Skip to main content
SpringerLink
Log in

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

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Graham S. H. and Chen J. (2001) Programmed cell death in crebral ischemia. J. Cereb. Blood Flow Metab. 21 (2), 99–109.

    PubMed  CAS  Google Scholar 

  2. Franke T. F., Hornik C. P., Segev L., Shostak G. A., and Sugimoto C. (2003) P13K/Akt and apoptosis: size matters. Oncogene 22(56), 8983–8998.

    PubMed  CAS  Google Scholar 

  3. Chan P. H. (2004) Mitochondria and neuronal death/survival signaling pathways in cerebral ischemia. Neurochem. Res. 29(11), 1943–1949.

    PubMed  CAS  Google Scholar 

  4. Zhao H., Shimohata T., Wang J. Q., et al. (2005) Akt contributes to neuroprotection by hypothermia against cerebral ischemia in rats. J. Neurosci. 25(42), 9794–9806.

    PubMed  CAS  Google Scholar 

  5. Jin G., Omori N., Li F., Nagano I. Manabe Y., Shoji M., and Abe K. (2003) Protection against ischemic brain damage by GDNF affecting cell survival and death signals. Neurol. Res. 25(3), 249–253.

    PubMed  CAS  Google Scholar 

  6. Kaya D., Gursoy-Ozdemir Y., Yemisci M., Tuncer N., Aktan S., and Dalkara T. (2005) VEGF protects brain against focal ischemia without increasing blood-brain permeability when administered intracerebroventricularly. J. Cereb. Blood Flow Metab. 25(9), 1111–1118.

    PubMed  CAS  Google Scholar 

  7. Garcia L., Burda J., Hrehorovska M., Burda R., Martin M. E., and Salinas M., (2004) Ischaemic preconditioning in the rat brain: effect on the activity of several initiation factors, Akt and extracellular signal-regulated protein kinase phosphorylation, and GRP78 and GADD34 expression. J. Neurochem. 88(1), 136–147.

    PubMed  CAS  Google Scholar 

  8. Namura S., Nagata I., Kikuchi H., Andreucci M., and Alessandrini A., (2000) Serine-threonine protein kinase Akt does not mediate ischemic tolerance after global ischemia in the gerbil. J. Cereb. Blood Flow Metab. 20(9), 1301–1305.

    PubMed  CAS  Google Scholar 

  9. Saito A., Hayashi T., Okuno S., Nishi T., and Chan P. H., (2004) Oxidative stress affects the integrin-linked kinase signaling pathway after transient focal cerebral ischemia. Stroke 35(11), 2560–2565.

    PubMed  CAS  Google Scholar 

  10. Yoshimoto T., Kanakaraj P., Ying Ma J., et al. (2002) NXY-059 maintains Akt activation and inhibits release of cytochrome C after focal cerebral ischemia. Brain Res. 947(2), 191–198.

    PubMed  CAS  Google Scholar 

  11. Zhang F., Signore A. P., Zhou Z., Wang S., Cao G., and Chen J., (2006) Erythropoietin protects CA1 neurons against global cerebral ischemia in rat: Potential signaling mechanisms. J. Neurosci. Res. 83(7), 1241–1251.

    PubMed  CAS  Google Scholar 

  12. Sugawara T., Fujimura M., Morita-Fujimura Y., Kawase M., and Chan P. H., (1999) Mitochondrial release of cytochrome c corresponds to the selective vulnerability of hippocampal CA1 neurons in rats after transient global cerebral ischemia. J. Neurosci. 19(22), CR39.

    Google Scholar 

  13. Zhao H., Yehari M. A., Cheng D., Barreto-Chang O. L., Sapolsky R. M., and Steinberg G. K., (2004) Bcl-2 transfection via herpes simplex virus blocks apoptosis inducing factor translocation after focal ischemia in rat. J. Cereb. Blood Flow Metab. 4(6), 681–692.

    Google Scholar 

  14. Zhao H., Yenari M. A., Cheng D., Sapolsky R. M., and Steinberg G. K., (2003) Bcl-2 overexpression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochromec translocation and caspase-3 activity. J. Neurochem. 85(4), 1026–1036.

    PubMed  CAS  Google Scholar 

  15. Le D. A., Wu Y., Huang Z., et al. (2002) Caspase activation and neuroprotection in caspase-3-deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation. Proc. Natl. Acad. Sci. USA 99(23), 15,188–15,193.

