title: Inhibition of receptor-interacting protein 3 upregulation and nuclear translocation involved in Necrostatin-1 protection against hippocampal neuronal programmed necrosis induced by ischemia/reperfusion injury.
abstract: Receptor-interacting protein 3 (RIP3) is a key molecular switch in tumor necrosis factor-induced necroptosis requiring the formation of an RIP3-RIP1 complex. We have recently shown that hippocampal cornu ammonis 1 (CA1) neuronal death induced by 20-min global cerebral ischemia/reperfusion (I/R) injury is a form of programmed necrosis. However, the mechanism behind this process is still unclear and was studied here. Global cerebral ischemia was induced by the four-vessel occlusion method and Necrostatin-1 (Nec-1), a specific inhibitor of necroptosis, was administered by intracerebroventricular injection 1h before ischemia. Normally, in the hippocampal CA1 neurons, RIP1 and RIP3 are located in the cytoplasm. However, after I/R injury, RIP3 was upregulated and translocated to the nucleus while RIP1 was not affected. Nec-1 pretreatment prevented hippocampal CA1 neuronal death and I/R induced changes in RIP3. Decreased level of NAD+ in hippocampus and the release of cathepsin-B from lysosomes after I/R injury were also inhibited by Nec-1. Our data demonstrate that Nec-1 inhibits neuronal death by preventing RIP3 upregulation and nuclear translocation, as well as NAD+ depletion and cathepsin-B release. The nuclear translocation of RIP3 has not been reported previously, so this may be an important role for RIP3 during ischemic injury.
authors: Department of Neurology, Brain Medical Centre, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China; Department of Neurology, Renmin Hospital of Wuhan University, 99 Zhangzhidong Road, Wuhan 430060, China.
authors: Bo
authors: B
authors: Yin
authors: Department of Neurology, Brain Medical Centre, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China.
authors: Yang
authors: Y
authors: Xu
authors: Department of Neurology, Brain Medical Centre, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China.
authors: Rui-Li
authors: RL
authors: Wei
authors: Department of Neurology, Brain Medical Centre, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China.
authors: Fangping
authors: F
authors: He
authors: Department of Neurology, Brain Medical Centre, First Affiliated Hospital, Zhejiang University School of Medicine, 79 Qingchun Road, Hangzhou 310003, China. Electronic address: luobenyan@zju.edu.cn.
authors: Ben-Yan
authors: BY
authors: Luo
authors: Department of Neurology, First Affiliated Hospital, Anhui Medical University, 218 Jixi Road, Hefei 230022, China. Electronic address: jyewang@163.com.
authors: Jing-Ye
authors: JY
authors: Wang
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D056547:CA1 Region, Hippocampal / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002401:Cathepsin B / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D003593:Cytoplasm / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009336:Necrosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D007093:Imidazoles; D007211:Indoles; D018696:Neuroprotective Agents; C507699:necrostatin-1; C499322:Parp1 protein, rat; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D017346:Protein Serine-Threonine Kinases; C586536:RIPK1 protein, rat; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C582791:Ripk3 protein, rat; D002401:Cathepsin B; C533916:Ctsb protein, rat
keywords: Global cerebral ischemia; Necrostatin-1; Nuclear translocation; Programmed necrosis; Receptor-interacting protein 3