Zhao Heng, Sapolsky Robert M, Steinberg Gary K
Departments of Neurosurgery and Stanford Stroke Center, Stanford University, Stanford, CA, USA.
Mol Neurobiol. 2006 Dec;34(3):249-70. doi: 10.1385/MN:34:3:249.
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 integrinlinked 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 kinase3beta (GSK3beta), 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 GSK3beta 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.
近年来，磷酸肌醇-3-激酶/蛋白激酶B（Akt）细胞存活信号通路在中风领域的研究越来越多。有研究表明，生长因子激活受体酪氨酸激酶后，可通过磷酸化作用上调Akt活性。虽然上游信号成分磷酸肌醇依赖性蛋白激酶（PDK）1和整合素连接激酶可增强Akt的活性，但10号染色体缺失的磷酸酶和张力蛋白同源物（PTEN）会降低其活性。激活后，Akt会使一系列分子发生磷酸化，包括糖原合酶激酶3β（GSK3β）、横纹肌肉瘤中的叉头同源物（FKHR）和Bcl-2相关死亡蛋白，从而阻止线粒体细胞色素c的释放和半胱天冬酶的活性。一般来说，局灶性缺血后，丝氨酸473位点的Akt磷酸化水平（P-Akt）会短暂升高，而PTEN、PDK1、叉头转录因子和GSK3β的磷酸化水平则会降低。许多化合物（如生长因子、雌激素、自由基清除剂和其他神经保护剂）可能通过上调P-Akt来减少缺血损伤。然而，预处理和低温通过抑制P-Akt的增加来阻止缺血损伤。抑制Akt信号通路会阻断预处理和低温的保护作用，这表明Akt信号通路有助于它们的保护作用，且P-Akt水平并不代表其真正的激酶活性。总之，Akt信号通路功能障碍的减轻有助于中风后神经元的存活。
