Neuroscience Bulletin

, Volume 28, Issue 5, pp 658–666 | Cite as

Neuronal autophagy in cerebral ischemia

Review

Abstract

Autophagy has evolved as a conserved process for the bulk degradation and recycling of cytosolic components, such as long-lived proteins and organelles. In neurons, autophagy is important for homeostasis and protein quality control and is maintained at relatively low levels under normal conditions, while it is upregulated in response to pathophysiological conditions, such as cerebral ischemic injury. However, the role of autophagy is more complex. It depends on age or brain maturity, region, severity of insult, and the stage of ischemia. Whether autophagy plays a beneficial or a detrimental role in cerebral ischemia depends on various pathological conditions. In this review, we elucidate the role of neuronal autophagy in cerebral ischemia.

Keywords

autophagy cerebral ischemia neuron apoptosis necrosis 

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References

  1. [1]
    Kunz JB, Schwarz H, Mayer A. Determination of four sequential stages during microautophagy in vitro. J Biol Chem 2004, 279: 9987–9996.PubMedCrossRefGoogle Scholar
  2. [2]
    Dice JF. Chaperone-mediated autophagy. Autophagy 2007, 3: 295–299.PubMedGoogle Scholar
  3. [3]
    Mizushima N, Levine B, Cuervo AM, Klionsky DJ. Autophagy fights disease through cellular self-digestion. Nature 2008, 451: 1069–1075.PubMedCrossRefGoogle Scholar
  4. [4]
    Klionsky DJ. Autophagy: from phenomenology to molecular understanding in less than a decade. Nat Rev Mol Cell Biol 2007, 8: 931–937.PubMedCrossRefGoogle Scholar
  5. [5]
    Rubinsztein DC, Gestwicki JE, Murphy LO, Klionsky DJ. Potential therapeutic applications of autophagy. Nat Rev Drug Discov 2007, 6: 304–312.PubMedCrossRefGoogle Scholar
  6. [6]
    Wong E, Cuervo AM. Autophagy gone awry in neurodegenerative diseases. Nat Neurosci 2010, 13: 805–811.PubMedCrossRefGoogle Scholar
  7. [7]
    Nixon RA. Autophagy in neurodegenerative disease: friend, foe or turncoat? Trends Neurosci 2006, 29: 528–535.PubMedCrossRefGoogle Scholar
  8. [8]
    Marino G, Madeo F, Kroemer G. Autophagy for tissue homeostasis and neuroprotection. Curr Opin Cell Biol 2011, 23: 198–206.PubMedCrossRefGoogle Scholar
  9. [9]
    Banerjee R, Beal MF, Thomas B. Autophagy in neurodegenerative disorders: pathogenic roles and therapeutic implications. Trends Neurosci 2010, 33: 541–549.PubMedCrossRefGoogle Scholar
  10. [10]
    Zhu C, Wang X, Xu F, Bahr BA, Shibata M, Uchiyama Y, et al. The influence of age on apoptotic and other mechanisms of cell death after cerebral hypoxia-ischemia. Cell Death Differ 2005, 12: 162–176.PubMedCrossRefGoogle Scholar
  11. [11]
    Zhu C, Xu F, Wang X, Shibata M, Uchiyama Y, Blomgren K, et al. Different apoptotic mechanisms are activated in male and female brains after neonatal hypoxia-ischaemia. J Neurochem 2006, 96: 1016–1027.PubMedCrossRefGoogle Scholar
  12. [12]
    Adhami F, Liao G, Morozov YM, Schloemer A, Schmithorst VJ, Lorenz JN, et al. Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy. Am J Pathol 2006, 169: 566–583.PubMedCrossRefGoogle Scholar
  13. [13]
    Adhami F, Schloemer A, Kuan CY. The roles of autophagy in cerebral ischemia. Autophagy 2007, 3: 42–44.PubMedGoogle Scholar
  14. [14]
    Koike M, Shibata M, Tadakoshi M, Gotoh K, Komatsu M, Waguri S, et al. Inhibition of autophagy prevents hippocampal pyramidal neuron death after hypoxic-ischemic injury. Am J Pathol 2008, 172: 454–469.PubMedCrossRefGoogle Scholar
  15. [15]
    Chu CT. Eaten alive: autophagy and neuronal cell death after hypoxia-ischemia. Am J Pathol 2008, 172: 284–287.PubMedCrossRefGoogle Scholar
  16. [16]