    CAS  Google Scholar 

  16. Plesnila N., Zhu C., Culmsee C., Groger M., Moskowitz M. A., and Blomgren K. (2004) Nuclear translocation of apoptosis-inducing factor after focal cerebral ischemia. J. Cereb. Blood Flow Metab. 24(4), 458–466.

    PubMed  Google Scholar 

  17. Mattson M. P. (2000) Apoptosis in neurodegenerative disorders. Nat. Rev. Mol. Cell Biol. 1(2), 120–129.

    PubMed  CAS  Google Scholar 

  18. Ning K., Pei L., Liao M., et al. (2004) Dual neuroprotective signaling mediated by downregulating two distinct phosphatase activities of PTEN. J. Neurosci. 24(16), 4052–4060.

    PubMed  CAS  Google Scholar 

  19. Yuan J. and Horvitz H. R. (2004) A first insight into the molecular mechanisms of apoptosis. Cell 116(2 Suppl), S53-S56, S 59.

    PubMed  CAS  Google Scholar 

  20. Fresno Vara J. A., Casado E., de Castro J., Cejas P., Belda-Iniesta C., and Gonzalez-Baron M. (2004) P13K/Akt signalling pathway and cancer. Cancer Treat. Rev. 30(2), 193–204.

    PubMed  Google Scholar 

  21. Edwards L. A., Thiessen B., Dragowska W. H., Daynard T., Bally M. B., and Dedhar S., (2005) Inhibition of ILK in PTEN-mutant human glioblastomas inhibits PKB/Akt activation, induces apoptosis, and delays tumor growth. Oncogene 24(22), 3596–3605.

    PubMed  CAS  Google Scholar 

  22. Troussard A. A., McDonald P. C., Wederell E. D., et al. (2006) Preferential dependence of breast cancer cells versus normal cells on integrinlinked kinase for protein kinase B/Akt activation and cell survival. Cancer Res. 66(1), 393–403.

    PubMed  CAS  Google Scholar 

  23. Hanada M., Feng J., and Hemmings B. A. (2004) Structure, regulation and function of PKB/AKT—a major therapeutic target. Biochim. Biophys. Acta 1697(1–2), 3–16.

    PubMed  CAS  Google Scholar 

  24. Brunet A., Datta S. R., and Greenberg M. E., (2001) Transcription-dependent and-independent control of neuronal survival by the PI3K-Akt signaling pathway. Curr. Opin. Neurobiol. 11(3), 297–305.

    PubMed  CAS  Google Scholar 

  25. Bhat R. V., Shanley J., Correll M. P., et al. (2000) Regulation and localization of tyrosine216 phosphorylation of glycogen synthase kinase-3beta in cellular and animal models of neuronal degeneration. Proc. Natl. Acad. Sci. USA 97(20), 11,074–11,079.

    CAS  Google Scholar 

  26. Nusse R. (2003) Wnts and Hedgehogs: lipidmodified proteins and similarities in signaling mechanisms at the cell surface. Development 130(22), 5297–5305.

    PubMed  CAS  Google Scholar 

  27. Alessi D. R., Andjelkovic M., Caudwell B., et al. (1996) Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J. 15(23), 6541–6551.

    PubMed  CAS  Google Scholar 

  28. Bellacosa A., Chan T. O., Ahmed N. N., et al. (1998) Akt activation by growth factors is a multiple-step process: the role of the PH domain. Oncogene 17(3), 313–325.

    PubMed  CAS  Google Scholar 

  29. Hill M. M., Andjelkovic M., Brazil D. P., Ferrari S., Fabbro D., and Hemmings B. A. (2001) Insulin-stimulated protein kinase B phosphorylation on Ser-473 is independent of its activity and occurs through a staurosporine-insensitive kinase. J. Biol. Chem. 276(28), 25,643–25,646.

    CAS  Google Scholar 

  30. Chen R., Kim O., Yang J., et al. (2001) Regulation of Akt/PKB activation by tyrosine phosphorylation. J. Biol. Chem. 276(34), 31,858–31,862.

    CAS  Google Scholar 

  31. Noshita N., Lewen A., Sugawara T., and Chan P. H. (2001) Evidence of phosphorylation of Akt and neuronal survival after transient focal cerebral ischemia in mice. J. Cereb. Blood Flow Metab. 21(12), 1442–1450.

    PubMed  CAS  Google Scholar 

  32. Osuka K., Watanabe Y., Usuda N., Nakazawa A., Tokuda M., and Yoshida J. (2004) Modification of endothelial NO synthase through protein phosphorylation after forebrain cerebral ischemia/reperfusion. Stroke 35(11), 2582–2586.

