title: Neuroprotection by MAPK/ERK kinase inhibition with U0126 against oxidative stress in a mouse neuronal cell line and rat primary cultured cortical neurons.
abstract: Oxidative stress is implicated in the pathogenesis of neuronal degenerative diseases. Oxidative stress has been shown to activate extracellular signal-regulated kinases (ERK)1/2. We investigated the role of these mitogen-activated protein kinases (MAPKs) in oxidative neuronal injury by using a mouse hippocampal cell line (HT22) and rat primary cortical cultures. Here, we show that a novel MAPK/ERK kinase (MEK) specific inhibitor U0126 profoundly protected HT22 cells against oxidative stress induced by glutamate, which was accompanied by an inhibition of phosphorylation of ERK1/2. U0126 also protected rat primary cultured cortical neurons against glutamate or hypoxia. However, U0126 was not protective against death caused by tumor necrosis factor alpha (TNFalpha), A23187, or staurosporine. These results indicate that MEK plays a central role in the neuronal death caused by oxidative stress.
authors.affiliation: Department of Neuroscience, Osaka Bioscience Institute, 6-2-4 Furuedai, Suita, 565-0874, Osaka, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Satoh
authors.forename: D
authors.initials: D
authors.lastname: Nakatsuka
authors.forename: Y
authors.initials: Y
authors.lastname: Watanabe
authors.forename: I
authors.initials: I
authors.lastname: Nagata
authors.forename: H
authors.initials: H
authors.lastname: Kikuchi
authors.forename: S
authors.initials: S
authors.lastname: Namura
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology*; D002460:Cell Line; D002540:Cerebral Cortex / Q000201:enzymology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D009570:Nitriles; C113580:U 0126; D020928:Mitogen-Activated Protein Kinases