Molecular Neurobiology

, Volume 37, Issue 1, pp 7–38 | Cite as

Molecular Mechanisms of Apoptosis in Cerebral Ischemia: Multiple Neuroprotective Opportunities

  • Venkata Prasuja Nakka
  • Anchal Gusain
  • Suresh L. Mehta
  • Ram Raghubir
Article

Abstract

Cerebral ischemia/reperfusion (I/R) injury triggers multiple and distinct but overlapping cell signaling pathways, which may lead to cell survival or cell damage. There is overwhelming evidence to suggest that besides necrosis, apoptosis do contributes significantly to the cell death subsequent to I/R injury. Both extrinsic and intrinsic apoptotic pathways play a vital role, and upon initiation, these pathways recruit downstream apoptotic molecules to execute cell death. Caspases and Bcl-2 family members appear to be crucial in regulating multiple apoptotic cell death pathways initiated during I/R. Similarly, inhibitor of apoptosis family of proteins (IAPs), mitogen-activated protein kinases, and newly identified apoptogenic molecules, like second mitochondrial-activated factor/direct IAP-binding protein with low pI (Smac/Diablo), omi/high-temperature requirement serine protease A2 (Omi/HtrA2), X-linked mammalian inhibitor of apoptosis protein-associated factor 1, and apoptosis-inducing factor, have emerged as potent regulators of cellular apoptotic/antiapoptotic machinery. All instances of cell survival/death mechanisms triggered during I/R are multifaceted and interlinked, which ultimately decide the fate of brain cells. Moreover, apoptotic cross-talk between major subcellular organelles suggests that therapeutic strategies should be optimally directed at multiple targets/mechanisms for better therapeutic outcome. Based on the current knowledge, this review briefly focuses I/R injury-induced multiple mechanisms of apoptosis, involving key apoptotic regulators and their emerging roles in orchestrating cell death programme. In addition, we have also highlighted the role of autophagy in modulating cell survival/death during cerebral ischemia. Furthermore, an attempt has been made to provide an encouraging outlook on emerging therapeutic approaches for cerebral ischemia.

Keywords

Cerebral ischemia Oxidative stress Apoptosis Caspases Bcl-2 family IAPs AIF Mitochondria Endoplasmic reticulum 

Notes

Acknowledgment

Mr. Venkata Prasuja Nakka, Ms. Anchal Gusain, and Mr. Suresh L Mehta received Senior Research Fellowship from the Council of Scientific and Industrial Research, New Delhi, India.