    PubMed  CAS  Google Scholar 

  33. Kawano T., Fukunaga K., Takeuchi Y., et al. (2001) Neuroprotective effect of sodium orthovanadate on delayed neuronal death after transient forebrain ischemia in gerbil hippocampus. J. Cereb. Blood Flow Metab. 21(11), 1268–1280.

    PubMed  CAS  Google Scholar 

  34. Jin K. L., Mao X. O., and Greenberg D. A. (2000) Vascular endothelial growth factor: direct neuroprotective effect in in vitro ischemia. Proc. Natl. Acad. Sci. USA 97(18), 10,242–10,247.

    CAS  Google Scholar 

  35. Ouyang Y. B., Tan Y., Comb M., et al. (1999) Survival- and death-promoting events after transient cerebral ischemia: phosphorylation of Akt, release of cytochrome C and activation of caspase-like proteases. J. Cereb. Blood Flow Metab. 19(10), 1126–1135.

    PubMed  CAS  Google Scholar 

  36. Endo H., Nito C., Kamada H., Nishi T., and Chan P. H. (2006) Activation of the Akt/GSK3beta signaling pathway mediates survival of vulnerable hippocampal neurons after transient global cerebral ischemia in rats. J. Cereb. Blood Flow Metab. March 15, epub ahead of print. doi: 10.1038/sj.jcbfm.9600303.

  37. Zablocka B., Dluzniewska J., Zajac H., and Domanska-Janik K., (2003) Opposite reaction of ERK and JNK in ischemia vulnerable and resistant regions of hippocampus: involvement of mitochondria. Brain Res. Mol. Brain Res. 110(2), 245–252.

    PubMed  CAS  Google Scholar 

  38. Yoshimoto T., Uchino H., He Q. P., Li P. A., and Siesjo B. K. (2001) Cyclosporin A, but not FK506, prevents the downregulation of phosphorylated Akt after transient focal ischemia in the rat. Brain Res. 899(1–2), 148–158.

    PubMed  CAS  Google Scholar 

  39. Kitagawa H., Warita H., Sasaki C., et al. (1999) Immunoreactive Akt, PI3-K and ERK protein kinase expression in ischemic rat brain. Neurosci. Lett. 274(1), 45–48.

    PubMed  CAS  Google Scholar 

  40. Jin K. L., Mao X. O., Nagayama T., Goldsmith P. C., and Greenberg D. A. (2000) Induction of vascular endothelial growth factor receptors and phosphatidylinositol 3′-kinase/Akt signaling by global cerebral ischemia in the rat. Neuroscience 100(4), 713–717.

    PubMed  CAS  Google Scholar 

  41. Bonny C., Borsello T., and Zine A. (2005) Targeting the NJK pathway as a therapeutic protective strategy for nervous system diseases. Rev. Neurosci. 16(1), 57–67.

    PubMed  CAS  Google Scholar 

  42. Irving E. A. and Bamford M. (2002) Role of mitogen- and stress-activated kinases in ischemic injury. J. Cereb. Blood Flow Metab. 22(6), 631–647.

    PubMed  CAS  Google Scholar 

  43. Chu C. T., Levinthal D. J., Kulich S. M., Chalovich E. M., and DeFranco D. B. (2004) Oxidative neuronal injury. The dark side of ERK1/2. Eur. J. Biochem. 271(11), 2060–2066.

    PubMed  CAS  Google Scholar 

  44. Kilic E., Kilic U., Wang Y., Bassetti C. L., Marti H. H., and Hermann D. M. (2006) The phosphatidy linositol-3 kinase/Akt pathway mediates VEGF's neuroprotective activity and induces blood brain barrier permeability after focal cerebral ischemia. FASEB J. 20, 1185–1187.

    PubMed  CAS  Google Scholar 

  45. Lee J. H., Kim K. Y., Lee Y. K., et al. (2004) Cilostazol prevents focal cerebral ischemic injury by enhancing casein kinase 2 phosphorylation and suppression of phosphatase and tensin homolog deleted from chromosome 10 phosphorylation in rats. J. Pharmacol. Exp. Ther. 308(3), 896–903.

    PubMed  Google Scholar 

  46. Omori N., Jin G., Li F., et al. (2002) Enhanced phosphorylation of PTEN in rat brain after transient middle cerebral artery occlusion. Brain Res. 954(2), 317–322.

    PubMed  CAS  Google Scholar 

  47. Kawano T., Morioka M., Yano S., et al. (2002) Decreased akt activity is associated with activation of forkhead transcription factor after transient forebrain ischemia in gerbil hippocampus. J. Cereb. Blood Flow Metab. 22(8), 926–934.

