Akt Signaling Pathway and Ischemic Stroke

Abstract

Abstract: In this paper, the biology of Akt and its physiological function in ischemic cerebral disease were discussed, and the latest research progress was introduced. Akt is highly expressed in cerebral ischemia- reperfusion injury, and has certain protective effect to this kind of brain damage. Recent research suggests that Akt has many features of stress reaction, and its effect on brain protection is related to its cooperative initiation with other pathways. The in-depth study of Akt will help the understanding of the role of the cerebral apoplexy and for new drug research and development.

Key words: AKT, cerebral stroke, ischemia and reperfusion

CLC Number:

R338

HU Jun, LEI Fan, XING Dong-ming, DU Li-jun. Akt Signaling Pathway and Ischemic Stroke[J]. Acta Neuropharmacologica, 2012, 2(4): 19-27.

References

[1] Stephen P Staal, Janet W Hartley, Wallace P Rowe. Isolation of transforming murine leukemia viruses from mice with a high incidence of spontaneous lymphoma[J]. Proc Natl Acad Sci USA, 1977, 74(7): 3065-3067.

[2] A Bellacosa, T F Franke, M E Gonzalezportal, et al. Structure, expression and chromosomal mapping of C-Akt-relationship to V-Akt and its implications[J]. Oncogene, 1993, 8(3): 745-754.

[3] Lana Bozulic, Brian A Hemmings. PIKKing on PKB: regulation of PKB activity by phosphorylation[J]. Curr Opin Cell Biol, 2009, 21(2): 256-261.

[4] Marie Vandromme, Anne Rochat, Roger Meier, et al. Protein kinase B beta/Akt2 plays a specific role in muscle differentiation[J]. J Biol Chem, 2001, 276 (11): 8173-8179.

[5] Annapurna Poduri, Gilad D Evrony, Xuyu Cai, et al. Somatic activation of AKT3 causes hemispheric developmental brain malformations[J]. Neuron, 2012, 74 (1): 41-48.

[6] Alex Toker, Alexandra C Newton. Cellular signaling: Pivoting around PDK-1[J]. Cell, 2000, 103(2): 185-188.

[7] Tung Jai-nien, Tsao Tang-yi, Chen Shun-liang, et al. Presence of secretory cellular apoptosis susceptibility protein in cerebrospinal fluids of patients with intracerebral hemorrhage caused by stroke and neurotrauma[J]. Neuroendocrinol Lett, 2010, 31(3): 390-398.

[8] X J Shu, W Liu, H Y Zhou, et al. Synergistic cognition-protective effects of bis(7)-tacrine inducing neurogenesis and inhibiting apoptosis in aged rats with acute ischemic Stroke[J]. Cerebrovasc Dis, 2010, 30(2): 213-214.

[9] B Liebelt, P Papapetrou, A Ali, et al. Exercise preconditioning reduces neuronal apoptosis in stroke by up-regulating heat shock protein-70 (Heat Shock Protein-72) and extracellular-signal-regulated-kinase 1/2[J]. Neuroscience, 2010, 166(4): 1091-1100.

[10] Ning Ke, Pei Lin, Liao Ming-xia, et al. Dual neuroprotective signaling mediated by downregulating two distinct phosphatase activities of PTEN[J]. J Neurosci, 2004, 24(16):4052-4060.

[11] Neil R Sims, Hakan Muyderman. Mitochondria, oxidative metabolism and cell death in stroke[J]. Biochimica et Biophysica Acta, 2010, 1802 (1): 80-91.

[12] Zhao Heng, Midori A Yenari, Cheng Dan-ye, et al. Bcl-2 transfection via herpes simplex virus blocks apoptosis-inducing factor translocation after focal ischemia in the rat[J]. J Cereb Blood Flow Metab, 2004, 24(6): 681-692.

[13] Armelle A Troussard, Paul C McDonald, Elizabeth D Wederell, et al. Preferential dependence of breast cancer cells versus normal cells on integrin-linked kinase for protein kinase B/Akt activation and cell survival[J]. Cancer Res, 2006, 66(1): 393-403.

