Phosphoinositide-3-kinase/Akt survival signal pathways are implicated in neuronal survival after stroke

被引:267
作者
Zhao, Heng [1 ]
Sapolsky, Robert M.
Steinberg, Gary K.
机构
[1] Stanford Univ, Dept Neurosurg, Stanford, CA 94305 USA
[2] Stanford Univ, Dept Biol Sci, Stanford, CA 94305 USA
[3] Stanford Univ, Stanford Stroke Ctr, Stanford, CA 94305 USA
关键词
Akt; PKB; apoptosis; cerebral ischemia; stroke; preconditioning; neuroprotection; PTEN;
D O I
10.1385/MN:34:3:249
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
In recent years, the phosphoinositide- 3- kinase/ Akt cell survival signaling pathway has been increasingly researched in the field of stroke. Akt activity is suggested to be upregulated by phosphorylation through the activation of receptor tyrosine kinases by growth factors. Although the upstream signaling components phosphoinositide- dependent protein kinase ( PDK) 1 and integrin-linked kinase enhance the activity of Akt, phosphatase and tensin homolog deleted on chromosome 10 ( PTEN) decreases it. Upon activation, Akt phosphorylates an array of molecules, including glycogen synthase kinase3 beta ( GSK3 beta), forkhead homolog in rhabdomyosarcoma ( FKHR), and Bcl- 2- associated death protein, thereby blocking mitochondrial cytochrome c release and caspase activity. Generally, the level of Akt phosphorylation at site Ser 473 ( P- Akt) transiently increases after focal ischemia, whereas the levels of phosphorylation of PTEN, PDK1, forkhead transcription factor, and GSK3 beta decrease. Numerous compounds ( such as growth factors, estrogen, free radical scavengers, and other neuroprotectants) reduce ischemic damage, possibly by upregulating P- Akt. However, preconditioning and hypothermia block ischemic damage by inhibiting an increase of P- Akt. Inhibition of the Akt pathway blocks the protective effect of preconditioning and hypothermia, suggesting the Akt pathway contributes to their protective effects and that the P- Akt level does not represent its true kinase activity. Together, attenuation of the Akt pathway dysfunction contributes to neuronal survival after stroke.
引用
收藏
页码:249 / 269
页数:21
相关论文
共 123 条
[1]   Altered Bad localization and interaction between Bad and Bcl-xL in the hippocampus after transient global ischemia [J].
Abe, T ;
Takagi, N ;
Nakano, M ;
Furuya, M ;
Takeo, S .
BRAIN RESEARCH, 2004, 1009 (1-2) :159-168
[2]   Mechanism of activation of protein kinase B by insulin and IGF-1 [J].
Alessi, DR ;
Andjelkovic, M ;
Caudwell, B ;
Cron, P ;
Morrice, N ;
Cohen, P ;
Hemmings, BA .
EMBO JOURNAL, 1996, 15 (23) :6541-6551
[3]  
Alonso de Lecinana M, 2006, CEREBROVASC DIS, V21, P48
[4]   Akt activation by growth factors is a multiple-step process: the role of the PH domain [J].
Bellacosa, A ;
Chan, TO ;
Ahmed, NN ;
Datta, K ;
Malstrom, S ;
Stokoe, D ;
McCormick, F ;
Feng, JN ;
Tsichlis, P .
ONCOGENE, 1998, 17 (03) :313-325
[5]   Regulation and localization of tyrosine216 phosphorylation of glycogen synthase kinase-3β in cellular and animal models of neuronal degeneration [J].
Bhat, RV ;
Shanley, J ;
Correll, MP ;
Fieles, WE ;
Keith, RA ;
Scott, CW ;
Lee, CM .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (20) :11074-11079
[6]  
Bonny C, 2005, REV NEUROSCIENCE, V16, P57
[7]   Protein kinase C δ mediates cerebral reperfusion injury in vivo [J].
Bright, R ;
Raval, AP ;
Dembner, JM ;
Pérez-Pinzón, MA ;
Steinberg, GK ;
Yenari, MA ;
Mochly-Rosen, D .
JOURNAL OF NEUROSCIENCE, 2004, 24 (31) :6880-6888
[8]   Transcription-dependent and -independent control of neuronal survival by the PI3K-Akt signaling pathway [J].
Brunet, A ;
Datta, SR ;
Greenberg, ME .
CURRENT OPINION IN NEUROBIOLOGY, 2001, 11 (03) :297-305
[9]   Growth hormone-releasing peptide hexarelin reduces neonatal brain injury and alters Akt/glycogen synthase kinase-3β phosphorylation [J].
Brywe, KG ;
Leverin, AL ;
Gustavsson, M ;
Mallard, C ;
Granata, R ;
Destefanis, S ;
Volante, M ;
Hagberg, H ;
Ghigo, E ;
Isgaard, JR .
ENDOCRINOLOGY, 2005, 146 (11) :4665-4672
[10]   IGF-I neuroprotection in the immature brain after hypoxia-ischemia, involvement of Akt and GSK3β? [J].
Brywe, KG ;
Mallard, C ;
Gustavsson, M ;
Hedtjärn, M ;
Leverin, AL ;
Wang, XY ;
Blomgren, K ;
Isgaard, J ;
Hagberg, H .
EUROPEAN JOURNAL OF NEUROSCIENCE, 2005, 21 (06) :1489-1502