Table of Contents Author Guidelines Submit a Manuscript
Evidence-Based Complementary and Alternative Medicine
Volume 2013, Article ID 459467, 16 pages
http://dx.doi.org/10.1155/2013/459467
Research Article

PI3K/Akt Pathway Contributes to Neurovascular Unit Protection of Xiao-Xu-Ming Decoction against Focal Cerebral Ischemia and Reperfusion Injury in Rats

1Department of Integrative Medicine, Zhongshan Hospital, and Laboratory of Neurology, Institute of Integrative Medicine, Fudan University, Shanghai 200032, China
2Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
3Guangzhou University of Traditional Chinese Medicine, Guangzhou 510006, China
4Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200021, China

Received 7 February 2013; Revised 31 March 2013; Accepted 9 April 2013

Academic Editor: Roman Huber

Copyright © 2013 Rui Lan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. E. H. Lo, T. Dalkara, and M. A. Moskowitz, “Mechanisms, challenges and opportunities in stroke,” Nature Reviews Neuroscience, vol. 4, no. 5, pp. 399–415, 2003. View at Publisher · View at Google Scholar · View at Scopus
  2. R. L. Vangilder, C. L. Rosen, T. L. Barr, and J. D. Huber, “Targeting the neurovascular unit for treatment of neurological disorders,” Pharmacology and Therapeutics, vol. 130, no. 3, pp. 239–247, 2011. View at Publisher · View at Google Scholar · View at Scopus
  3. R. Liu, T. T. Zhang, C. X. Wu, X. Lan, and G. H. Du, “Targeting the neurovascular unit: development of a new model and consideration for novel strategy for Alzheimer's disease,” Brain Research Bulletin, vol. 86, no. 1-2, pp. 13–21, 2011. View at Google Scholar
  4. B. R. S. Broughton, D. C. Reutens, and C. G. Sobey, “Apoptotic mechanisms after cerebral ischemia,” Stroke, vol. 40, no. 5, pp. e331–e339, 2009. View at Publisher · View at Google Scholar · View at Scopus
  5. S. T. Hou and J. P. MacManus, “Molecular mechanisms of cerebral ischemia-induced neuronal death,” International Review of Cytology, vol. 221, pp. 93–148, 2002. View at Publisher · View at Google Scholar · View at Scopus
  6. Y. M. Zhu, C. C. Wang, L. Chen et al., “Both PI3K/Akt and ERK1/2 pathways participate in the protection by dexmedetomidine against transient focal cerebral ischemia/reperfusion injury in rats,” Brain Research, vol. 1494, pp. 1–8, 2013. View at Google Scholar
  7. H. Endo, C. Nito, H. Kamada, T. Nishi, and P. H. Chan, “Activation of the Akt/GSK3β signaling pathway mediates survival of vulnerable hippocampal neurons after transient global cerebral ischemia in rats,” Journal of Cerebral Blood Flow and Metabolism, vol. 26, no. 12, pp. 1479–1489, 2006. View at Publisher · View at Google Scholar · View at Scopus
  8. H. Zhao, R. M. Sapolsky, and G. K. Steinberg, “Phosphoinositide-3-kinase/Akt survival signal pathways are implicated in neuronal survival after stroke,” Molecular Neurobiology, vol. 34, no. 3, pp. 249–269, 2006. View at Publisher · View at Google Scholar · View at Scopus
  9. A. Saito, T. Hayashi, S. Okuno, M. Ferrand-Drake, and P. H. Chan, “Overexpression of copper/zinc superoxide dismutase in transgenic mice protects against neuronal cell death after transient focal ischemia by blocking activation of the bad cell death signaling pathway,” Journal of Neuroscience, vol. 23, no. 5, pp. 1710–1718, 2003. View at Google Scholar · View at Scopus
  10. T. Kawano, M. Morioka, S. Yano et al., “Decreased Akt activity is associated with activation of forkhead transcription factor after transient forebrain ischemia in gerbil hippocampus,” Journal of Cerebral Blood Flow and Metabolism, vol. 22, no. 8, pp. 926–934, 2002. View at Google Scholar · View at Scopus
