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The mechanisms of brain ischemic insult and potential protective interventions

脑缺血的损伤机制及其保护性干预

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Abstract

The mechanisms of brain ischemic insult include glutamate excitoxicity, calcium toxicity, free radicals, nitric oxide, inflammatory reactions, as well as dysfunctions of endoplasmic reticulum and mitochondrion. These injury cascades are interconnected in complex ways, thus it is hard to compare their pathogenic importances in ischemia models. And the research in cellular and molecular pathways has spurred the studies in potential neuroprotections mainly in pharmacological fields, such as anti-excitotoxic treatment, calcium-channel antagonism, approaches for inhibition of oxidation, inflammation and apoptosis, etc. Besides, other protective interventions including thrombolysis, arteriogenesis, regeneration therapy, and ischemia preconditioning or postconditioning, are also under investigations. Despite the present difficulties, we are quite optimistic towards future clinical applications of neuroprotective agents, by optimizing experimental approaches and clinical trials.

摘要

脑缺血的损伤机制包括谷氨酸兴奋毒性、 钙毒性、 自由基、 一氧化氮、 炎性反应以及内质网和线粒体功能障碍等。 这些损伤性级联反应相互联系, 错综复杂, 很难比较它们在不同模型中的主次作用。 越来越多的对细胞及分子损伤途径的基础研究, 推动了对脑保护治疗的研究。 迄今为止, 脑保护治疗仍以药物治疗为主, 例如, 抗兴奋毒性治疗、 钙通道阻滞、 抗氧化、 抗炎、 抗凋亡治疗等。 此外一些研究还包括溶栓、 动脉生成和神经元再生, 以及缺血前适应和缺血后适应等。 虽然将这些研究成果应用于临床还存在许多困难, 但是通过改进动物实验和临床实验方法, 我们有理由对脑保护治疗持乐观的态度。

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References

  1. Ginsberg MD. Adventures in the pathophysiology of brain ischemia: penumbra, gene expression, neuroprotection: the 2002 Thomas Willis Lecture. Stroke 2003, 34(1): 214–223.

    Article  PubMed  Google Scholar 

  2. Heiss WD, Kracht LW, Thiel A, Grond M, Pawlik G. Penumbral probability thresholds of cortical flumazenil binding and blood flow predicting tissue outcome in patients with cerebral ischaemia. Brain 2001, 124(Pt 1): 20–29.

    Article  PubMed  CAS  Google Scholar 

  3. Hossmann KA. Pathophysiology and therapy of experimental stroke. Cell Mol Neurobiol 2006, 26(7–8): 1057–1083.

    PubMed  Google Scholar 

  4. Ginsberg MD. The New Language of Cerebral Ischemia. Am J Neuroradiol 1997, 18(8): 1435–1445.

    PubMed  CAS  Google Scholar 

  5. Mehta SL, Manhas N, Raghubir R. Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev 2007, 54(1): 34–66.

    Article  PubMed  CAS  Google Scholar 

  6. Kristián T, Siesjö BK. Calcium in ischemic cell death. Stroke 1998, 29(3): 705–718.

    PubMed  Google Scholar 

  7. Chen M, Lu TJ, Chen XJ, Zhou Y, Chen Q, Feng XY, et al. Differential roles of NMDA receptor subtypes in ischemic neuronal cell death and ischemic tolerance. Stroke 2008, 39(11): 3042–3048.

    Article  PubMed  CAS  Google Scholar 

  8. Berridge MJ. Cell signalling. A tale of two messengers. Nature 1993, 365(6445): 388–389.

    Article  PubMed  CAS  Google Scholar 

  9. Paschen W. Disturbances of calcium homeostasis within the endoplasmic reticulum may contribute to the development of ischemic-cell damage. Med Hypotheses 1996, 47(4): 283–288.

    Article  PubMed  CAS  Google Scholar 

  10. Sugimoto K, Iadecola C. Delayed effect of administration of COX-2 inhibitor in mice with acute cerebral ischemia. Brain Res 2003, 960(1–2): 273–276.

