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

• Published in: Brain research Vol. 1035; no. 1; pp. 51 - 59
• Main Authors: Guan, Qiu-Hua, Pei, Dong-Sheng, Zhang, Quan-Guang, Hao, Zhi-Bin, Xu, Tian-Le, Zhang, Guang-Yi
• Format: Journal Article
• Language: English
• Published: London Elsevier B.V 21.02.2005; Amsterdam Elsevier; New York, NY
• Subjects: Analysis of Variance; Animals; Anthracenes - therapeutic use; Bcl-2; Biological and medical sciences; Blotting, Western - methods; Brain ischemia; c-Jun; Cell Count - methods; Cell Death - drug effects; Disease Models, Animal; Gene Expression Regulation - drug effects; Hippocampus - cytology; Hippocampus - pathology; Immunoprecipitation - methods; Ischemic Attack, Transient - drug therapy; Ischemic Attack, Transient - pathology; JNK; JNK Mitogen-Activated Protein Kinases - metabolism; Male; MAP Kinase Kinase 4; Medical sciences; Mitogen-Activated Protein Kinase Kinases - metabolism; Neurology; Neurons - drug effects; Neurons - 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; Reperfusion Injury - prevention & control; Signal Transduction - drug effects; SP600125; Staining and Labeling - methods; Time Factors; Vascular diseases and vascular malformations of the nervous system; Bcl-2; Brain ischemia; Disorders of the nervous system; c-Jun; JNK; SP600125; Neuroprotection; Nervous system diseases; Rat; Rodentia; Central nervous system; Brain death; Cardiovascular disease; Cerebral disorder; Vascular disease; Vertebrata; Mammalia; Neuron; Cell death; Animal; Central nervous system disease; Cerebrovascular disease; Hippocampus; Protooncogene; Immediate early gene
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2004.11.050

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.