  11. J. Zhang, Z. Deng, J. Liao et al., “Leptin attenuates cerebral ischemia injury through the promotion of energy metabolism via the PI(3)K/Akt pathway,” Journal of Cerebral Blood Flow & Metabolism, vol. 33, no. 4, pp. 567–574, 2013. View at Publisher · View at Google Scholar
  12. G. B. Mackensen, M. Patel, H. Sheng et al., “Neuroprotection from delayed postischemic administration of a metalloporphyrin catalytic antioxidant,” Journal of Neuroscience, vol. 21, no. 13, pp. 4582–4592, 2001. View at Google Scholar · View at Scopus
  13. B. Xing, H. Chen, M. Zhang et al., “Ischemic postconditioning inhibits apoptosis after focal cerebral ischemia/reperfusion injury in the rat,” Stroke, vol. 39, no. 8, pp. 2362–2369, 2008. View at Publisher · View at Google Scholar · View at Scopus
  14. S. Y. Li, D. Yang, Z. J. Fu, T. Woo, D. Wong, and A. C. Lo, “Lutein enhances survival and reduces neuronal damage in a mouse model of ischemic stroke,” Neurobiology of Disease, vol. 45, no. 1, pp. 624–632, 2012. View at Google Scholar
  15. S. S. Baliga, K. M. Jaques-Robinson, N. M. Hadzimichalis, R. Golfetti, and G. F. Merrill, “Acetaminophen reduces mitochondrial dysfunction during early cerebral postischemic reperfusion in rats,” Brain Research, vol. 1319, pp. 142–154, 2010. View at Publisher · View at Google Scholar · View at Scopus
  16. M. Gelderblom, F. Leypoldt, J. Lewerenz et al., “The flavonoid fisetin attenuates postischemic immune cell infiltration, activation and infarct size after transient cerebral middle artery occlusion in mice,” Journal Cerebral Blood Flow & Metabolism, vol. 32, no. 5, pp. 835–843, 2012. View at Google Scholar
  17. R. L. Zhang, M. Chopp, N. Jiang et al., “Anti-intercellular adhesion molecule-1 antibody reduces ischemic cell damage after transient but not permanent middle cerebral artery occlusion in the Wistar rat,” Stroke, vol. 26, no. 8, pp. 1438–1443, 1995. View at Google Scholar · View at Scopus
  18. S. Kawasaki-Yatsugi, C. Ichiki, S. I. Yatsugi et al., “Neuroprotective effects of an AMPA receptor antagonist YM872 in a rat transient middle cerebral artery occlusion model,” Neuropharmacology, vol. 39, no. 2, pp. 211–217, 2000. View at Publisher · View at Google Scholar · View at Scopus
  19. T. Baba, M. Kameda, T. Yasuhara et al., “Electrical stimulation of the cerebral cortex exerts antiapoptotic, angiogenic, and anti-inflammatory effects in ischemic stroke rats through phosphoinositide 3-kinase/akt signaling pathway,” Stroke, vol. 40, no. 11, pp. e598–e605, 2009. View at Publisher · View at Google Scholar · View at Scopus
  20. C. Berthet, H. Lei, J. Thevenet, R. Gruetter, P. J. Magistretti, and L. Hirt, “Neuroprotective role of lactate after cerebral ischemia,” Journal of Cerebral Blood Flow and Metabolism, vol. 29, no. 11, pp. 1780–1789, 2009. View at Publisher · View at Google Scholar · View at Scopus
  21. J. Ros, N. Pecinska, B. Alessandri, H. Landolt, and M. Fillenz, “Lactate reduces glutamate-induced neurotoxicity in rat cortex,” Journal of Neuroscience Research, vol. 66, no. 5, pp. 790–794, 2001. View at Publisher · View at Google Scholar · View at Scopus
  22. Y. D. Cheng, L. Al-Khoury, and J. A. Zivin, “Neuroprotection for ischemic stroke: two decades of success and failure,” The Journal of The American Society for Experimental NeuroTherapeutics, vol. 1, no. 1, pp. 36–45, 2004. View at Publisher · View at Google Scholar · View at Scopus
  23. P. Huang, C. M. Zhou, Qin-Hu et al., “Cerebralcare Granule(R) attenuates blood-brain barrier disruption after middle cerebral artery occlusion in rats,” Experimental Neurology, vol. 237, no. 2, pp. 453–463, 2012. View at Google Scholar