    Article  PubMed  CAS  Google Scholar 

  11. Iadecola C, Niwa K, Nogawa S, Zhao X, Nagayama M, Araki E, et al. Reduced susceptibility to ischemic brain injury and N-methyl-d-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice. Proc Natl Acad Sci USA 2001, 98(3): 1294–1299.

    Article  PubMed  CAS  Google Scholar 

  12. Xu X, Kim JA, Zuo Z. Isoflurane preconditioning reduces mouse microglial activation and injury induced by lipopolysaccharide and interferon-gamma. Neuroscience 2008, 154(3):1002–1008.

    Article  PubMed  CAS  Google Scholar 

  13. Tikka TM, Koistinaho JE. Minocycline provides neuroprotection against N-methyl-D-aspartate neurotoxicity by inhibiting microglia. J Immunol 2001, 166(12): 7527–7533.

    PubMed  CAS  Google Scholar 

  14. Swanson RA, Ying W, Kauppinen TM. Astrocyte influences on ischemic neuronal death. Curr Mol Med 2004, 4(2): 193–205.

    Article  PubMed  CAS  Google Scholar 

  15. Paschen W, Mengesdorf T. Endoplasmic reticulum stress response and neurodegeneration. Cell Calcium 2005, 38(3–4): 409–415.

    Article  PubMed  CAS  Google Scholar 

  16. Garaschuk O, Yaari Y, Konnerth A. Release and sequestration of calcium by ryanodine-sensitive stores in rat hippocampal neurones. J Physiol 1997, 502(Pt 1): 13–30.

    Article  PubMed  CAS  Google Scholar 

  17. Verkhratsky A. Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons. Physiol Rev 2005, 85(1): 201–279.

    Article  PubMed  CAS  Google Scholar 

  18. Kaufman RJ. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev 1999, 13(10): 1211–1233.

    Article  PubMed  CAS  Google Scholar 

  19. Paschen W, Mengesdorf T. Cellular abnormalities linked to endoplasmic reticulum dysfunction in cerebrovascular disease—therapeutic potential. Pharmacol Ther 2005, 108(3): 362–375.

    Article  PubMed  CAS  Google Scholar 

  20. Harding HP, Zhang Y, Ron D. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature 1999, 397(6716): 271–274.

    Article  PubMed  CAS  Google Scholar 

  21. Shen X, Ellis RE, Lee K, Liu CY, Yang K, Solomon A, et al. Complementary signaling pathways regulate the unfolded protein response and are required for C. elegans development. Cell 2001, 107(7): 893–903.

    Article  PubMed  CAS  Google Scholar 

  22. Yoshida H, Matsui T, Yamamoto A, Okada T, Mori K. XBP1 mRNA is induced by ATF6 and spliced by IRE1 in response to ER stress to produce a highly active transcription factor. Cell 2001, 107(7): 881–891.

    Article  PubMed  CAS  Google Scholar 

  23. Calfon M, Zeng H, Urano F, Till JH, Hubbard SR, Harding HP, et al. IRE1 couples endoplasmic reticulum load to secretory capacity by processing the XBP-1 mRNA. Nature 2002, 415(6867): 92–96.

    Article  PubMed  CAS  Google Scholar 

  24. Harding HP, Novoa I, Zhang Y, Zeng H, Wek R, Schapira M, et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell 2000, 6(5): 1099–1108.

    Article  PubMed  CAS  Google Scholar 

  25. Harding HP, Zhang Y, Zeng H, Novoa I, Lu PD, Calfon M, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell 2003, 11(3): 619–633.

    Article  PubMed  CAS  Google Scholar 

  26. Novoa I, Zeng H, Harding HP, Ron D. Feedback inhibition of the unfolded protein response by GADD34-mediated dephosphorylation of eIF2alpha. J Cell Biol 2001, 153(5): 1011–1022.