[14] Marco Falasca. PI3K/Akt signalling pathway specific inhibitors: a novel strategy to sensitize cancer cells to anti-cancer drugs[J]. Curr Pharm Des, 2010, 16(12): 1410-1416.

[15] Gernot Hahne, Tom N. Grossmann. Direct targeting of b-catenin: Inhibition of protein–protein interactions for the inactivation of Wnt signaling[J]. Bioorg Medicin Chem, 2013, 21 (14): 4020- 4026.

[16] Koji Osuka, Yasuo Watanabe, Nobuteru Usuda, et al. Modification of endothelial NO synthase through protein phosphorylation after forebrain cerebral ischemia/reperfusion[J]. Stroke, 2004, 35(11): 2582-2586.

[17] Miho Nakano, Kenichi Osada, Atsushi Misonoo, et al. Fluvoxamine and sigma-1 receptor agonists dehydroepiandrosterone (DHEA)-sulfate induces the Ser473- phosphorylation of Akt-1 in PC12 cells[J]. Life Sci, 2010, 86 (9-10): 309-314.

[18] Zhao Heng, Robert M Sapolsky, Gary K Steinberg. Phosphoinositide-3-kinase/Akt survival signal pathways are implicated in neuronal survival after stroke[J]. Mol Neurobiol, 2006, 34(3): 249-269.

[19] Barbara Zablocka, Joanna Duzniewska, Halina Zajac, et al. Opposite reaction of ERK and JNK in ischemia vulnerable and resistant regions of hippocampus: involvement of mitochondria[J]. Mol Brain Res, 2003, 110(2): 245-252.

[20] Tetsuyuki Yoshimoto, Hiroyuki Uchino, Qing P He, et al. Cyclosporin A, but not FK506, prevents the downregulation of phosphorylated Akt after transient focal ischemia in the rat[J]. Brain Res, 2001, 899(1-2): 148-158.

[21] M Gao, J Liang, Y Lu, et al. Site-specific activation of AKT protects cells from death induced by glucose deprivation[J]. Oncogene, 2013; doi: 10.1038/ onc. 2013.2.

[22] Chih-Hao Su, Cheng-Yi Wang, Keng-Hsin Lan, et al. Akt phosphorylation at Thr308 and Ser473 is required for CHIP-mediated ubiquitination of the kinase[J]. Cellular Signalling, 2011, 23(11): 1824-1830.

[23] Hisashi Kitagawa, Hitoshi Warita, Chihoko Sasaki, et al. Immunoreactive Akt, PI3-K and ERK protein kinase expression in ischemic rat brain[J]. Neurosci Lett, 1999, 274(1): 45-48.

[24] Hu Jun, Chai Yu-shuang, Wang Yu-gang, et al. PI3K p55γ promoter activity enhancement is involved in the anti-apoptotic effect of berberine against cerebral ischemia–reperfusion[J]. Eur J Pharmacol, 2012, 674 (2-3): 132-142.

[25] Chai Yu-shuang, Hu Jun, Lei Fan, et al. Effect of berberine on cell cycle arrest and cell survival during cerebral ischemia and reperfusion and correlations with p53/cyclin D1 and PI3K/Akt[J]. Eur J Pharmacol, 2013, 708(1-3): 44-55.

[26] K L Jin, X O Mao, T Nagayama, et al. Induction of vascular endothelial growth factor receptors and phosphatidylinositol 3'-kinase/Akt signaling by global cerebral ischemia in the rat[J]. Neuroscience, 2000, 100(4): 713-717.

[27] Wei Cui, Li Wen-ming, Han Ren-wen, et al. PI3-K/Akt and ERK pathways activated by VEGF play opposite roles in MPP+-induced neuronal apoptosis[J]. Neurochem Intern, 2011, 59(6): 945- 953.

[28] Christophc Bonny, Tiziana Borsello, Azel Zine. Targeting the JNK pathway as a therapeutic protective strategy for nervous system diseases[J]. Rev Neurosci, 2005, 16(1): 57-67.

[29] Qi Da-shi, Liu Hong-zhi, Niu Jian, et al. Heat shock protein 72 inhibits c-Jun N-terminal kinase 3 signaling pathway via Akt1 during cerebral ischemia[J]. J Neurol Sci, 2012, 317(1-2): 123-129.

[30] Charleen T Chu, David J Levinthal, Scott M Kulich, et al. Oxidative neuronal injury - The dark side of ERK1/2[J]. Eur J Biochem, 2004, 271(11): 2060-2066.

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

[32] Alexey Goltsov, Dana Faratian, Simon P Langdon, et al. Compensatory effects in the PI3K/PTEN/ AKT signaling network following receptor tyrosine kinase inhibition [J]. Cellular Signalling, 2011, 23 (2): 407-416.

[33] Takayuki Kawano, Motohiro Morioka, Shigetoshi Yano, et al. Decreased Akt activity is associated with activation of forkhead transcription factor after transient forebrain ischemia in gerbil hippocampus[J]. J Cereb Blood Flow Metab, 2002, 22(8): 926-934.

[34] L S Ling, D Voskas, J R Woodgett. Activation of PDK-1 maintains mouse embryonic stem cell self-renewal in a PKB-dependent manner[J]. Oncogene, 2013, 32(3): 5397-5408.

[35] Marjelo A Mines, Richard S Jope. Brain region differences in regulation of Akt and GSK3 by chronic stimulant administration in mice[J]. Cellular Signalling, 2012, 24(7): 1398-1405.

[36] B Friguls, C Justicia, M Pallas, et al. Focal cerebral ischemia causes two temporal waves of Akt activation[J]. Neuroreport, 2001, 12(15): 3381- 3384.

[37] Age Aleksander Skjevik, Mauro Mileni, Anne Baumann, et al. The N-Terminal sequence of tyrosine hydroxylase is a conformationally versatile motif that binds 14-3-3 proteins and membranes[J]. J Mol Biol, 2014, 426(1): 150-168.

[38] Atsushi Saito, Takeshi Hayashi, Shuzo Okuno, et al. Modulation of proline-rich Akt substrate survival signaling pathways by oxidative stress in mouse brains after transient focal cerebral ischemia[J]. Stroke, 2006, 37(2): 513-517.

[39] Juan-Hua Quan, Guang-Ho Cha, Wei Zhou, et al. Involvement of PI3 kinase/Akt-dependent Bad phosphorylation in Toxoplasma gondii-mediated inhibition of host cell apoptosis[J]. Exp Parasitol, 2013, 133(4): 462-471.

[40] Xie Rong, Cheng Michelle, Li Mei, et al. Akt isoforms differentially protect against stroke-induced neuronal injury by regulating mTOR activities[J]. J Cereb Blood Flow Metab, 2013, 33 (12): 1875-1885.

[41] Magda Guerra-Crespo, Andres Sistos, Darius Gleason, et al. Intranasal administration of PEGylated transforming growth factor-a improves behavioral deficits in a chronic stroke model[J]. J Stroke Cereb Diseases, 2010, 19(1): 3-9.

[42] Lin-hui Ruan, Benson Wui-Man Lau, Jixian Wang, et al. Neurogenesis in neurological and psychiatric diseases and brain 3 injury: From bench to bedside[J]. Prog Neurobiol, 2013, http://dx.doi.org/10.1016/j. pneurobio.2013.12.006.

[43] Katarina G Brywe, Carina Mallard, Malin Gustavsson, et al. IGF-I neuroprotection in the immature brain after hypoxia-ischemia, involvement of Akt and GSK3 beta[J]. Eur J Neurosci, 2005, 21(6): 1489-1502.

[44] Luo You-gen, Yang Xi-fei, Zhao Shen-ting, et al. Hydrogen sulfide prevents OGD/R-induced apoptosis via improving mitochondrial dysfunction and suppressing an ROS-mediated caspase-3 pathway in cortical neurons[J]. Neurochem Int, 2013, 63(8): 826- 831.

[45] Pearl Chang, Elise Cheng, Brooke Shelia, et al. Marked differences in the efficacy of post-insult gene therapy with catalase versus glutathione peroxidase[J]. Brain Res, 2005, 1063(1): 27-31.

[46] Yan Qiao, Qisen Xiang, Li Yuan, et al. Herbacetin induces apoptosis in HepG2 cells: Involvements of ROS and PI3K/Akt pathway[J]. Food Chem Toxicol, 2013, 51(1): 426-433.