  24. J. Xiang, Y. P. Tang, P. Wu, J. P. Gao, and D. F. Cai, “Chinese medicine Nao-Shuan-Tong attenuates cerebral ischemic injury by inhibiting apoptosis in a rat model of stroke,” Journal of Ethnopharmacology, vol. 131, no. 1, pp. 174–181, 2010. View at Publisher · View at Google Scholar · View at Scopus
  25. H. W. Wang, K. T. Liou, Y. H. Wang et al., “Deciphering the neuroprotective mechanisms of Bu-yang Huan-wu decoction by an integrative neurofunctional and genomic approach in ischemic stroke mice,” Journal of Ethnopharmacology, vol. 138, no. 1, pp. 22–33, 2011. View at Google Scholar
  26. X. M. Li, X. C. Bai, L. N. Qin, H. Huang, Z. J. Xiao, and T. M. Gao, “Neuroprotective effects of Buyang Huanwu Decoction on neuronal injury in hippocampus after transient forebrain ischemia in rats,” Neuroscience Letters, vol. 346, no. 1-2, pp. 29–32, 2003. View at Publisher · View at Google Scholar · View at Scopus
  27. J. J. Lee, W. H. Hsu, T. L. Yen et al., “Traditional Chinese medicine, Xue-Fu-Zhu-Yu decoction, potentiates tissue plasminogen activator against thromboembolic stroke in rats,” Journal of Ethnopharmacology, vol. 134, no. 3, pp. 824–830, 2011. View at Publisher · View at Google Scholar · View at Scopus
  28. X. H. Zhu, S. J. Li, H. H. Hu, L. R. Sun, M. Das, and T. M. Gao, “Neuroprotective effects of Xiao-Xu-Ming decoction against ischemic neuronal injury in vivo and in vitro,” Journal of Ethnopharmacology, vol. 127, no. 1, pp. 38–46, 2010. View at Publisher · View at Google Scholar · View at Scopus
  29. Y. H. Wang, X. L. He, H. G. Yang, H. L. Qin, and G. H. Du, “Effects of the effective components groups of Xiao-Xu-Ming decoction on MCAO rats,” Chinese Pharmaceutical Journal, vol. 47, no. 3, pp. 94–198, 2012 (Chinese). View at Google Scholar
  30. Y. H. Wang, X. L. He, X. X. Lee, H. L. Qin, and G. H. Du, “Effects of the effective component group of Chinese herbal medicine Xiao-Xu-Ming decoction on brain mitochondria in rats with chronic cerebral ischemia,” Journal of Chinese Integrative Medicine, vol. 10, no. 5, pp. 569–576, 2012 (Chinese). View at Google Scholar
  31. D. F. Cai, Y. K. Yang, X. X. Gu et al., “Clinical trial on treatment of acute cerebral infarction with TCM treatment according to syndrome differentiation combining Western medicine by staging,” Zhongguo Zhong xi yi jie he za zhi Zhongguo Zhongxiyi jiehe zazhi = Chinese journal of integrated traditional and Western medicine / Zhongguo Zhong xi yi jie he xue hui, Zhongguo Zhong yi yan jiu yuan zhu ban, vol. 27, no. 9, pp. 789–792, 2007 (Chinese). View at Google Scholar · View at Scopus
  32. S. Zhou, “Clinical Research on Xiao-Xu-Ming decoction treating the stroke patients with neurological deficits,” Journal of New Chinese Medicine, vol. 43, no. 5, pp. 17–18, 2011 (Chinese). View at Google Scholar
  33. J. H. Huang, X. H. Huang, Z. Y. Chen, Q. S. Zheng, and R. Y. Sun, “Dose conversion among different animals and healthy volunteers in pharmacological study,” Chinese Journal of Clinical Pharmacology and Therapeutics, vol. 9, no. 9, pp. 1069–1072, 2004 (Chinese). View at Google Scholar
  34. J. Xiang, R. Lan, Y. P. Tang, Y. P. Chen, and D. F. Cai, “Apocynum venetum leaf extract attenuates disruption of the blood-brain barrier and upregulation of matrix metalloproteinase-9/-2 in a rat model of cerebral ischemia-reperfusion injury,” Neurochemical Research, vol. 37, no. 8, pp. 1820–1828, 2012. View at Google Scholar
  35. G. J. Zarow, H. Karibe, B. A. States, S. H. Graham, and P. R. Weinstein, “Endovascular suture occlusion of the middle cerebral artery in rats: effect of suture insertion distance on cerebral blood flow, infarct distribution and infarct volume,” Neurological Research, vol. 19, no. 4, pp. 409–416, 1997. View at Google Scholar · View at Scopus