    Article  PubMed  CAS  Google Scholar 

  27. Luo S, Baumeister P, Yang S, Abcouwer SF, Lee AS. Induction of Grp78/BiP by translational block: activation of the Grp78 promoter by ATF4 through and upstream ATF/CRE site independent of the endoplasmic reticulum stress elements. J Biol Chem 2003, 278(39): 37375–37385.

    Article  PubMed  CAS  Google Scholar 

  28. Averous J, Bruhat A, Jousse C, Carraro V, Thiel G, Fafournoux P. Induction of CHOP expression by amino acid limitation requires both ATF4 expression and ATF2 phosphorylation. J Biol Chem 2004, 279(7): 5288–5297.

    Article  PubMed  CAS  Google Scholar 

  29. Ma Y, Hendershot LM. Herp is dually regulated by both the endoplasmic reticulum stress-specific branch of the unfolded protein response and a branch that is shared with other cellular stress pathways. J Biol Chem 2004, 279(14): 13792–13799.

    Article  PubMed  CAS  Google Scholar 

  30. Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 2004, 11(4): 381–389.

    Article  PubMed  CAS  Google Scholar 

  31. Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, et al. Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 2000, 403(6765): 98–103.

    Article  PubMed  CAS  Google Scholar 

  32. Häcki J, Egger L, Monney L, Conus S, Rossé T, Fellay I, et al. Apoptotic crosstalk between the endoplasmic reticulum and mitochondria controlled by Bcl-2. Oncogene 2000, 19(19): 2286–2295.

    Article  PubMed  Google Scholar 

  33. Boya P, Cohen I, Zamzami N, Vieira HL, Kroemer G. Endoplasmic reticulum stress-induced cell death requires mitochondrial membrane permeabilization. Cell Death Differ 2002, 9(4): 465–467.

    Article  PubMed  CAS  Google Scholar 

  34. Germain M, Mathai JP, Shore GC. BH-3-only BIK functions at the endoplasmic reticulum to stimulate cytochrome c release from mitochondria. J Biol Chem 2002, 277(20): 18053–18060.

    Article  PubMed  CAS  Google Scholar 

  35. Hori O, Ichinoda F, Tamatani T, Yamaguchi A, Sato N, Ozawa K, et al. Transmission of cell stress from endoplasmic reticulum to mitochondria: enhanced expression of Lon protease. J Cell Biol 2002, 157(7): 1151–1160.

    Article  PubMed  CAS  Google Scholar 

  36. Lipton P. Ischemic cell death in brain neurons. Physiol Rev 1999, 79(4): 1431–1568.

    PubMed  CAS  Google Scholar 

  37. Bursch W, Ellinger A, Kienzl H, Török L, Pandey S, Sikorska M, et al. Active cell death induced by the anti-estrogens tamoxifen and ICI 164 384 in human mammary carcinoma cells (MCF-7) in culture: the role of autophagy. Carcinogenesis 1996, 17(8): 1595–1607.

    Article  PubMed  CAS  Google Scholar 

  38. Maiese K, Boniece IR, Skurat K, Wagner JA. Protein kinases modulate the sensitivity of hippocampal neurons to nitric oxide toxicity and anoxia. J Neurosci Res 1993, 36(1): 77–87.

    Article  PubMed  CAS  Google Scholar 

  39. Bano D, Nicotera P. Ca2+ signals and neuronal death in brain ischemia. Stroke 2007, 38(2 Suppl): 674–676.

    Article  PubMed  CAS  Google Scholar 

  40. Qin AP, Zhang HL, Qin ZH. Mechanisms of lysosomal proteases participating in cerebral ischemia-induced neuronal death. Neurosci Bull 2008, 24(2): 117–123.

    Article  PubMed  CAS  Google Scholar 

  41. Busch HJ, Buschmann IR, Mies G, Bode C, Hossmann KA. Arteriogenesis in hypoperfused rat brain. J Cereb Blood Flow Metab 2003, 23(5): 621–628.

    Article  PubMed  Google Scholar 

  42. Buschmann IR, Busch HJ, Mies G, Hossmann KA. Therapeutic induction of arteriogenesis in hypoperfused rat brain via granulocyte-macrophage colony-stimulating factor. Circulation 2003, 108(5): 610–615.

