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: Bo Yin, Yang Xu, Rui-Li Wei, Fangping He, Ben-Yan Luo, Jing-Ye Wang
• Journal: Brain research (Brain Res) Vol. 1609 Pg. 63-71 (Jun 03 2015) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 25801119 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Imidazoles
• Indoles
• Neuroprotective Agents
• necrostatin-1
• Parp1 protein, rat
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases
• Protein Serine-Threonine Kinases
• RIPK1 protein, rat
• Receptor-Interacting Protein Serine-Threonine Kinases
• receptor-interacting protein 3, rat
• Cathepsin B
• Ctsb protein, rat

Topics

• Animals
• Brain Ischemia (drug therapy, metabolism, pathology)
• CA1 Region, Hippocampal (drug effects, metabolism, pathology)
• Cathepsin B (metabolism)
• Cell Death (drug effects, physiology)
• Cytoplasm (drug effects, metabolism)
• Dose-Response Relationship, Drug
• Imidazoles (pharmacology)
• Indoles (pharmacology)
• Lysosomes (drug effects, metabolism, pathology)
• Male
• Necrosis (drug therapy, metabolism, pathology)
• Neurons (drug effects, metabolism, pathology)
• Neuroprotective Agents (pharmacology)
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases (metabolism)
• Protein Serine-Threonine Kinases (metabolism)
• Rats, Sprague-Dawley
• Receptor-Interacting Protein Serine-Threonine Kinases (metabolism)
• Reperfusion Injury (drug therapy, metabolism, pathology)
• Up-Regulation (drug effects)