    Uchiyama Y, Koike M, Shibata M. Autophagic neuron death in neonatal brain ischemia/hypoxia. Autophagy 2008, 4: 404–408.PubMedGoogle Scholar
  17. [17]
    Carloni S, Buonocore G, Balduini W. Protective role of autophagy in neonatal hypoxia-ischemia induced brain injury. Neurobiol Dis 2008, 32: 329–339.PubMedCrossRefGoogle Scholar
  18. [18]
    Balduini W, Carloni S, Buonocore G. Autophagy in hypoxia-ischemia induced brain injury: evidence and speculations. Autophagy 2009, 5: 221–223.PubMedCrossRefGoogle Scholar
  19. [19]
    Ginet V, Puyal J, Clarke PG, Truttmann AC. Enhancement of autophagic flux after neonatal cerebral hypoxia-ischemia and its region-specific relationship to apoptotic mechanisms. Am J Pathol 2009, 175: 1962–1974.PubMedCrossRefGoogle Scholar
  20. [20]
    Nitatori T, Sato N, Waguri S, Karasawa Y, Araki H, Shibanai K, et al. Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis. J Neurosci 1995, 15: 1001–1011.PubMedGoogle Scholar
  21. [21]
    Wang JY, Xia Q, Chu KT, Pan J, Sun LN, Zeng B, et al. Severe global cerebral ischemia-induced programmed necrosis of hippocampal CA1 neurons in rat is prevented by 3-methyladenine: a widely used inhibitor of autophagy. J Neuropathol Exp Neurol 2011, 70: 314–322.PubMedCrossRefGoogle Scholar
  22. [22]
    Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N, et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 2005, 1: 112–119.PubMedCrossRefGoogle Scholar
  23. [23]
    Rami A, Langhagen A, Steiger S. Focal cerebral ischemia induces upregulation of Beclin 1 and autophagy-like cell death. Neurobiol Dis 2008, 29: 132–141.PubMedCrossRefGoogle Scholar
  24. [24]
    Rami A. Upregulation of Beclin 1 in the ischemic penumbra. Autophagy 2008, 4: 227–229.PubMedGoogle Scholar
  25. [25]
    Rami A, Kogel D. Apoptosis meets autophagy-like cell death in the ischemic penumbra: Two sides of the same coin? Autophagy 2008, 4: 422–426.PubMedGoogle Scholar
  26. [26]
    Wen YD, Sheng R, Zhang LS, Han R, Zhang X, Zhang XD, et al. Neuronal injury in rat model of permanent focal cerebral ischemia is associated with activation of autophagic and lysosomal pathways. Autophagy 2008, 4: 762–769.PubMedGoogle Scholar
  27. [27]
    Puyal J, Vaslin A, Mottier V, Clarke PG. Postischemic treatment of neonatal cerebral ischemia should target autophagy. Ann Neurol 2009, 66: 378–389.PubMedCrossRefGoogle Scholar
  28. [28]
    Puyal J, Clarke PG. Targeting autophagy to prevent neonatal stroke damage. Autophagy 2009, 5: 1060–1061.PubMedCrossRefGoogle Scholar
  29. [29]
    Liu C, Gao Y, Barrett J, Hu B. Autophagy and protein aggregation after brain ischemia. J Neurochem 2010, 115: 68–78.PubMedCrossRefGoogle Scholar
  30. [30]
    Zheng YQ, Liu JX, Li XZ, Xu L, Xu YG. RNA interference-mediated downregulation of Beclin1 attenuates cerebral ischemic injury in rats. Acta Pharmacol Sin 2009, 30: 919–927.PubMedCrossRefGoogle Scholar
  31. [31]
    Chen Y, Klionsky DJ. The regulation of autophagy — unanswered questions. J Cell Sci 2011, 124: 161–170.PubMedCrossRefGoogle Scholar
  32. [32]
    Jung CH, Jun CB, Ro SH, Kim YM, Otto NM, Cao J, et al. ULKAtg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery. Mol Biol Cell 2009, 20: 1992–2003.PubMedCrossRefGoogle Scholar
  33. [33]
    Ganley IG, Lam du H, Wang J, Ding X, Chen S, Jiang X. ULK1. ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem 2009, 284: 12297–12305.PubMedCrossRefGoogle Scholar
  34. [34]
    Hosokawa N, Hara T, Kaizuka T, Kishi C, Takamura A, Miura Y, et al. Nutrient-dependent mTORC1 association with the ULK1-Atg13-FIP200 complex required for autophagy. Mol Biol Cell 2009, 20: 1981–1991.PubMedCrossRefGoogle Scholar
  35. [35]
    Mercer CA, Kaliappan A, Dennis PB. A novel, human Atg13 binding protein, Atg101, interacts with ULK1 and is essential for macroautophagy. Autophagy 2009, 5: 649–662.PubMedCrossRefGoogle Scholar