  36. R. Schmid-Elsaesser, S. Zausinger, E. Hungerhuber, A. Baethmann, and H. J. Reulen, “A critical reevaluation of the intraluminal thread model of focal cerebral ischemia: evidence of inadvertent premature reperfusion and subarachnoid hemorrhage in rats by laser-Doppler flowmetry,” Stroke, vol. 29, no. 10, pp. 2162–2170, 1998. View at Google Scholar · View at Scopus
  37. Q. Zhao, H. Memezawa, M. L. Smith, and B. K. Siesjo, “Hyperthermia complicates middle cerebral artery occlusion induced by an intraluminal filament,” Brain Research, vol. 649, no. 1-2, pp. 253–259, 1994. View at Publisher · View at Google Scholar · View at Scopus
  38. K. M. Sicard and M. Fisher, “Animal models of focal brain ischemia,” Experimental & Translational Stroke Medicine, vol. 1, article 7, 2009. View at Google Scholar
  39. H. Zhao, T. Shimohata, J. Q. Wang et al., “Akt contributes to neuroprotection by hypothermia against cerebral ischemia in rats,” Journal of Neuroscience, vol. 25, no. 42, pp. 9794–9806, 2005. View at Publisher · View at Google Scholar · View at Scopus
  40. G. Paxinos and C. Watson, The Rat Brain in Stereotaxic Coordinates, Compact, San Diego Academic Press, California, Calif, USA, 3rd edition, 1997.
  41. H. Hara, P. L. Huang, N. Panahian, M. C. Fishman, and M. A. Moskowitz, “Reduced brain edema and infarction volume in mice lacking the neuronal isoform of nitric oxide synthase after transient MCA occlusion,” Journal of Cerebral Blood Flow and Metabolism, vol. 16, no. 4, pp. 605–611, 1996. View at Google Scholar · View at Scopus
  42. C. Zhou, J. Tu, Q. Zhang et al., “Delayed ischemic postconditioning protects hippocampal CA1 neurons by preserving mitochondrial integrity via Akt/GSK3beta signaling,” Neurochemistry International, vol. 59, no. 6, pp. 749–758, 2011. View at Google Scholar
  43. G. J. Del Zoppo, K. Poeck, M. S. Pessin et al., “Recombinant tissue plasminogen activator in acute thrombotic and embolic stroke,” Annals of Neurology, vol. 32, no. 1, pp. 78–86, 1992. View at Publisher · View at Google Scholar · View at Scopus
  44. Z. Li, K. Ni, and G. Du, “Simultaneous analysis of six effective components in the anti-Alzheimer's disease effective component group of Xiao-Xu-Ming decoction,” Chinese Journal of Chromatography (Se Pu), vol. 25, no. 1, pp. 80–83, 2007 (Chinese). View at Google Scholar · View at Scopus
  45. K. Du, C. Wu, C. Ding, S. Zhao, H. Qin, and J. Zhang, “Simultaneous LC-MS analysis and of wogonin and oroxylin a in rat plasma, and pharmacokinetic studies after administration of the active fraction from Xiao-Xu-Ming decoction,” Chromatographia, vol. 69, no. 11-12, pp. 1259–1266, 2009. View at Publisher · View at Google Scholar · View at Scopus
  46. Y. Wang, C. Ding, K. Du et al., “Identification of active compounds and their metabolites by high-performance liquid chromatography/electrospray ionization Fourier transform ion cyclotron resonance mass spectrometry from Xiao-Xu-Ming decoction (XXMD),” Rapid Communications in Mass Spectrometry, vol. 23, no. 17, pp. 2724–2732, 2009. View at Publisher · View at Google Scholar · View at Scopus
  47. N. Y. Tang, C. H. Liu, C. T. Hsieh, and C. L. Hsieh, “The anti-inflammatory effect of paeoniflorin on cerebral infarction induced by ischemia-reperfusion injury in sprague-dawley rats,” American Journal of Chinese Medicine, vol. 38, no. 1, pp. 51–64, 2010. View at Publisher · View at Google Scholar · View at Scopus