    Article  PubMed  CAS  Google Scholar 

  43. Busch HJ, Buschmann I, Schneeloch E, Bode C, Mies G, Hossmann KA. Therapeutically induced arteriogenesis in the brain. A new approach for the prevention of cerebral ischemia with vascular stenosis. Nervenarzt 2006, 77(2): 215–220.

    Article  PubMed  Google Scholar 

  44. Lees KR. Cerestat and other NMDA antagonists in ischemic stroke. Neurology 1997, 49(5 Suppl 4): S66–69.

    PubMed  CAS  Google Scholar 

  45. Muir KW, Lees KR. Clinical experience with excitatory amino acid antagonist drugs. Stroke 1995, 26(3): 503–513.

    PubMed  CAS  Google Scholar 

  46. Schachter SC, Tarsy D. Remacemide: current status and clinical applications. Expert Opin Investig Drugs 2000, 9(4): 871–883.

    Article  PubMed  CAS  Google Scholar 

  47. Kato T. Role of magnesium ions on the regulation of NMDA receptor—a pharmacopathology of memantine. Clin Calcium 2004, 14(8): 76–80.

    PubMed  Google Scholar 

  48. Sun A, Cheng J. Novel targets for therapeutic intervention against ischemic brain injury. Clin Neuropharmacol 1999, 22(3): 164–171.

    PubMed  CAS  Google Scholar 

  49. Gill R. The pharmacology of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainate antagonists and their role in cerebral ischaemia. Cerebrovasc Brain Metab Rev 1994, 6(3): 225–256.

    PubMed  CAS  Google Scholar 

  50. Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and (−)Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci USA 1998, 95(14): 8268–8273.

    Article  PubMed  CAS  Google Scholar 

  51. Zhang Y, Deng P, Ruan Y, Xu ZC. Dopamine D1-like receptors depress excitatory synaptic transmissions in striatal neurons after transient forebrain ischemia. Stroke 2008, 39(8): 2370–2376.

    Article  PubMed  CAS  Google Scholar 

  52. O’Neill MJ, Hicks CA, Ward MA, Cardwell GP, Reymann JM, Allain H, et al. Dopamine D2 receptor agonists protect against ischaemia-induced hippocampal neurodegeneration in global cerebral ischaemia. Eur J Pharmacol 1998, 352(1): 37–46.

    Article  PubMed  Google Scholar 

  53. Kuhmonen J, Pokorný J, Miettinen R, Haapalinna A, Jolkkonen J, Riekkinen P Sr, et al. Neuroprotective effects of dexmedetomidine in the gerbil hippocampus after transient global ischemia. Anesthesiology 1997, 87(2): 371–377.

    Article  PubMed  CAS  Google Scholar 

  54. Marcoli M, Cervetto C, Castagnetta M, Sbaffi P, Maura G. 5-HT control of ischemia-evoked glutamate efflux from human cerebrocortical slices. Neurochem Int 2004, 45(5): 687–691.

    Article  PubMed  CAS  Google Scholar 

  55. Zhou C, Li C, Yu HM, Zhang F, Han D, Zhang GY. Neuroprotection of gamma-aminobutyric acid receptor agonists via enhancing neuronal nitric oxide synthase (Ser847) phosphorylation through increased neuronal nitric oxide synthase and PSD95 interaction and inhibited protein phosphatase activity in cerebral ischemia. J Neurosci Res 2008, 86(13): 2973–2983.

    Article  PubMed  CAS  Google Scholar 

  56. Zhang DJ, Xu GR, Li ZY, Li YZ, Xu LX, Lu FY, et al. The effects of Shuxuetong on the pathology of cerebral ischemia-reperfusion injury and GABA and TNF-alpha expression in gerbil models. Neurosci Bull 2006, 22(1): 41–46.

    PubMed  CAS  Google Scholar 

  57. Stone TW. Purines and neuroprotection. Adv Exp Med Biol 2002, 513: 249–280.

    PubMed  CAS  Google Scholar 

  58. Schurr A. Neuroprotection against ischemic/hypoxic brain damage: blockers of ionotropic glutamate receptor and voltage sensitive calcium channels. Curr Drug Targets 2004, 5(7): 603–618.