    PubMed  CAS  Google Scholar 

  48. Abe T., Takagi N., Nakano M., Furuya M., and Takeo S. (2004) Altered Bad localization and interaction between Bad and Bcl-xL in the hippocampus after transient global ischemia. Brain Res. 1009(1–2), 159–168.

    PubMed  CAS  Google Scholar 

  49. Friguls B., Justicia C., Pallas M., and Planas A. M. (2001) Focal cerebral ischemia causes two temporal waves of Akt activation. Neuroreport 12(15), 3381–3384.

    PubMed  CAS  Google Scholar 

  50. Noshita N., Sugawara T., Lewen A., Hayashi T., and Chan P. H., (2003) Copper-zinc super-oxide dismutase affects Akt activation after transient focal cerebral ischemia in mice. Stroke 34(6), 1513–1518.

    PubMed  CAS  Google Scholar 

  51. Kovacina K. S., Park G. Y., Bae S. S., et al. (2003) Identification of a proline-rich Akt substrate as a 14-3-3 binding partner. J. Biol. Chem., 278(12), 10,189–10,194.

    CAS  Google Scholar 

  52. Saito A., Hayashi T., Okuno S., Nishi T., and Chan P. H., (2006) Modulation of proline-rich akt substrate survival signaling pathways by oxidative stress in mouse brains after transient focal cerebral ischemia. Stroke 37(2, 513–517.

    PubMed  CAS  Google Scholar 

  53. Saito A., Narasimhan P., Hayashi T., Okuno S., Ferrand-Drake M., and Chan P. H., (2004) Neuroprotective role of a proline-rich Akt substrate in apoptotic neuronal cell death after stroke: relationships with nerve growth factor. J. Neurosci. 24(7), 1584–1593.

    PubMed  CAS  Google Scholar 

  54. Fukunaga K., Ishigami T., and Kawano T. (2005) Transcriptional regulation of neuronal genes and its effect on neural functions: expression and function of forkhead transcription factors in neurons. J. Pharmacol. Sci. 98(3), 205–211.

    PubMed  CAS  Google Scholar 

  55. Petegnief V., Friguls B., Sanfeliu C., Sunol C., and Planas A. M. (2003) Transforming growth factor-alpha attenuates N-methyl-D-aspartic acid toxicity in cortical cultures by preventing protein synthesis inhibition through an Erk1/2-dependent mechanism. J. Biol. Chem. 278(32) 29,552–29,559.

    CAS  Google Scholar 

  56. Friguls B., Petegnief V., Justicia C., Pallas M., and Planas A. M. (2002) Activation of ERK and Akt signaling in focal cerebral ischemia: modulation by TGF-alpha and involvement of NMDA receptor. Neurobiol. Dis. 11(3) 443–456.

    PubMed  CAS  Google Scholar 

  57. Kilic E., Kilic U., Soliz J., Bassetti C. L., Gassmann M., and Hermann D. M. (2005) Brain-derived erythropoietin protects from focal cerebral ischemia by dual activation of ERK-1/-2 and Akt Pathways. FASEB J. 19(14), 2026–2028.

    PubMed  CAS  Google Scholar 

  58. Brywe K. G., Leverin A. L., Gustavsson M., et al. (2005) Growth hormone-releasing peptide hexarelin reduces neonatal brain injury and alters Akt/glycogen synthase kinase-3beta phosphorylation. Endocrinology 146(11) 4665–4662.

    PubMed  CAS  Google Scholar 

  59. Brywe K. G., Mallard C., Gustavsson M., et al. (2005) IGF-I neuroprotection in the immature brain after hypoxia-ischemia, involvement of Akt and GSK3beta? Eur. J. Neurosci. 21(6), 1489–1502.

    PubMed  Google Scholar 

  60. Han B. H. and Holtzman D. M. (2000) BDNF protects the neonatal brain from hypoxicischemic injury in vivo via the ERK pathway. J. Neurosci. 20(15), 5775–5781.

    PubMed  CAS  Google Scholar 

  61. Chan P. H. (1996) Role of oxidants in ischemic brain damage. Stroke 27(6), 1124–1129.

    PubMed  CAS  Google Scholar 

  62. Kim G. W., Sugawara T., and Chan P. H., (2000) Involvement of oxidative stress and caspase-3 in cortical infarction after photothrombotic ischemia in mice. J. Cereb. Blood Flow Metab. 20(12), 1690–1701.

    PubMed  CAS  Google Scholar 

  63. Group, E. A. I. S. (2003) Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebocontrolled, double-blind study at multicenters. Cerebrovasc. Dis. 15(3), 222–229.