  48. D. M. Chen, L. Xiao, X. Cai, R. Zeng, and X. Z. Zhu, “Involvement of multitargets in paeoniflorin-induced preconditioning,” Journal of Pharmacology and Experimental Therapeutics, vol. 319, no. 1, pp. 165–180, 2006. View at Publisher · View at Google Scholar · View at Scopus
  49. L. Xiao, Y. Z. Wang, J. Liu, X. T. Luo, Y. Ye, and X. Z. Zhu, “Effects of paeoniflorin on the cerebral infarction, behavioral and cognitive impairments at the chronic stage of transient middle cerebral artery occlusion in rats,” Life Sciences, vol. 78, no. 4, pp. 413–420, 2005. View at Publisher · View at Google Scholar · View at Scopus
  50. X. K. Tu, W. Z. Yang, R. S. Liang et al., “Effect of baicalin on matrix metalloproteinase-9 expression and blood-brain barrier permeability following focal cerebral ischemia in rats,” Neurochemical Research, vol. 36, no. 11, pp. 2022–2028, 2011. View at Google Scholar
  51. X. Xue, X. J. Qu, Y. Yang et al., “Baicalin attenuates focal cerebral ischemic reperfusion injury through inhibition of nuclear factor κB p65 activation,” Biochemical and Biophysical Research Communications, vol. 403, no. 3-4, pp. 398–404, 2010. View at Publisher · View at Google Scholar · View at Scopus
  52. X. K. Tu, W. Z. Yang, S. S. Shi et al., “Baicalin inhibits TLR2/4 signaling pathway in rat brain following permanent cerebral ischemia,” Inflammation, vol. 34, no. 5, pp. 463–470, 2011. View at Google Scholar
  53. X. K. Tu, W. Z. Yang, S. S. Shi, C. H. Wang, and C. M. Chen, “Neuroprotective effect of baicalin in a rat model of permanent focal cerebral ischemia,” Neurochemical Research, vol. 34, no. 9, pp. 1626–1634, 2009. View at Publisher · View at Google Scholar · View at Scopus
  54. J. Cho and H. K. Lee, “Wogonin inhibits ischemic brain injury in a rat model of permanent middle cerebral artery occlusion,” Biological and Pharmaceutical Bulletin, vol. 27, no. 10, pp. 1561–1564, 2004. View at Publisher · View at Google Scholar · View at Scopus
  55. Z. P. Hua, A. J. Shun, S. C. Hyang, J. C. Lee, and W. K. Kim, “Neuroprotective effect of wogonin: potential roles of inflammatory cytokines,” Archives of Pharmacal Research, vol. 27, no. 9, pp. 930–936, 2004. View at Google Scholar · View at Scopus
  56. K. van Leyen, H. Y. Kim, S. R. Lee, G. Jin, K. Arai, and E. H. Lo, “Baicalein and 12/15-lipoxygenase in the ischemic brain,” Stroke, vol. 37, no. 12, pp. 3014–3018, 2006. View at Publisher · View at Google Scholar · View at Scopus
  57. Y. W. Xu, L. Sun, H. Liang, G. M. Sun, and Y. Cheng, “12/15-Lipoxygenase inhibitor baicalein suppresses PPARγ expression and nuclear translocation induced by cerebral ischemia/reperfusion,” Brain Research, vol. 1307, pp. 149–157, 2010. View at Publisher · View at Google Scholar · View at Scopus
  58. L. Cui, X. Zhang, R. Yang et al., “Baicalein is neuroprotective in rat MCAO model: role of 12/15-lipoxygenase, mitogen-activated protein kinase and cytosolic phospholipase A2,” Pharmacology Biochemistry and Behavior, vol. 96, no. 4, pp. 469–475, 2010. View at Publisher · View at Google Scholar · View at Scopus
  59. C. Liu, J. Wu, K. Xu et al., “Neuroprotection by baicalein in ischemic brain injury involves PTEN/AKT pathway,” Journal of Neurochemistry, vol. 112, no. 6, pp. 1500–1512, 2010. View at Publisher · View at Google Scholar · View at Scopus
  60. P. A. Lapchak, P. Maher, D. Schubert, and J. A. Zivin, “Baicalein, an antioxidant 12/15-lipoxygenase inhibitor improves clinical rating scores following multiple infarct embolic strokes,” Neuroscience, vol. 150, no. 3, pp. 585–591, 2007. View at Publisher · View at Google Scholar · View at Scopus
  61. S. W. Kim, Y. Jin, J. H. Shin et al., “Glycyrrhizic acid affords robust neuroprotection in the postischemic brain via anti-inflammatory effect by inhibiting HMGB1 phosphorylation and secretion,” Neurobiology of Disease, vol. 46, no. 1, pp. 147–156, 2012. View at Google Scholar
