Molecular Neurobiology

, Volume 34, Issue 3, pp 249–269 | Cite as

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

  • Heng ZhaoEmail author
  • Robert M. Sapolsky
  • Gary K. Steinberg


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, phsophatase and tensin homolog deleted on chromosome 10 (PTEN) decreases it. Upon activation, Akt phosphorylates an array of molecules, including glycogen synthase kinase3β (GSK3β), 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 GSK3β 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.

Index Entries

Akt PKB apoptosis cerebral ischemia stroke preconditioning neuroprotection PTEN 


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Copyright information

© Humana Press Inc 2006

Authors and Affiliations

  • Heng Zhao
    • 1
    • 3
    Email author
  • Robert M. Sapolsky
    • 1
    • 2
    • 3
  • Gary K. Steinberg
    • 1
    • 3
  1. 1.Department of NeurosurgeryStanford UniversityStanford
  2. 2.Department of Biological SciencesStanford UniversityStanford
  3. 3.Department of Stanford Stroke CenterStanford UniversityStanford

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