title: RIP1 mediates the protection of geldanamycin on neuronal injury induced by oxygen-glucose deprivation combined with zVAD in primary cortical neurons.
abstract: Caspase-dependent apoptosis is considered one of the most important cell death pathways. When the apoptotic process is blocked, a form of programmed necrosis called necroptosis occurs. Apoptosis and necroptosis may share some regulatory mechanisms. Recent studies indicated that receptor interacting protein 1 (RIP1), an Hsp90-associated kinase, is an important regulatory switch between apoptosis and necroptosis. In this study, we showed that oxygen-glucose deprivation (OGD) combined with a caspase inhibitor zVAD (OGD/zVAD)-induced RIP1 protein expression in a time-dependent manner. We found that geldanamycin (GA), a benzoquinone ansamycin, protected against neuronal injury induced by OGD/zVAD treatment in cultured primary neurons. More importantly, GA decreased RIP1 protein level in a time- and concentration-dependent manner. In this study, we found that GA also decreased the Hsp90 protein level, which caused instability of RIP1 protein, resulting in decreased RIP1 protein level but not RIP1 mRNA level after GA treatment. We concluded that the GA-mediated protection against OGD/zVAD-induced neuronal injury was associated with enhanced RIP1 protein instability by decreasing Hsp90 protein level. GA and its derivatives may be promising for the prevention of neuronal injury during ischemic injury.
authors: Department of Neurology, Xuzhou Medical College Affiliated Hospital, Xuzhou, Jiangsu Province, China.
authors: Wei-Wei
authors: WW
authors: Chen
authors: Hailong
authors: H
authors: Yu
authors: Hong-Bin
authors: HB
authors: Fan
authors: Cui-Cui
authors: CC
authors: Zhang
authors: Min
authors: M
authors: Zhang
authors: Caiyi
authors: C
authors: Zhang
authors: Yanbo
authors: Y
authors: Cheng
authors: Jiming
authors: J
authors: Kong
authors: Chun-Feng
authors: CF
authors: Liu
authors: Deqin
authors: D
authors: Geng
authors: Xingshun
authors: X
authors: Xu
mesh_terms: D000818:Animals; D016227:Benzoquinones / Q000494:pharmacology*; D015153:Blotting, Western; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects*; D002540:Cerebral Cortex / Q000166:cytology* / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005455:Fluorescent Antibody Technique; D020690:GTPase-Activating Proteins / Q000502:physiology*; D005947:Glucose / Q000172:deficiency*; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D047468:Immunoprecipitation; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D051379:Mice; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents; D009842:Oligopeptides / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011485:Protein Binding
chemical_list: D016227:Benzoquinones; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D020690:GTPase-Activating Proteins; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; D018696:Neuroprotective Agents; D009842:Oligopeptides; C490620:Ralbp1 protein, mouse; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; D007770:L-Lactate Dehydrogenase; D005947:Glucose; C001277:geldanamycin