    Google Scholar 

  64. Ferro J. M. and Davalos A. (2006) Other neuroprotective therapies on trial in acute stroke. Cerebrovasc. Dis. 21(Suppl 2), 127–130.

    PubMed  CAS  Google Scholar 

  65. Edaravone-Acute-Infarction-Study-Group, N. A. I., (2003). Effect of a novel free radical scavenger, edaravone (MCI-186), on acute brain infarction. Randomized, placebo-controlled, double-blind study at multicenters. Cerebrovasc. Dis. 15(3), 222–229.

  66. ——, (1994). Safety study of tirilazad mesylate in patients with acute ischemic stroke (STIPAS). Stroke 25(2), 418–423.

  67. Chang P., Cheng E., Brooke S., and Sapolsky R. (2005) Marked differences in the efficacy of post-insult gene therapy with catalase versus glutathione peroxidase. Brain Res. 1063(1), 27–31.

    PubMed  CAS  Google Scholar 

  68. Taylor J. M., Ali U., Iannello R. C., Hertzog P., and Crack P. J. (2005) Diminished Akt phosphorylation in neurons lacking glutathione peroxidase-1 (Gpx1) leads to increased susceptibility to oxidative stress-induced cell death. J. Neurochem. 92(2), 283–293.

    PubMed  CAS  Google Scholar 

  69. Lees K. R., Zivin J. A., Ashwood T., et al. (2006) NXY-059 for acute ischemic stroke. N. Engl. J. Med. 354(6), 588–600.

    PubMed  CAS  Google Scholar 

  70. Kilic U., Kilic E., Reiter R. J., Bassetti C. L., and Hermann D. M. (2005) Signal transduction pathways involved in melatonin-induced neuroprotection after focal cerebral ischemia in mice. J. Pineal Res. 38(1) 67–71.

    PubMed  CAS  Google Scholar 

  71. Scharfman H. E. and Maclusky N. J. (2005) Similarities between actions of estrogen and BDNF in the hippocampus: coincidence or clue? Trends Neurosci. 28(2), 79–85.

    PubMed  CAS  Google Scholar 

  72. Morale M. C., Serra P. A., L'Episcope F., et al. (2006) Estrogen, neuroinflammation and neuro-protection in Parkinson's disease: glia dictates resistance versus vulnerability to neurodegeneration. Neuroscience 138(3), 869–878.

    PubMed  CAS  Google Scholar 

  73. Merchenthaler I., Dellovade T. L., and Shughrue P. J. (2003) Neuroprotection by estrogen in animal models of global and focal ischemia. Ann. NY Acad. Sci. 1007, 89–100.

    PubMed  CAS  Google Scholar 

  74. Wise P. M., Dubal D. B., Rau S. W., Brown C. M., and Suzuki S. (2005) Are estrogens protective or risk factors in brain injury and neurodegeneration? Reevaluation after the Women's health initiative. Endocr. Rev. 26(3), 308–312.

    PubMed  CAS  Google Scholar 

  75. Alonso de Lecinana M. and Egido J. A. (2006) Estrogens as neuroprotectants against ischemic stroke. Cerebrovasc. Dis. 21 (Suppl 2), 48–53.

    PubMed  CAS  Google Scholar 

  76. Wilson M. E., Liu Y., and Wise, P. M. (2002) Estradiol enhances Akt activation in cortical explant cultures following neuronal injury. Brain Res. Mol. Brain Res. 102(1–2), 48–54.

    PubMed  CAS  Google Scholar 

  77. Cimarosti H., Zamin L. L., Frozza, R. et al. (2005) Estradiol protects against oxygen and glucose deprivation in rat hippocampal organotypic cultures and activates Akt and inactivates GSK-3beta. Neurochem. Res. 30(2), 191–199.

    PubMed  CAS  Google Scholar 

  78. Won C. K., Ha S. J., Noh H. S., et al. (2005) Estradiol prevents the injury-induced decrease of Akt activation and Bad phosphorylation. Neurosci. Lett. 387(2), 115–119.

    PubMed  CAS  Google Scholar 

  79. Choi Y. C., Lee J. H., Hong K. W., and Lee K. S. (2004) 17 Beta-estradiol prevents focal cerebral ischemic damages via activation of Akt and CREB in association with reduced PTEN phosphorylation in rats. Fundam. Clin. Pharmacol. 18(5), 547–557.

