Originally published In Press as doi:10.1074/jbc.M500003200 on March 29, 2005
J. Biol. Chem., Vol. 280, Issue 23, 21693-21699, June 10, 2005
Neuroprotective Effects of Preconditioning Ischemia on Ischemic Brain Injury through Down-regulating Activation of JNK1/2 via N-Methyl-D-aspartate Receptor-mediated Akt1 Activation*
Bei Miao
,
Xiao-Hui Yin,
Dong-Sheng Pei,
Quan-Guang Zhang, and
Guang-Yi Zhang
From the
Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, Xuzhou 221002, China
Our previous studies have demonstrated that the JNK signaling pathway plays an important role in ischemic brain injury and is mediated via glutamate receptor 6. Others studies have shown that N-methyl-D-aspartate (NMDA) receptor is involved in the neuroprotection of ischemic preconditioning. Here we examined whether ischemic preconditioning down-regulates activation of the mixed lineage kinase-JNK signaling pathway via NMDA receptor-mediated Akt1 activation. In our present results, ischemic preconditioning could not only inhibit activations of mixed lineage kinase 3, JNK1/2, and c-Jun but also enhanced activation of Akt1. In addition, both NMDA (an agonist of NMDA receptor) and preconditioning showed neuroprotective effects. In contrast, ketamine, an antagonist of NMDA receptor, prevented the above effects of preconditioning. Further studies indicated that LY294002, an inhibitor of phosphoinositide 3-kinase that is an upstream signaling protein of Akt1, could block neuroprotection of preconditioning, and KN62, an inhibitor of calmodulin-dependent protein kinase, also achieved the same effects as LY294002. Therefore, both phosphoinositide 3-kinase and calmodulin-dependent protein kinase are involved in the activation of Akt1 in ischemic tolerance. Taken together, our results indicate that preconditioning can inhibit activation of JNK signaling pathway via NMDA receptor-mediated Akt1 activation and induce neuroprotection in hippocampal CA1 region.
Received for publication, January 1, 2005
, and in revised form, March 18, 2005.
* This work was supported by Grant 30330190 from the Key Project of the National Natural Science Foundation of China. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Both authors contributed equally to this work.
To whom correspondence should be addressed: Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College, 84 West Huai-hai Rd., Xuzhou, Jiangsu, 221002 China. Tel.: 86-516-574-8486; Fax: 86-516-574-8486; E-mail: gyzhang{at}xzmc.edu.cn.
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Copyright © 2005 by the American Society for Biochemistry and Molecular Biology.