References

  1. 1.
    Eng HL, Dalkara T, Moskowitz MA (2003) Mechanisms, challenges and opportunities in stroke. Nat Neurosci 4:399–415Google Scholar
  2. 2.
    Smith WS (2004) Pathophysiology of focal cerebral ischemia: a therapeutic perspective. J Vasc Interv Radiol 15:S3–S12PubMedGoogle Scholar
  3. 3.
    Traystman RJ (2003) Animal models of focal and global cerebral ischemia. ILAR 44:85–95Google Scholar
  4. 4.
    Kirino T (1982) Delayed neuronal death in the gerbil hippocampus following ischemia. Brain Res 230:57–69Google Scholar
  5. 5.
    Pulsinelli WA, Brierley JB, Plum F (1982) Temporal profile of neuronal damage in a model of transient forebrain ischemia. Ann Neurol 11:491–498PubMedGoogle Scholar
  6. 6.
    Bonnekoh P, Barbier A, Oschlies U, Hossmann KA (1990) Selective vulnerability in the gerbil hippocampus: morphological changes after 5-min ischemia and long survival times. Acta Neuropathol (Berl) 80:18–25Google Scholar
  7. 7.
    Petito CK, Feldmann E, Pulsinelli WA, Plum F (1987) Delayed hippocampal damage in humans following cardiorespiratory arrest. Neurology 37:1281–1286PubMedGoogle Scholar
  8. 8.
    Horn M, Schlote W (1992) Delayed neuronal death and delayed neuronal recovery in the human brain following global ischemia. Acta Neuropathol (Berl) 85:79–87Google Scholar
  9. 9.
    Kirino T (2000) Delayed neuronal death. Neuropathology 20:S95–S97PubMedGoogle Scholar
  10. 10.
    Lipton P (1999) Ischemic cell death in brain neurons. Physiol Rev 79:1431–1568PubMedGoogle Scholar
  11. 11.
    Astrup J, Siesjö BK, Symon L (1981) Thresholds in cerebral ischemia—the ischemic penumbra. Stroke 12:723–725PubMedGoogle Scholar
  12. 12.
    Ginsberg MD (2003) Adventures in the pathophysiology of brain ischemia: penumbra, gene expression, neuroprotection: the 2002 Thomas Willis lecture. Stroke 34:214–223PubMedGoogle Scholar
  13. 13.
    Ferrer I (2006) Apoptosis: future targets for neuroprotective strategies. Cerebrovasc Dis 2:9–20Google Scholar
  14. 14.
    Linnik MD, Zobrist RH, ad Hatfield MD (1993) Evidence supporting a role for programmed cell death in focal cerebral ischemia in rats. Stroke 24:2002–2009PubMedGoogle Scholar
  15. 15.
    Charriaut-Marlangue C, Margaill I, Represa A, Popovici T, Plotkine M, Ben Ari Y (1996) Apoptosis and necrosis after reversible focal ischemia: an in situ DNA fragmentation analysis. J Cereb Blood Flow Metab 16:186–194PubMedGoogle Scholar
  16. 16.
    Li Y, Chopp M, Jiang N, Zaloga C (1995) In situ detection of DNA fragmentation after focal cerebral ischemia in mice. Brain Res Mol Brain Res 28:164–168PubMedGoogle Scholar
  17. 17.
    Ferrer I, Planas AM (2003) Signaling of cell death and cell survival following focal cerebral ischemia: life and death struggle in the penumbra. J Neuropathol Exp Neurol 62:329–339PubMedGoogle Scholar
  18. 18.
    Ferrer I, Friguls B, Dalfó E, Justicia C, Planas AM (2003) Caspase-dependent and caspase-independent signalling of apoptosis in the penumbra following middle cerebral artery occlusion in the adult rat. Neuropathol Appl Neurobiol 29:472–481PubMedGoogle Scholar
  19. 19.
    Benchoua A, Guegan C, Couriaud C, Hosseini H, Sampaio N, Morin D, Onteniente B (2001) Specific caspase pathways are activated in the two stages of cerebral infarction. J Neurosci 21:7127–7134PubMedGoogle Scholar
  20. 20.
    Nicotera P, Leist M, Ferrando-May E (1998) Intracellular ATP, a switch in the decision between apoptosis and necrosis. Toxicol Lett 102–103:139–142PubMedGoogle Scholar
  21. 21.
    Schwab BL, Guerini D, Didszun C, Bano D, Ferrando-May E, Fava E, Tam J, Xu D, Xanthoudakis S, Nicholson DW, Carafoli E, Nicotera P (2002) Cleavage of plasma membrane calcium pumps by caspases: a link between apoptosis and necrosis. Cell Death Differ 9:818–831PubMedGoogle Scholar
  22. 22.
    Bano D, Young KW, Guerin CJ, Lefeuvre R, Rothwell NJ, Naldini L, Rizzuto R, Carafoli E, Nicotera P (2005) Cleavage of the plasma membrane Na+2 /Ca2+ exchanger in excitotoxicity. Cell 120:275–285PubMedGoogle Scholar
  23. 23.
    Pulsinelli WA, Buchan AM (1988) The four-vessel occlusion rat model: method for complete occlusion of vertebral arteries and control of collateral circulation. Stroke 19:913–914PubMedGoogle Scholar
  24. 24.
