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Neuroprotection against focal ischemic brain injury by inhibition of c-Jun N-terminal kinase and attenuation of the mitochondrial apoptosis-signaling pathway.
J Cereb Blood Flow Metab 2005; 25(6):694-712JC

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+Show Affiliations

Department of Neurology, University of Pittsburgh School of Medicine, Pennsylvania, USANo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

15716857

Citation

Gao, Yanqin, et al. "Neuroprotection Against Focal Ischemic Brain Injury By Inhibition of c-Jun N-terminal Kinase and Attenuation of the Mitochondrial Apoptosis-signaling Pathway." Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, vol. 25, no. 6, 2005, pp. 694-712.
Gao Y, Signore AP, Yin W, et al. Neuroprotection against focal ischemic brain injury by inhibition of c-Jun N-terminal kinase and attenuation of the mitochondrial apoptosis-signaling pathway. J Cereb Blood Flow Metab. 2005;25(6):694-712.
Gao, Y., Signore, A. P., Yin, W., Cao, G., Yin, X. M., Sun, F., ... Chen, J. (2005). Neuroprotection against focal ischemic brain injury by inhibition of c-Jun N-terminal kinase and attenuation of the mitochondrial apoptosis-signaling pathway. Journal of Cerebral Blood Flow and Metabolism : Official Journal of the International Society of Cerebral Blood Flow and Metabolism, 25(6), pp. 694-712.
Gao Y, et al. Neuroprotection Against Focal Ischemic Brain Injury By Inhibition of c-Jun N-terminal Kinase and Attenuation of the Mitochondrial Apoptosis-signaling Pathway. J Cereb Blood Flow Metab. 2005;25(6):694-712. PubMed PMID: 15716857.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Neuroprotection against focal ischemic brain injury by inhibition of c-Jun N-terminal kinase and attenuation of the mitochondrial apoptosis-signaling pathway. AU - Gao,Yanqin, AU - Signore,Armando P, AU - Yin,Wei, AU - Cao,Guodong, AU - Yin,Xiao-Ming, AU - Sun,Fengyan, AU - Luo,Yumin, AU - Graham,Steven H, AU - Chen,Jun, PY - 2005/2/18/pubmed PY - 2005/6/23/medline PY - 2005/2/18/entrez SP - 694 EP - 712 JF - Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism JO - J. Cereb. Blood Flow Metab. VL - 25 IS - 6 N2 - 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. SN - 0271-678X UR - https://www.unboundmedicine.com/medline/citation/15716857/Neuroprotection_against_focal_ischemic_brain_injury_by_inhibition_of_c_Jun_N_terminal_kinase_and_attenuation_of_the_mitochondrial_apoptosis_signaling_pathway_ L2 - http://journals.sagepub.com/doi/full/10.1038/sj.jcbfm.9600062?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -