing
authors: Q
authors: Li
authors: Guoyong
authors: G
authors: Yin
authors: Ning
authors: N
authors: Zhang
authors: Weihua
authors: W
authors: Cai
mesh_terms: D051701:Activating Transcription Factor 4; D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D000983:Antipyrine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053454:Caspase 12 / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D000077553:Edaravone; D004622:Embryo, Mammalian; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D016166:Free Radical Scavengers / Q000494:pharmacology*; D018698:Glutamic Acid / Q000633:toxicity; D046529:Microscopy, Electron, Transmission; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects*; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D017304:Annexin A5; D016166:Free Radical Scavengers; D008869:Microtubule-Associated Proteins; D051701:Activating Transcription Factor 4; D018698:Glutamic Acid; D053454:Caspase 12; D000077553:Edaravone; D000983:Antipyrine