[47] Kilic U, Kilic E, Reiter RJ, et al. Signal transduction pathways involved in melatonin-induced neuroprotection after focal cerebral ischemia in mice[J]. J Pineal Res, 2005, 38(1): 67-71.

[48] R Mehra, M K Varshney, K Felszeghy, et al. An overview into the role of estrogen in hippocampal synaptic plasticity and neuroprotection[J]. Acta Physiol Hung, 2010, 97(1): 122-123.

[49] Joachim G Elzer, Sajjad Muhammad, Tim M Wintermantel, et al. Neuronal estrogen receptor-alpha mediates neuroprotection by 17 beta-estradiol[J]. J Cereb Blood Flow Metab, 2010, 30(5): 935-942.

[50] Melinda E Wilson, Liu Ying, Phyllis M Wise. Estradiol enhances Akt activation in cortical explant cultures following neuronal injury[J]. Mol Brain Res, 2002, 102(1-2): 48-54.

[51] Chung Kil Won, Seung Jun Ha, Hae Sook Noh, et al. Estradiol prevents the injury-induced decrease of Akt activation and Bad phosphorylation[J]. Neurosci Lett, 2005, 387(2): 115-119.

[52] Yeoung Cheul Choi, Jeong Hyun Lee, Ki Whan Hong, et al. 17 beta-estradiol prevents focal cerebral ischemic damages via activation of Akt and CREB in association with reduced PTEN phosphorylation in rats[J]. Fundam Clin Pharmacol, 2004, 18(5): 547-557.

[53] Cheng-Hsing Kao, Chih-Zen Chang, Yu-Feng Su, et al. 17beta-Estradiol attenuates secondary injury through activation of Akt signaling via estrogen receptor alpha in rat brain following subarachnoid hemorrhage[J]. J Surg Res, 2013, 18 (1): e23- e30.

[54] Ted Weita Lai, Shu Zhang, Yu Tian Wang. Excitotoxicity and stroke: Identifying novel targets for neuroprotection[J]. Prog Neurobiol, 2013, Doi:10.1016/j. pneurobio. 2013.11. 006

[55] Yu Hasegawa, Jun-Ichiro Hamada, Motohiro Morioka, et al. Neuroprotective effect of postischemic administration of sodium orthovanadate in rats with transient middle cerebral artery occlusion[J]. J Cereb Blood Flow Metab, 2003, 23(9): 1040-1051.

[56] Yasushi Takagi, Jun Harada, Alberto Chiarugi, et al. STAT1 is activated in neurons after ischemia and contributes to ischemic brain injury[J]. J Cereb Blood Flow Metab, 2002, 22(11): 1311-1318.

[57] Robert Meller, Susan L Stevens, Manabu Minami, et al. Neuroprotection by osteopontin in stroke[J]. J Cereb Blood Flow Metab, 2005, 25(2): 217-225.

[58] Wang Ying-yi, Wei Yan, Lu Xiao-ming, et al. Overexpression of osteopontin induces angiogenesis of endothelial progenitor cells via the avβ3/PI3K/AKT/eNOS/NO signaling pathway in glioma cells[J]. Eur J Cell Biol, 2011, 90(8): 642-648.

[59] Bozena Gabryel, Anna Pudelko, Andrizej Malecki. Erk1/2 and Akt kinases are involved in the protective effect of aniracetam in astrocytes subjected to simulated ischemia in vitro[J]. Eur J Pharmacol, 2004, 494(2-3): 111-120.

[60] Seong Ho Koh, Younjoo Park, Chi Won Song, et al. The effect of PARP inhibitor on ischaemic cell death, its related inflammation and survival signals[J]. Eur J Neurosci, 2004, 20(6): 1461-1472.

[61] Miao-Kun Sun, Daniel L Alkon. Pharmacology of protein kinase C activators: Cognition-enhancing and antidementic therapeutics[J]. Pharmacol Ther, 2010, 127(1): 66-77.

[62] Lin Hung-wei, R Anthony DeFazio, D Della-Morte, et al. Derangements of post-ischemic cerebral blood flow by protein kinase C delta[J]. Neuroscience, 2010, 171(2): 566-576.