    PubMed  CAS  Google Scholar 

  80. Song R. X., Zhang, Z., and Santen R. J. (2005) Estrogen rapid action via protein complex formation involving ERalpha and Src. Trends Endocrinol. Metab. 16(8), 347–353.

    PubMed  CAS  Google Scholar 

  81. Bright R., Raval A. P., Dembner J. M., et al. (2004) Protein kinase C delta mediates cerebral reperfusion injury in vivo. J. Neurosci. 24(31), 6880–6888.

    PubMed  CAS  Google Scholar 

  82. Noji T., Karasawa A., and Kusaka H. (2004) Adenosine uptake inhibitors. Eur. J. Pharmacol. 495(1), 1–16.

    PubMed  CAS  Google Scholar 

  83. Marcoli M., Raiteri L., Bonfanti A. et al. (2003) Sensitivity to selective adenosine A1 and A2A receptor antagonists of the release of glutamate induced by ischemia in rat cerebrocortical slices. Neuropharmacology 45(2), 201–210.

    PubMed  CAS  Google Scholar 

  84. Uchino H., Minamikawa-Tachino R., Kristian, T., et al. (2002) Differential neuroprotection by cyclosporin A and FK506 following ischemia corresponds with differing abilities to inhibit calcineurin and the mitochondrial permeability transition. Neurobiol. Dis. 10(3), 219–233.

    PubMed  CAS  Google Scholar 

  85. Hasegawa Y., Hamada J., Morioka M., et al. (2003) Neuroprotective effect of postischemic administration of sodium orthovanadate in rats with transient middle cerebral artery occlusion. J. Cereb. Blood Flow Metab. 23(9), 1040–1051.

    PubMed  CAS  Google Scholar 

  86. Silva C. M. (2004) Role of STATs as downstream signal transducers in Src family kinase-mediated tumorigenesis. Oncogene 23(48), 8017–8023.

    PubMed  CAS  Google Scholar 

  87. Takagi Y., Harada J., Chiarugi A., and Moskowitz M. A. (2002) STAT1 is activated in neurons after ischemia and contributes to ischemic brain injury. J. Cereb. Blood Flow Metab. 22(11), 1311–1318.

    PubMed  CAS  Google Scholar 

  88. Meller R., Stevens S. L., Minami M., et al. (2005) Neuroprotection by osteopontin in stroke. J. Cereb. Blood Flow Metab. 25(2), 217–225.

    PubMed  CAS  Google Scholar 

  89. Gabryel B., Pudelko A., and Malecki A. (2004) Erk1/2 and Akt kinases are involved in the protective effect of aniracetam in astrocytes subjected to simulated ischemia in vitro. Eur. J. Pharmacol. 494(2–3), 111–120.

    PubMed  CAS  Google Scholar 

  90. Koh S. H., Park Y., Song C. W., et al. (2004) The effect of PARP inhibitor on ischaemic cell death, its related inflammation and survival signals. Eur. J. Neurosci. 20(6), 1461–1472.

    PubMed  Google Scholar 

  91. Lee J. H., Park S. Y., Lee W. S., and Hong K. W. (2005) Lack of antiapoptotic effects of antiplatelet drug, aspirin and clopidogrel, and antioxidant, MCI-186, against focal ischemic brain damage in rats. Neurol. Res. 27(5), 483–492.

    PubMed  CAS  Google Scholar 

  92. Wang S. J., Omori N., Li F., et al. (2002) Potentiation of Akt and suppression of caspase-9 activations by electroacupuncture after transient middle cerebral artery occlusion in rats. Neurosci. Lett. 331(2), 115–118.

    PubMed  CAS  Google Scholar 

  93. Kilic E., Kilic U., Reiter R. J., Bassetti C. L., and Hermann D. M. (2005) Tissue-plasminogen activator-induced ischemic brain injury is reversed by melatonin: role of iNOS and Akt. J. Pineal Res. 39(2), 151–155.

    PubMed  CAS  Google Scholar 

  94. Kato H., Liu Y., Araki T., and Kogure K. (1992) MK-801, but not anisomycin, inhibits the induction of tolerance to ischemia in the gerbil hippocampus. Neurosci. Lett. 139(1), 118–121.

    PubMed  CAS  Google Scholar 

  95. Kato H., Araki T., and Kogure K. (1992) Preserved neurotransmitter receptor binding following ischemia in preconditioned gerbil brain. Brain Res. Bull. 29(3–4), 395–400.

    PubMed  CAS  Google Scholar 

  96. Nakajima T., Iwabuchi S., Miyazaki, H., et al. (2004) Preconditioning prevents ischemia induced neuronal death through persistent Akt activation in the penumbra region of the rat brain. J. Vet. Med. Sci. 66(5), 521–527.