    Article  PubMed  CAS  Google Scholar 

  59. Yenari MA, Palmer JT, Sun GH, de Crespigny A, Mosely ME, Steinberg GK. Time-course and treatment response with SNX-111, an N-type calcium channel blocker, in a rodent model of focal cerebral ischemia using diffusion-weighted MRI. Brain Res 1996, 739(1–2): 36–45.

    Article  PubMed  CAS  Google Scholar 

  60. Campbell CA, Mackay KB, Patel S, King PD, Stretton JL, Hadingham SJ, et al. Effects of isradipine, an L-type calcium channel blocker on permanent and transient focal cerebral ischemia in spontaneously hypertensive rats. Exp Neurol 1997, 148(1): 45–50.

    Article  PubMed  CAS  Google Scholar 

  61. Xiong ZG, Zhu XM, Chu XP, Minami M, Hey J, Wei WL, et al. Neuroprotection in ischemia: blocking calcium-permeable acid-sensing ion channels. Cell 2004, 118(6): 687–698.

    Article  PubMed  CAS  Google Scholar 

  62. Zhang H, Song LC, Liu YY, Ma Y, Lu YL. Pinacidil reduces neuronal apoptosis following cerebral ischemia-reperfusion in rats through both mitochondrial and death-receptor signal pathways. Neurosci Bull 2007, 23(3): 145–150.

    Article  PubMed  CAS  Google Scholar 

  63. Sharma SS, Gupta S. Neuroprotective effect of MnTMPyP, a superoxide dismutase/catalase mimetic in global cerebral ischemia is mediated through reduction of oxidative stress and DNA fragmentation. Eur J Pharmacol 2007, 561(1–3): 72–79.

    Article  PubMed  CAS  Google Scholar 

  64. Park CK, Hall ED. Dose-response analysis of the effect of 21-aminosteroid tirilazad mesylate (U-74006F) upon neurological outcome and ischemic brain damage in permanent focal cerebral ischemia. Brain Res 1994, 645(1–2): 157–163.

    PubMed  CAS  Google Scholar 

  65. Villa RF, Gorini A. Pharmacology of lazaroids and brain energy metabolism: a review. Pharmacol Rev 1997, 49(1): 99–136.

    PubMed  CAS  Google Scholar 

  66. Yoshida H, Yanai H, Namiki Y, Fukatsu-Sasaki K, Furutani N, Tada N. Neuroprotective effects of edaravone: a novel free radical scavenger in cerebrovascular injury. CNS Drug Rev 2006, 12(1): 9–20.

    Article  PubMed  CAS  Google Scholar 

  67. MacGregor DG, Avshalumov MV, Rice ME. Brain edema induced by in vitro ischemia: causal factors and neuroprotection. J Neurochem 2003, 85(6): 1402–1411.

    Article  PubMed  CAS  Google Scholar 

  68. Lapchak PA, Araujo DM, Song D, Wei J, Zivin JA. Neuroprotective effects of the spin trap agent disodium-[(tert-butylimino)methyl] benzene-1,3-disulfonate N-oxide (generic NXY-059) in a rabbit small clot embolic stroke model: combination studies with the thrombolytic tissue plasminogen activator. Stroke 2002, 33(5): 1411–1415.

    Article  PubMed  CAS  Google Scholar 

  69. Vaughan CJ, Delanty N. Neuroprotective properties of statins in cerebral ischemia and stroke. Stroke 1999, 30(9): 1969–1973.

    PubMed  CAS  Google Scholar 

  70. Cai ZY, Yan Y, Sun SQ, Zhang J, Huang LG, Yan N, et al. Minocycline attenuates cognitive impairment and restrains oxidative stress in the hippocampus of rats with chronic cerebral hypoperfusion. Neurosci Bull 2008, 24(5): 305–313.