    Eklof B, Siesjo BK (1972a) The effect of bilateral carotid artery ligation upon acid-base parameters and substrate levels in the rat brain. Acta Physiol Scand 86:528–538PubMedGoogle Scholar
  25. 25.
    Eklof B, Siesjo BK (1972b) The effect of bilateral carotid artery ligation upon the blood flow and the energy state of the rat brain. Acta Physiol Scand 86:155–165PubMedGoogle Scholar
  26. 26.
    Tamura A, Graham DI, McCulloch J, Teasdale GM (1981) Focal cerebral ischaemia in the rat: 1. Description of technique and early neuropathological consequences following middle cerebral artery occlusion. J Cereb Blood Flow Metab 1:53–60PubMedGoogle Scholar
  27. 27.
    Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL, Bartkowski H (1986) Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke 17:472–476PubMedGoogle Scholar
  28. 28.
    Longa EZ, Weinstein PR, Carlson S, Cummins R (1989) Reversible middle cerebral artery occlusion without craniectomy in rats. Stroke 20:84–91PubMedGoogle Scholar
  29. 29.
    Mehta SL, Manhas N, Raghubir R (2007) Molecular targets in cerebral ischemia for developing novel therapeutics. Brains Res Rev 54:34–66Google Scholar
  30. 30.
    Moroa MA, Almeida A, Bolanos JP, Lizasoain I (2005) Mitochondrial respiratory chain and free radical generation in stroke. Free Radic Biol Med 39:1291–1304Google Scholar
  31. 31.
    Eng HL, Dalkara T, Moskowitz MA (2003) Mechanisms, challenges and opportunities in stroke. Nat Neurosci 4:399–415Google Scholar
  32. 32.
    Beal MF (1992) Mechanisms of excitotoxicity in neurologic diseases. FASEB J 6:3338–3344PubMedGoogle Scholar
  33. 33.
    Zhang YM, Bhavnani BR (2006) Glutamate-induced apoptosis in neuronal cells is mediated via caspase-dependent and independent mechanisms involving calpain and caspase-3 proteases as well as apoptosis inducing factor (AIF) and this process is inhibited by equine estrogens. BMC Neurosci 7:49PubMedGoogle Scholar
  34. 34.
    Xiong ZG, Chu XP, Simon RP (2006) Ca2+-permeable acid-sensing ion channels and ischemic brain injury. J Membr Biol 209:59–68PubMedGoogle Scholar
  35. 35.
    Xiong ZG, Zhu XM, Chu XP, Minami M, Hey J, Wei WL, MacDonald JF, Wemmie JA, Price MP, Welsh MJ, Simon RP (2004) Neuroprotection in ischemia: blocking calcium permeable acid-sensing ion channels. Cell 118:687–698PubMedGoogle Scholar
  36. 36.
    Gao J, Duan B, Wang DG, Deng XH, Zhang GY, Xu L, Xu TL (2005) Coupling between NMDA receptor and acid-sensing ion channel contributes to ischemic neuronal death. Neuron 48:635–646PubMedGoogle Scholar
  37. 37.
    Pignataro G, Simon RP, Xiong ZG (2007) Prolonged activation of ASIC1a and the time window for neuroprotection in cerebral ischaemia. Brain 130:151–158PubMedGoogle Scholar
  38. 38.
    Nita DA, Nita V, Spulber S, Moldovan M, Popa DP, Zagrean AM, Zagrean L (2001) Oxidative damage following cerebral ischemia depends on reperfusion- a biochemical study in rat. J Cell Mol Med 5:163–170PubMedGoogle Scholar
  39. 39.
    Lewen A, Matz P, Chan PH (2000) Free radical pathways in CNS injury. J Neurotrauma 17:871–890PubMedCrossRefGoogle Scholar
  40. 40.
    Chan PH (2001) Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab 21:2–14PubMedGoogle Scholar
  41. 41.
    Halliwell B, Gulteridge JMC (eds) (1989) Free radicals in biology and medicine, 2nd edn. Oxford, ClarendonGoogle Scholar
  42. 42.
    Liu PK (2003) Ischemia–reperfusion-related repair deficit after oxidative stress: implications of faulty transcripts in neuronal sensitivity after brain injury. J Biomed Sci 10:4–13PubMedGoogle Scholar
  43. 43.
    Warner DS, Sheng H, Batinic-Haberle I (2004) Oxidants, antioxidants and the ischemic brain. J Exp Biol 207:3221–3231PubMedGoogle Scholar
  44. 44.
    Love S (1999) Oxidative stress in brain ischemia. Brain Pathol 9:119–131PubMedCrossRefGoogle Scholar
  45. 45.
    Chong ZZ, Li F, Maiese K (2005) Oxidative stress in the brain: novel cellular targets that govern survival during neurodegenerative disease. Prog Neurobiol 75:207–246PubMedGoogle Scholar
  46. 46.
    Yamamoto T, Maruyama W, Kato Y, Yi H, Shamoto-Nagai M, Tanaka M, Sato Y, Naoi M (2002) Selective nitration of mitochondrial complex I by peroxynitrite: involvement in mitochondria dysfunction and cell death of dopaminergic SH-SY5Y cells. J Neural Transm 109:1–13PubMedGoogle Scholar
  47. 47.