  62. T. K. Kao, Y. C. Ou, J. S. Kuo et al., “Neuroprotection by tetramethylpyrazine against ischemic brain injury in rats,” Neurochemistry International, vol. 48, no. 3, pp. 166–176, 2006. View at Publisher · View at Google Scholar · View at Scopus
  63. S. L. Liao, T. K. Kao, W. Y. Chen et al., “Tetramethylpyrazine reduces ischemic brain injury in rats,” Neuroscience Letters, vol. 372, no. 1-2, pp. 40–45, 2004. View at Publisher · View at Google Scholar · View at Scopus
  64. T. F. Franke, C. P. Hornik, L. Segev, G. A. Shostak, and C. Sugimoto, “PI3K/Akt and apoptosis: size matters,” Oncogene, vol. 22, no. 56, pp. 8983–8998, 2003. View at Publisher · View at Google Scholar · View at Scopus
  65. M. P. Scheid, P. A. Marignani, and J. R. Woodgett, “Multiple phosphoinositide 3-kinase-dependent steps in activation of protein kinase B,” Molecular and Cellular Biology, vol. 22, no. 17, pp. 6247–6260, 2002. View at Publisher · View at Google Scholar · View at Scopus
  66. J. Á. F. Vara, E. Casado, J. de Castro, P. Cejas, C. Belda-Iniesta, and M. González-Barón, “P13K/Akt signalling pathway and cancer,” Cancer Treatment Reviews, vol. 30, no. 2, pp. 193–204, 2004. View at Publisher · View at Google Scholar · View at Scopus
  67. N. Omori, G. Jin, F. Li et al., “Enhanced phosphorylation of PTEN in rat brain after transient middle cerebral artery occlusion,” Brain Research, vol. 954, no. 2, pp. 317–322, 2002. View at Publisher · View at Google Scholar · View at Scopus
  68. K. Ning, L. Pei, M. Liao et al., “Dual neuroprotective signaling mediated by downregulating two distinct phosphatase activities of PTEN,” Journal of Neuroscience, vol. 24, no. 16, pp. 4052–4060, 2004. View at Publisher · View at Google Scholar · View at Scopus
  69. D. N. Wu, D. S. Pei, Q. Wang, and G. Y. Zhang, “Down-regulation of PTEN by sodium orthovanadate inhibits ASK1 activation via PI3-K/Akt during cerebral ischemia in rat hippocampus,” Neuroscience Letters, vol. 404, no. 1-2, pp. 98–102, 2006. View at Publisher · View at Google Scholar · View at Scopus
  70. J. H. Lee, K. Y. Kim, Y. K. Lee et al., “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,” Journal of Pharmacology and Experimental Therapeutics, vol. 308, no. 3, pp. 896–903, 2004. View at Publisher · View at Google Scholar · View at Scopus
  71. T. F. Franke, D. R. Kaplan, and L. C. Cantley, “PI3K: downstream AKTion blocks apoptosis,” Cell, vol. 88, no. 4, pp. 435–437, 1997. View at Publisher · View at Google Scholar · View at Scopus
  72. K. Fukunaga and T. Kawano, “Akt is a molecular target for signal transduction therapy in brain ischemic insult,” Journal of Pharmacological Sciences, vol. 92, no. 4, pp. 317–327, 2003. View at Google Scholar · View at Scopus
  73. M. Pap and G. M. Cooper, “Role of glycogen synthase kinase-3 in the phosphatidylinositol 3- kinase/Akt cell survival pathway,” Journal of Biological Chemistry, vol. 273, no. 32, pp. 19929–19932, 1998. View at Publisher · View at Google Scholar · View at Scopus
  74. R. V. Bhat, J. Shanley, M. P. Correll et al., “Regulation and localization of tyrosine216 phosphorylation of glycogen synthase kinase-3β in cellular and animal models of neuronal degeneration,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 20, pp. 11074–11079, 2000. View at Google Scholar · View at Scopus
  75. S. Zimmermann and K. Moelling, “Phosphorylation and regulation of Raf by Akt (protein kinase B),” Science, vol. 286, no. 5445, pp. 1741–1744, 1999. View at Publisher · View at Google Scholar · View at Scopus