The neuroprotective action of SP600125, a new inhibitor of JNK, on transient brain ischemia/reperfusion-induced neuronal death in rat hippocampal CA1 via nuclear and non-nuclear pathways.

Abstract

Increasing evidence suggests that c-Jun N-terminal kinase (JNK) is an important kinase mediating neuronal apoptosis in brain ischemia. To further study the roles of JNK activation in hippocampal CA1 neurons in a rat model of transient global ischemia, we assessed the effect of JNK inhibition by SP600125 on the degree of brain injury. Our results demonstrated that SP600125 significantly increased the number of surviving cells in hippocampal CA1 subfield and decreased the activation of p-JNK1/2 and p-JNK3 at 30 min and 3 days after brain ischemia. Moreover, SP600125 significantly diminished the increased levels of phosphorylated-c-Jun (Ser63/73) and phosphorylated-Bcl-2 (Ser87) at 3 h after brain ischemia. These results indicate that SP600125, a new inhibitor of JNK, protected transient brain ischemia/reperfusion-induced neuronal death in rat hippocampal CA1 region at least via suppressing the activation of nuclear substrate (c-Jun) and inactivating non-nuclear substrate (Bcl-2) induced by ischemic insult. Thus, inhibiting JNK activity by SP600125 may represent a new and effective strategy to treat ischemic stoke.

• Authors: Qiu-Hua Guan, Dong-Sheng Pei, Quan-Guang Zhang, Zhi-Bin Hao, Tian-Le Xu, Guang-Yi Zhang
• Journal: Brain research (Brain Res) Vol. 1035 Issue 1 Pg. 51-9 (Feb 21 2005) ISSN: 0006-8993 [Print] Netherlands
• PMID: 15713276 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anthracenes
• Neuroprotective Agents
• Proto-Oncogene Proteins c-bcl-2
• Proto-Oncogene Proteins c-jun
• pyrazolanthrone
• JNK Mitogen-Activated Protein Kinases
• MAP Kinase Kinase 4
• Mitogen-Activated Protein Kinase Kinases

Topics

• Analysis of Variance
• Animals
• Anthracenes (therapeutic use)
• Blotting, Western (methods)
• Cell Count (methods)
• Cell Death (drug effects)
• Disease Models, Animal
• Gene Expression Regulation (drug effects)
• Hippocampus (cytology, pathology)
• Immunoprecipitation (methods)
• Ischemic Attack, Transient (drug therapy, pathology)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• MAP Kinase Kinase 4
• Male
• Mitogen-Activated Protein Kinase Kinases (metabolism)
• Neurons (drug effects, pathology)
• Neuroprotective Agents (therapeutic use)
• Phosphorylation
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Proto-Oncogene Proteins c-jun (metabolism)
• Rats
• Rats, Sprague-Dawley
• Reperfusion Injury (pathology, prevention & control)
• Signal Transduction (drug effects)
• Staining and Labeling (methods)
• Time Factors