  36. [36]
    Funderburk SF, Wang QJ, Yue Z. The Beclin 1-VPS34 complex—at the crossroads of autophagy and beyond. Trends Cell Biol 2010, 20: 355–362.PubMedCrossRefGoogle Scholar
  37. [37]
    Yang Z, Klionsky DJ. Mammalian autophagy: core molecular machinery and signaling regulation. Curr Opin Cell Biol 2010, 22: 124–131.PubMedCrossRefGoogle Scholar
  38. [38]
    Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N, et al. Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 2009, 11: 385–396.PubMedCrossRefGoogle Scholar
  39. [39]
    Zhong Y, Wang QJ, Li X, Yan Y, Backer JM, Chait BT, et al. Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex. Nat Cell Biol 2009, 11: 468–476.PubMedCrossRefGoogle Scholar
  40. [40]
    Di Bartolomeo S, Corazzari M, Nazio F, Oliverio S, Lisi G, Antonioli M, et al. The dynamic interaction of AMBRA1 with the dynein motor complex regulates mammalian autophagy. J Cell Biol 2010, 191: 155–168.PubMedCrossRefGoogle Scholar
  41. [41]
    Fimia GM, Stoykova A, Romagnoli A, Giunta L, Di Bartolomeo S, Nardacci R, et al. Ambra1 regulates autophagy and development of the nervous system. Nature 2007, 447: 1121–1125.PubMedGoogle Scholar
  42. [42]
    Liang C, Lee JS, Inn KS, Gack MU, Li Q, Roberts EA, et al. Beclin1-binding UVRAG targets the class C Vps complex to coordinate autophagosome maturation and endocytic trafficking. Nat Cell Biol 2008, 10: 776–787.PubMedCrossRefGoogle Scholar
  43. [43]
    Takahashi Y, Coppola D, Matsushita N, Cualing HD, Sun M, Sato Y, et al. Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol 2007, 9: 1142–1151.PubMedCrossRefGoogle Scholar
  44. [44]
    Ohsumi Y. Molecular dissection of autophagy: two ubiquitin-like systems. Nat Rev Mol Cell Biol 2001, 2: 211–216.PubMedCrossRefGoogle Scholar
  45. [45]
    Geng J, Klionsky DJ. The Atg8 and Atg12 ubiquitin-like conjugation systems in macroautophagy.’ Protein modifications: beyond the usual suspects’ review series. EMBO Rep 2008, 9: 859–864.PubMedCrossRefGoogle Scholar
  46. [46]
    Fujita N, Itoh T, Omori H, Fukuda M, Noda T, Yoshimori T. The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol Biol Cell 2008, 19: 2092–2100.PubMedCrossRefGoogle Scholar
  47. [47]
    Hanada T, Noda NN, Satomi Y, Ichimura Y, Fujioka Y, Takao T, et al. The Atg12-Atg5 conjugate has a novel E3-like activity for protein lipidation in autophagy. J Biol Chem 2007, 282: 37298–37302.PubMedCrossRefGoogle Scholar
  48. [48]
    Jager S, Bucci C, Tanida I, Ueno T, Kominami E, Saftig P, et al. Role for Rab7 in maturation of late autophagic vacuoles. J Cell Sci 2004, 117: 4837–4848.PubMedCrossRefGoogle Scholar
  49. [49]
    Tanaka Y, Guhde G, Suter A, Eskelinen EL, Hartmann D, Lullmann-Rauch R, et al. Accumulation of autophagic vacuoles and cardiomyopathy in LAMP-2-deficient mice. Nature 2000, 406: 902–906.PubMedCrossRefGoogle Scholar
  50. [50]
    Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell 2004, 15: 1101–1111.PubMedCrossRefGoogle Scholar
  51. [51]
    Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature 2006, 441: 885–889.PubMedCrossRefGoogle Scholar
  52. [52]
    Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I, et al. Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature 2006, 441: 880–884.PubMedCrossRefGoogle Scholar
  53. [53]
    Komatsu M, Wang QJ, Holstein GR, Friedrich VL Jr, Iwata J, Kominami E, et al. Essential role for autophagy protein Atg7 in the maintenance of axonal homeostasis and the prevention of axonal degeneration. Proc Natl Acad Sci U S A 2007, 104: 14489–14494.PubMedCrossRefGoogle Scholar
  54. [54]
    Wang QJ, Ding Y, Kohtz DS, Mizushima N, Cristea IM, Rout MP, et al. Induction of autophagy in axonal dystrophy and degeneration. J Neurosci 2006, 26: 8057–8068.PubMedCrossRefGoogle Scholar