    Article  PubMed  CAS  Google Scholar 

  71. Bartus RT, Baker KL, Heiser AD, Sawyer SD, Dean RL, Elliott PJ, et al. Postischemic administration of AK275, a calpain inhibitor, provides substantial protection against focal ischemic brain damage. J Cereb Blood Flow Metab 1994, 14(4): 537–544.

    PubMed  CAS  Google Scholar 

  72. Liao SL, Chen WY, Raung SL, Chen CJ. Neuroprotection of naloxone against ischemic injury in rats: role of mu receptor antagonism. Neurosci Lett 2003, 345(3): 169–172.

    Article  PubMed  CAS  Google Scholar 

  73. Yenari MA, Kunis D, Sun GH, Onley D, Watson L, Turner S, et al. Hu23F2G, an antibody recognizing the leukocyte CD11/CD18 integrin, reduces injury in a rabbit model of transient focal cerebral ischemia. Exp Neurol 1998, 153(2): 223–233.

    Article  PubMed  CAS  Google Scholar 

  74. Morales JR, Ballesteros I, Deniz JM, Hurtado O, Vivancos J, Nombela F, et al. Activation of liver X receptors promotes neuroprotection and reduces brain inflammation in experimental stroke. Circulation 2008, 118(14): 1450–1459.

    Article  PubMed  CAS  Google Scholar 

  75. Szydlowska K, Zawadzka M, Kaminska B. Neuroprotectant FK506 inhibits glutamate-induced apoptosis of astrocytes in vitro and in vivo. J Neurochem 2006, 99(3): 965–975.

    Article  PubMed  CAS  Google Scholar 

  76. Ebisu T, Mori Y, Katsuta K, Fujikawa A, Matsuoka N, Aoki I, et al. Neuroprotective effects of an immunosuppressant agent on diffusion/perfusion mismatch in transient focal ischemia. Magn Reson Med 2004, 51(6): 1173–1180.

    Article  PubMed  CAS  Google Scholar 

  77. Uchino H, Morota S, Takahashi T, Ikeda Y, Kudo Y, Ishii N, et al. A novel neuroprotective compound FR901459 with dual inhibition of calcineurin and cyclophilins. Acta Neurochir Suppl 2006, 96: 157–162.

    Article  PubMed  CAS  Google Scholar 

  78. Kaminska B, Gaweda-Walerych K, Zawadzka M. Molecular mechanisms of neuroprotective action of immunosuppressants—facts and hypotheses. J Cell Mol Med 2004, 8(1): 45–58.

    Article  PubMed  CAS  Google Scholar 

  79. Pedata F, Gianfriddo M, Turchi D, Melani A. The protective effect of adenosine A2A receptor antagonism in cerebral ischemia. Neurol Res 2005, 27(2): 169–174.

    Article  PubMed  CAS  Google Scholar 

  80. Brambilla R, Cottini L, Fumagalli M, Ceruti S, Abbracchio MP. Blockade of A2A adenosine receptors prevents basic fibroblast growth factor-induced reactive astrogliosis in rat striatal primary astrocytes. Glia 2003, 43(2): 190–194.

    Article  PubMed  Google Scholar 

  81. Han BH, Holtzman DM. BDNF protects the neonatal brain from hypoxic-ischemic injury in vivo via the ERK pathway. J Neurosci 2000, 20(15): 5775–5781.

    PubMed  CAS  Google Scholar 

  82. Robertson GS, Crocker SJ, Nicholson DW, Schulz JB. Neuroprotection by the inhibition of apoptosis. Brain Pathol 2000, 10(2): 283–292.

    Article  PubMed  CAS  Google Scholar 

  83. Hoffman GE, Merchenthaler I, Zup SL. Neuroprotection by ovarian hormones in animal models of neurological disease. Endocrine 2006, 29(2): 217–231.

    Article  PubMed  CAS  Google Scholar 

  84. Kotani Y, Shimazawa M, Yoshimura S, Iwama T, Hara H. The experimental and clinical pharmacology of propofol, an anesthetic agent with neuroprotective properties. CNS Neurosci Ther 2008, 14(2): 95–106.