    PubMed  CAS  Google Scholar 

  97. Yano S., Morioka M., Kuratsu J., and Fukunaga K. (2005) Functional proteins involved in regulation of intracellular Ca(2+) for drug development: role of calcium/calmodulin-dependent protein kinases in ischemic neuronal death. J. Pharmacol. Sci. 97(3), 351–354.

    PubMed  CAS  Google Scholar 

  98. Yin X. H., Zhang Q. G., Miao B., and Zhang G. Y. (2005) Neuroprotective effects of preconditioning ischaemia on ischaemic brain injury through inhibition of mixed-lineage kinase 3 via NMDA receptor-mediated Akt1 activation. J. Neurochem. 93(4), 1021–1029.

    PubMed  CAS  Google Scholar 

  99. Miao B., Yin X. H., Pei D. S., Zhang Q. G., and Zhang G. Y. (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. J. Biol. Chem. 280(23), 21,693–21,699.

    CAS  Google Scholar 

  100. Yano S., Morioka M., Fukunaga K., et al. (2001) Activation of Akt/protein kinase B contributes to induction of ischemic tolerance in the CA1 subfield of gerbil hippocampus. J. Cereb. Blood Flow Metab. 21(4), 351–360.

    PubMed  CAS  Google Scholar 

  101. Meller R., Minami M., Cameron J. A., et al. (2005) CREB-mediated Bcl-2 protein expression after ischemic preconditioning. J. Cereb. Blood Flow Metab. 25(2), 234–246.

    PubMed  CAS  Google Scholar 

  102. Wick A., Wick W., Waltenberger J., Weller M., Dichgans J., and Schulz J. B. (2002) Neuroprotection by hypoxic preconditioning requires sequential activation of vascular endothelial growth factor receptor and Akt. J. Neurosci. 22(15), 6401–6407.

    PubMed  CAS  Google Scholar 

  103. Busto R., Dietrich W. D., Globus M. Y., and Ginsberg M. D. (1989) The importance of brain temperature in cerebral ischemic injury. Stroke 20(8), 1113–1114.

    PubMed  CAS  Google Scholar 

  104. Krieger D. W. and Yenari M. A. (2004) Therapeutic hypothermia for acute ischemic stroke: What do laboratory studies teach us? Stroke 35(6), 1482–1489.

    PubMed  Google Scholar 

  105. Busto R., Globus M. Y., Dietrich W. D., Martinez E., Valdes I., and Ginsberg M. D. (1989) Effect of mild hypothermia on ischemia-induced release of neurotransmitters and free fatty acids in rat brain. Stroke 20(7), 904–910.

    PubMed  CAS  Google Scholar 

  106. Zhao H, Asai S., Kohno T., and Ishikawa K. (1998) Effects of brain temperature on CBF thresholds for extracellular glutamate release and reuptake in the striatum in a rat model of graded global ischemia. Neuroreport 9(14), 3183–3188.

    PubMed  CAS  Google Scholar 

  107. McManus T., Sadgrove M., Pringle A. K., Chad J. E., and Sundstrom L. E. (2004) Intraischaemic hypothermia reduces free radical production and protects against ischaemic insults in cultured hippocampal slices. J. Neurochem. 91(2), 327–336.

    PubMed  CAS  Google Scholar 

  108. Zhao H., Yenari M. A., Cheng D., Sapolsky R. M., and Steinberg G. K. (2005) Biphasic cytochrome c release after transient global ischemia and its inhibition by hypothermia. J. Cereb. Blood Flow Metab. 25(9), 1119–1129.

    PubMed  CAS  Google Scholar 

  109. Deng H., Han H. S., Cheng D., Sun G. H., and Yenari M. A. (2003) Mild hypothermia inhibits inflammation after experimental stroke and brain inflammation. Stroke 34(10), 2495–2501.

    PubMed  Google Scholar 

  110. Zhu C., Wang X., Xu F., et al. (2006) Intraischemic mild hypothermia prevents neuronal cell death and tissue loss after neonatal cerebral hypoxia-ischemia. Eur. J. Neurosci. 23(2), 387–393.

    PubMed  Google Scholar 

  111. Tomimatsu T., Fukuda H., Endo M., et al. (2001) Effects of hypothermia on neonatal hypoxic-ischemic brain injury in the rat: phosphorylation of Akt, activation of caspase-3-like protease. Neurosci. Lett. 312(1), 21–24.

