title: The MLN4924 inhibitor exerts a neuroprotective effect against oxidative stress injury via Nrf2 protein accumulation.
abstract: It was explored the cytoprotective and antioxidant effect of MLN4924, a specific inhibitor of Nedd8-activating enzyme (NAE), against hydrogen peroxide (H2O2)-induced damage in cerebellar granule neurons (CGNs). Primary cultures of CGNs were exposed to H2O2 after preincubation with MLN4924. The compounds were removed, and CGNs were incubated in culture medium for 24h in order to determine cell viability by 3-[4,5-dimethylthiazol-2-yl)]-2,5-diphenyl-tetrazolium bromide (MTT) and fluorescein diacetate (FDA) assays. It was demonstrated that MLN4924 remarkably attenuated H2O2-induced cell damage. Meanwhile reactive oxygen species (ROS) production was evaluated with the fluorescent probe dihydroethidium (DHE). Interestingly H2O2-induced ROS production was inhibited by pretreatment with MLN4924. MLN4924 treatment in CGNs resulted in nuclear factor E2-related factor 2 (Nrf2) protein accumulation. Intriguingly this effect was observed in the cytosolic and nuclear compartments of the CGNs. The cytoprotective effect of MLN4924 was associated with its ability to diminish ROS production induced by H2O2 and the accumulation of Nrf2 protein levels in the cytoplasm and nucleus of the CGNs.
authors.affiliation: Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), University City, 04510 Mexico City, Mexico.
authors.forename: Ana Cristina
authors.initials: AC
authors.lastname: Andérica-Romero
authors.affiliation: Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), University City, 04510 Mexico City, Mexico.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Hernández-Damián
authors.affiliation: Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), University City, 04510 Mexico City, Mexico.
authors.forename: Gustavo Ignacio
authors.initials: GI
authors.lastname: Vázquez-Cervantes
authors.affiliation: Animal Care Unit, Faculty of Medicine, National Autonomous University of Mexico (UNAM), University City, 04510 Mexico City, Mexico.
authors.forename: Ismael
authors.initials: I
authors.lastname: Torres
authors.forename: Irma Gabriela
authors.lastname: González-Herrera
authors.affiliation: Department of Biology, Faculty of Chemistry, National Autonomous University of Mexico (UNAM), University City, 04510 Mexico City, Mexico. Electronic address: pedraza@unam.mx.
authors.forename: José
authors.initials: J
authors.lastname: Pedraza-Chaverri
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D002470:Cell Survival / Q000187:drug effects; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D003517:Cyclopentanes / Q000008:administration & dosage*; D019610:Cytoprotection / Q000235:genetics*; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D051267:NF-E2-Related Factor 2 / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D018384:Oxidative Stress / Q000187:drug effects*; D061251:Primary Cell Culture; D011743:Pyrimidines / Q000008:administration & dosage*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics
chemical_list: D000975:Antioxidants; D003517:Cyclopentanes; D051267:NF-E2-Related Factor 2; D018696:Neuroprotective Agents; C495637:Nfe2l2 protein, rat; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D006861:Hydrogen Peroxide; D044764:Ubiquitin-Activating Enzymes; C491802:NAE protein, human; C539933:pevonedistat
keywords: H(2)O(2); MLN4924; Neuroprotective; Nrf2; Oxidative stress