    Article  PubMed  CAS  Google Scholar 

  85. Luo Y, Ma D, Ieong E, Sanders RD, Yu B, Hossain M, et al. Xenon and sevoflurane protect against brain injury in a neonatal asphyxia model. Anesthesiology 2008, 109(5): 782–789.

    Article  PubMed  CAS  Google Scholar 

  86. Schmid-Elsaesser R, Hungerhuber E, Zausinger S, Baethmann A, Reulen HJ. Combination drug therapy and mild hypothermia: a promising treatment strategy for reversible, focal cerebral ischemia. Stroke 1999, 30(9): 1891–1899.

    PubMed  CAS  Google Scholar 

  87. Wang XS, Ruan XZ, Wang W. Protective Effect of Ginkgo Biloba Extract on Brain Injury Induced by Ischemia/Reperfusion in Rats. J Huazhong Univ Sci Tech[Health Sci] 2003, 32(5): 500–502.

    CAS  Google Scholar 

  88. Hu XS, Zhou D, Zhou DM. Protective effects of PTS on cerebral ischemia—reperfusion injury in rat. J Apoplexy and Nervous Disease 2004, 21(4): 354–356.

    Google Scholar 

  89. Wu HQ, Chang MZ, Zhang GL, Zhao YX. The mechanism of protective effects of puerarin on learning-memory disorder after global cerebral ischemic reperfusive injury in rats. J Apoplexy and Nervous Disease 2004, 21(4): 350–353.

    Google Scholar 

  90. Kirino T. Ischemic tolerance. J Cereb Blood Flow Metab. 2002, 22(11): 1283–1296.

    Article  PubMed  Google Scholar 

  91. Stagliano NE, Pérez-Pinzón MA, Moskowitz MA, Huang PL. Focal ischemic preconditioning induces rapid tolerance to middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 1999, 19(7): 757–761.

    Article  PubMed  CAS  Google Scholar 

  92. Dirnagl U, Simon RP, Hallenbeck JM. Ischemic tolerance and endogenous neuroprotection. Trends Neurosci 2003, 26(5): 248–254.

    Article  PubMed  CAS  Google Scholar 

  93. Ge PF, Luo TF, Zhang JZ, Chen DW, Luan YX, Fu SL. Ischemic preconditioning induces chaperone hsp70 expression and inhibits protein aggregation in the CA1 neurons of rats. Neurosci Bull 2008, 24(5): 288–296.

    Article  PubMed  CAS  Google Scholar 

  94. Obrenovitch TP. Molecular physiology of preconditioning-induced brain tolerance to ischemia. Physiol Rev 2008, 88(1): 211–247.

    Article  PubMed  CAS  Google Scholar 

  95. Xing B, Chen H, Zhang M, Zhao D, Jiang R, Liu X, et al. Ischemic postconditioning inhibits apoptosis after focal cerebral ischemia/reperfusion injury in the rat. Stroke 2008, 39(8): 2362–2369.

    Article  PubMed  CAS  Google Scholar 

  96. Wang JY, Shen J, Gao Q, Ye ZG, Yang SY, Liang HW, et al. Ischemic postconditioning protects against global cerebral ischemia/reperfusion-induced injury in rats. Stroke 2008, 39(3): 983–990.

    Article  PubMed  Google Scholar 

  97. Faden AI, Stoica B. Neuroprotection: challenges and opportunities. Arch Neurol 2007, 64(6): 794–800.

    Article  PubMed  Google Scholar 

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  1. Department of Neurology, the Second Affiliated Hospital of Harbin Medical University, Harbin, 150086, China

    Zhao-Hui Guo  (郭朝晖), Feng Li  (李峰) & Wei-Zhi Wang  (王维治)

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Correspondence to Feng Li  (李峰).

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Guo, ZH., Li, F. & Wang, WZ. The mechanisms of brain ischemic insult and potential protective interventions. Neurosci. Bull. 25, 139–152 (2009). https://doi.org/10.1007/s12264-009-0104-3

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