    PubMed  CAS  Google Scholar 

  112. Xia C. F., Yin H., Borlongan C. V., Chao J., and Chao L. (2004) Adrenomedullin gene delivery protects against cerebral ischemic injury by promoting astrocyte migration and survival. Hum. Gene Ther. 15(12), 1243–1254.

    PubMed  CAS  Google Scholar 

  113. Jiang Z., Zhang Y., Chen X. Q., et al. (2003) Apoptosis and activation of Erkl/2 and Akt in astrocytes postischemia. Neurochem. Res. 28(6), 831–837.

    PubMed  CAS  Google Scholar 

  114. Li F., Omori N., Jin G., et al. (2003) Cooperative expression of survival p-ERK and p-Akt signals in rat brain neurons after transient MCAO. Brain Res. 962(1–2), 21–26.

    PubMed  CAS  Google Scholar 

  115. Fukunaga K. (2003) (Signal transduction and development of drug for brain ischemic insult). Nippon Yakurigaku Zasshi. 122(Suppl), 22P-24P.

    PubMed  Google Scholar 

  116. Lenhard T., Schober A., Suter-Crazzolara C., and Unsicker K. (2002) Fibroblast growth factor-2 requires glial-cell-line-derived neurotrophic factor for exerting its neuroprotective actions on glutamate-lesioned hippocampal neurons. Mol. Cell Neurosci. 20(2), 181–197.

    PubMed  CAS  Google Scholar 

  117. Hui L., Pei D. S., Zhang Q. G., Guan Q. H., and Zhang G. Y. (2005) The neuroprotection of insulin on ischemic brain injury in rat hippocampus through negative regulation of JNK signaling pathway by PI3K/Akt activation. Brain Res. 1052(1), 1–9.

    PubMed  CAS  Google Scholar 

  118. Limbourg F. P., Huang Z., Plumier J. C., et al. (2002) Rapid nontranscriptional activation of endothelial nitric oxide synthase mediates increased cerebral blood flow and stroke protection by corticosteroids. J. Clin. Invest. 110(11), 1729–1738.

    PubMed  CAS  Google Scholar 

  119. Xia C. F., Yin H., Borlongan C. V., Chao L., and Chao J. (2004) Kallikrein gene transfer protects against ischemic stroke by promoting glial cell migration and inhibiting apoptosis. Hypertension 43(2), 452–459.

    PubMed  CAS  Google Scholar 

  120. Gervitz L. M., Nalbant D., Williams S. C., and Fowler J. C. (2002) Adenosine-mediated activation of Akt/protein kinase B in the rat hippocampus in vitro and in vivo. Neurosci. Lett. 328(2), 175–179.

    PubMed  CAS  Google Scholar 

  121. Siren A. L., Fratelli M., Brines M., et al. (2001) Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc. Natl. Acad. Sci. USA. 98(7), 4044–4049.

    PubMed  CAS  Google Scholar 

  122. Troglio F., Echart C., Gobbi A., et al. (2004) The Rai (Shc C) adaptor protein regulates the neuronal stress response and protects against cerebral ischemia. Proc. Natl. Acad. Sci. USA. 101(43), 15,476–15,481.

    CAS  Google Scholar 

  123. Hashiguchi A., Yano S., Morioka M., et al. (2004) Up-regulation of endothelial nitric oxide synthese via phosphatidylinositol 3-kinase pathway contributes to ischemic tolerance in the CA1 subfield of gerbil hippocampus. J. Cereb. Blood Flow Metab. 24(3), 271–279.

    PubMed  CAS  Google Scholar 

  124. Jones N. M. and Bergeron M. (2004) Hypoxia-induced ischemic tolerance in neonatal rat brain involves enhanced ERK1/2 signaling. J. Neurochem. 89(1), 157–167.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurosurgery, Stanford University, Stanford, CA

    Heng Zhao, Robert M. Sapolsky & Gary K. Steinberg

  2. Department of Biological Sciences, Stanford University, Stanford, CA

    Robert M. Sapolsky

  3. Department of Stanford Stroke Center, Stanford University, Stanford, CA

    Heng Zhao, Robert M. Sapolsky & Gary K. Steinberg

Authors
  1. Heng Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Robert M. Sapolsky
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gary K. Steinberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Heng Zhao.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhao, H., Sapolsky, R.M. & Steinberg, G.K. Phosphoinositide-3-kinase/Akt survival signal pathways are implicated in neuronal survival after stroke. Mol Neurobiol 34, 249–269 (2006). https://doi.org/10.1385/MN:34:3:249

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1385/MN:34:3:249

Index Entries

Search

Navigation