  55. [55]
    Rabinowitz JD, White E. Autophagy and metabolism. Science 2010, 330: 1344–1348.PubMedCrossRefGoogle Scholar
  56. [56]
    He C, Klionsky DJ. Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet 2009, 43: 67–93.PubMedCrossRefGoogle Scholar
  57. [57]
    Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell 2000, 103: 253–262.PubMedCrossRefGoogle Scholar
  58. [58]
    Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 1997, 7: 261–269.PubMedCrossRefGoogle Scholar
  59. [59]
    Stokoe D, Stephens LR, Copeland T, Gaffney PR, Reese CB, Painter GF, et al. Dual role of phosphatidylinositol-3,4,5-trisphosphate in the activation of protein kinase B. Science 1997, 277: 567–570.PubMedCrossRefGoogle Scholar
  60. [60]
    Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell 2003, 115: 577–590.PubMedCrossRefGoogle Scholar
  61. [61]
    Manning BD, Tee AR, Logsdon MN, Blenis J, Cantley LC. Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway. Mol Cell 2002, 10: 151–162.PubMedCrossRefGoogle Scholar
  62. [62]
    Long X, Lin Y, Ortiz-Vega S, Yonezawa K, Avruch J. Rheb binds and regulates the mTOR kinase. Curr Biol 2005, 15: 702–713.PubMedCrossRefGoogle Scholar
  63. [63]
    Carloni S, Girelli S, Scopa C, Buonocore G, Longini M, Balduini W. Activation of autophagy and Akt/CREB signaling play an equivalent role in the neuroprotective effect of rapamycin in neonatal hypoxia-ischemia. Autophagy 2010, 6: 366–377.PubMedCrossRefGoogle Scholar
  64. [64]
    Liang J, Shao SH, Xu ZX, Hennessy B, Ding Z, Larrea M, et al. The energy sensing LKB1-AMPK pathway regulates p27(kip1) phosphorylation mediating the decision to enter autophagy or apoptosis. Nat Cell Biol 2007, 9: 218–224.PubMedCrossRefGoogle Scholar
  65. [65]
    Hoyer-Hansen M, Bastholm L, Szyniarowski P, Campanella M, Szabadkai G, Farkas T, et al. Control of macroautophagy by calcium, calmodulin-dependent kinase kinase-beta, and Bcl-2. Mol Cell 2007, 25: 193–205.PubMedCrossRefGoogle Scholar
  66. [66]
    Wang P, Guan YF, Du H, Zhai QW, Su DF, Miao CY. Induction of autophagy contributes to the neuroprotection of nicotinamide phosphoribosyltransferase in cerebral ischemia. Autophagy 2012, 8: 77–87.PubMedCrossRefGoogle Scholar
  67. [67]
    Oberstein A, Jeffrey PD, Shi Y. Crystal structure of the Bcl-XLBeclin 1 peptide complex: Beclin 1 is a novel BH3-only protein. J Biol Chem 2007, 282: 13123–13132.PubMedCrossRefGoogle Scholar
  68. [68]
    Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell 2005, 122: 927–939.PubMedCrossRefGoogle Scholar
  69. [69]
    He C, Levine B. The Beclin 1 interactome. Curr Opin Cell Biol 2010, 22: 140–149.PubMedCrossRefGoogle Scholar
  70. [70]
    Maiuri MC, Criollo A, Kroemer G. Crosstalk between apoptosis and autophagy within the Beclin 1 interactome. EMBO J 2010, 29: 515–516.PubMedCrossRefGoogle Scholar
  71. [71]
    Matsui Y, Takagi H, Qu X, Abdellatif M, Sakoda H, Asano T, et al. Distinct roles of autophagy in the heart during ischemia and reperfusion: roles of AMP-activated protein kinase and Beclin 1 in mediating autophagy. Circ Res 2007, 100: 914–922.PubMedCrossRefGoogle Scholar
  72. [72]
    Kang R, Zeh HJ, Lotze MT, Tang D. The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ 2011, 18: 571–580.PubMedCrossRefGoogle Scholar
  73. [73]
    Xin XY, Pan J, Wang XQ, Ma JF, Ding JQ, Yang GY, et al. 2-methoxyestradiol attenuates autophagy activation after global ischemia. Can J Neurol Sci 2011, 38: 631–638.PubMedGoogle Scholar
  74. [74]
    Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, et al. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 2008, 283: 10892–10903.PubMedCrossRefGoogle Scholar
  75. [75]
