title: Neuroprotection against focal ischemic brain injury by inhibition of c-Jun N-terminal kinase and attenuation of the mitochondrial apoptosis-signaling pathway.
abstract: c-Jun N-terminal kinase (JNK) is an important stress-responsive kinase that is activated by various forms of brain insults. In this study, we have examined the role of JNK activation in neuronal cell death in a murine model of focal ischemia and reperfusion; furthermore, we investigated the mechanism of JNK in apoptosis signaling, focusing on the mitochondrial-signaling pathway. We show here that JNK activity was induced in the brain 0.5 to 24 h after ischemia. Systemic administration of SP600125, a small molecule JNK-specific inhibitor, diminished JNK activity after ischemia and dose-dependently reduced infarct volume. c-Jun N-terminal kinase inhibition also attenuated ischemia-induced expression of Bim, Hrk/DP5, and Fas, but not the expression of Bcl-2 or FasL. In strong support of a role for JNK in promoting the mitochondrial apoptosis-signaling pathway, JNK inhibition prevented ischemia-induced mitochondrial translocation of Bax and Bim, release of cytochrome c and Smac, and activation of caspase-9 and caspase-3. The potential mechanism by which JNK promoted Bax translocation after ischemia was further studied using coimmunoprecipitation, and the results revealed that JNK activation caused serine phosphorylation of 14-3-3, a cytoplasmic sequestration protein of Bax, leading to Bax disassociation from 14-3-3 and subsequent translocation to mitochondria. These results confirm the role of JNK as a critical cell death mediator in ischemic brain injury, and suggest that one of the mechanisms by which JNK triggers the mitochondrial apoptosis-signaling pathway is via promoting Bax and Bim translocation.
authors.affiliation: Department of Neurology, University of Pittsburgh School of Medicine, Pennsylvania, USA
authors.forename: Yanqin
authors.initials: Y
authors.lastname: Gao
authors.forename: Armando P
authors.initials: AP
authors.lastname: Signore
authors.forename: Wei
authors.initials: W
authors.lastname: Yin
authors.forename: Guodong
authors.initials: G
authors.lastname: Cao
authors.forename: Xiao-Ming
authors.initials: XM
authors.lastname: Yin
authors.forename: Fengyan
authors.initials: F
authors.lastname: Sun
authors.forename: Yumin
authors.initials: Y
authors.lastname: Luo
authors.forename: Steven H
authors.initials: SH
authors.lastname: Graham
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D000873:Anthracenes / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D002545:Brain Ischemia / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D002544:Cerebral Infarction / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051028:bcl-2-Associated X Protein
chemical_list: D048948:14-3-3 Proteins; D000873:Anthracenes; D051017:Apoptosis Regulatory Proteins; C494827:Bax protein, mouse; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D002352:Carrier Proteins; D004791:Enzyme Inhibitors; D008565:Membrane Proteins; D018696:Neuroprotective Agents; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; C432165:pyrazolanthrone; D048031:JNK Mitogen-Activated Protein Kinases