    Maiuri MC, Le Toumelin G, Criollo A, Rain JC, Gautier F, Juin P, et al. Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J 2007, 26: 2527–2539.PubMedCrossRefGoogle Scholar
  76. [76]
    Banasiak KJ, Haddad GG. Hypoxia-induced apoptosis: effect of hypoxic severity and role of p53 in neuronal cell death. Brain Res 1998, 797: 295–304.PubMedCrossRefGoogle Scholar
  77. [77]
    Crighton D, Wilkinson S, O’Prey J, Syed N, Smith P, Harrison PR, et al. DRAM, a p53-induced modulator of autophagy, is critical for apoptosis. Cell 2006, 126: 121–134.PubMedCrossRefGoogle Scholar
  78. [78]
    Zhang XD, Wang Y, Zhang X, Han R, Wu JC, Liang ZQ, et al. p53 mediates mitochondria dysfunction-triggered autophagy activation and cell death in rat striatum. Autophagy 2009, 5: 339–350.PubMedCrossRefGoogle Scholar
  79. [79]
    Wang Y, Dong XX, Cao Y, Liang ZQ, Han R, Wu JC, et al. p53 induction contributes to excitotoxic neuronal death in rat striatum through apoptotic and autophagic mechanisms. Eur J Neurosci 2009, 30: 2258–2270.PubMedCrossRefGoogle Scholar
  80. [80]
    Wu YT, Tan HL, Shui G, Bauvy C, Huang Q, Wenk MR, et al. Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase. J Biol Chem 2010, 285: 10850–10861.PubMedCrossRefGoogle Scholar
  81. [81]
    Sheng R, Zhang LS, Han R, Liu XQ, Gao B, Qin ZH. Autophagy activation is associated with neuroprotection in a rat model of focal cerebral ischemic preconditioning. Autophagy 2010, 6: 482–494.CrossRefGoogle Scholar
  82. [82]
    Northington FJ, Chavez-Valdez R, Martin LJ. Neuronal cell death in neonatal hypoxia-ischemia. Ann Neurol 2011, 69: 743–758.PubMedCrossRefGoogle Scholar
  83. [83]
    Puyal J, Ginet V, Grishchuk Y, Truttmann AC, Clarke PG. Neuronal autophagy as a mediator of life and death: contrasting roles in chronic neurodegenerative and acute neural disorders. Neuroscientist 2012, 18: 224–236.PubMedCrossRefGoogle Scholar
  84. [84]
    Carloni S, Carnevali A, Cimino M, Balduini W. Extended role of necrotic cell death after hypoxia-ischemia-induced neurodegeneration in the neonatal rat. Neurobiol Dis 2007, 27: 354–361.PubMedCrossRefGoogle Scholar
  85. [85]
    Northington FJ, Zelaya ME, O’Riordan DP, Blomgren K, Flock DL, Hagberg H, et al. Failure to complete apoptosis following neonatal hypoxia-ischemia manifests as „continuum“ phenotype of cell death and occurs with multiple manifestations of mitochondrial dysfunction in rodent forebrain. Neuroscience 2007, 149: 822–833.PubMedCrossRefGoogle Scholar
  86. [86]
    Portera-Cailliau C, Price DL, Martin LJ. Excitotoxic neuronal death in the immature brain is an apoptosis-necrosis morphological continuum. J Comp Neurol 1997, 378: 70–87.PubMedGoogle Scholar
  87. [87]
    Nakajima W, Ishida A, Lange MS, Gabrielson KL, Wilson MA, Martin LJ, et al. Apoptosis has a prolonged role in the neurodegeneration after hypoxic ischemia in the newborn rat. J Neurosci 2000, 20: 7994–8004.PubMedGoogle Scholar
  88. [88]
    Sheldon RA, Hall JJ, Noble LJ, Ferriero DM. Delayed cell death in neonatal mouse hippocampus from hypoxia-ischemia is neither apoptotic nor necrotic. Neurosci Lett 2001, 304: 165–168.PubMedCrossRefGoogle Scholar
  89. [89]
    Grishchuk Y, Ginet V, Truttmann AC, Clarke PG, Puyal J. Beclin 1-independent autophagy contributes to apoptosis in cortical neurons. Autophagy 2011, 7: 1115–1131.PubMedCrossRefGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  1. 1.Department of Neurosurgery, Huashan HospitalFudan UniversityShanghaiChina
  2. 2.Department of PharmacologyNantong University School of MedicineNantongChina
  3. 3.Department of Pharmacology and Laboratory of Aging and Nervous DiseasesSoochow University School of Pharmaceutical ScienceSuzhouChina

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