    Kim GW, Kondo T, Noshita N, Chan PH (2002) Manganese superoxide dismutase deficiency exacerbates cerebral infarction after focal cerebral ischemia/reperfusion in mice: implications for the production and role of superoxide radicals. Stroke 33:809–815PubMedGoogle Scholar
  48. 48.
    Murakami K, Kondo T, Kawase M, Li Y, Sato S, Chen SF, Chan PH (1998) Mitochondrial susceptibility to oxidative stress exacerbates cerebral infarction that follows permanent focal cerebral ischemia in mutant mice with manganese superoxide dismutase deficiency. J Neurosci 18:205–213PubMedGoogle Scholar
  49. 49.
    Hayashi T, Saito A, Okuno S, Ferrand-Drake M, Doddand RL, Chan PK (2005) Damage to the endoplasmic reticulum and activation of apoptotic machinery by oxidative stress in ischemic neurons. J Cereb Blood Flow Metab 25:41–53PubMedGoogle Scholar
  50. 50.
    Chan PH (2001) Reactive oxygen radicals in signaling and damage in the ischemic brain. J Cereb Blood Flow Metab 21:2–14PubMedGoogle Scholar
  51. 51.
    Crack PJ, Taylor JM (2005) Reactive oxygen species and the modulation of stroke. Free Radic Biol Med 38:1433–1444PubMedGoogle Scholar
  52. 52.
    McCulloch J, Dewar D (2001) A radical approach to stroke therapy. Proc Natl Acad Sci USA 98:10989–10999PubMedGoogle Scholar
  53. 53.
    Huang J, Upadhyay UM, Tamargo RJ (2006) Inflammation in stroke and focal cerebral ischemia. Surgical Neurol 66:232–245Google Scholar
  54. 54.
    Fassbender K, Mossner R, Motsch L, Kischka U, Grau A, Hennerici M (1995) Circulating selectin- and immunoglobulin-type adhesion molecules in acute ischemic stroke. Stroke 26:1361–1364PubMedGoogle Scholar
  55. 55.
    Huang J, Kim LJ, Mealey R, Marsh HC Jr, Zhang Y, Tenner AJ, Connolly ES Jr, Pinsky DJ (1999) Neuronal protection in stroke by an sLex-glycosylated complement inhibitory protein. Science 285:595–599PubMedGoogle Scholar
  56. 56.
    Okada Y, Copeland BR, Mori E, Tung MM, Thomas WS, del Zoppo GJ (1994) P-selectin and intercellular adhesion molecule-1 expression after focal brain ischemia and reperfusion. Stroke 25:202–211PubMedGoogle Scholar
  57. 57.
    Huang J, Choudhri TF, Winfree CJ, McTaggart RA, Kiss S, Mocco J, Kim LJ, Protopsaltis TS, Zhang Y, Pinsky DJ, Connolly ES Jr (2000) Postischemic cerebrovascular E-selectin expression mediates tissue injury in murine stroke. Stroke 31:3047–3053PubMedGoogle Scholar
  58. 58.
    Mayadas TN, Johnson RC, Rayburn H, Hynes RO, Wagner DD (1993) Leukocyte rolling and extravasation are severely compromised in P selectin-deficient mice. Cell 74:541–554PubMedGoogle Scholar
  59. 59.
    Mocco J, Choudri T, Huang J, Harfeldt E, Efros L, Klingbeil C, Vexler W, Hall W, Zhang Y, Mack W, Popilskis S, Pinsky DJ, Connolly ES (2002) HuEP5C7 as a humanized monoclonal anti-E/P Selectin neurovascular protective strategy in a blinded placebo-controlled trial of nonhuman primate stroke. Circ Res 91:907–914PubMedGoogle Scholar
  60. 60.
    Morikawa E, Zhang SM, Seko Y, Toyoda T, Kirino T (1996) Treatment of focal cerebral ischemia with synthetic oligopeptide corresponding to lectin domain of selectin. Stroke 27:951–955PubMedGoogle Scholar
  61. 61.
    Zhang RL, Chopp M, Zaloga C, Zhang ZG, Jiang N, Gautam SC, Tang WX, Tsang W, Anderson DC, Manning AM (1995a) The temporal profiles of ICAM-1 protein and mRNA expression after transient MCA occlusion in the rat. Brain Res 682:182–188PubMedGoogle Scholar
  62. 62.
    Lindsberg PJ, Carpen O, Paetau A, Karjalainen-Lindsberg ML, Kaste M (1996) Endothelial ICAM-1 expression associated with inflammatory cell response in human ischemic stroke. Circulation 94:939–945PubMedGoogle Scholar
  63. 63.
    Fiszer U, Korczak-Kowalska G, Palasik W, Korlak J, Gorski A, Czlonkowska A (1998) Increased expression of adhesion molecule CD18 (LFA-1beta) on the leukocytes of peripheral blood in patients with acute ischemic stroke. Acta Neurol Scand 97:221–224PubMedCrossRefGoogle Scholar
  64. 64.
    del Zoppo GJ, Schmid-Schonbein GW, Mori E, Copeland BR, Chang CM (1991) Polymorphonuclear leukocytes occlude capillaries following middle cerebral artery occlusion and reperfusion in baboons. Stroke 22:1276–1283PubMedGoogle Scholar
  65. 65.
    Soriano SG, Coxon A, Wang YF, Frosch MP, Lipton SA, Hickey PR, Mayadas TN (1999) Mice deficient in Mac-1 (CD11b/CD18) are less susceptible to cerebral ischemia/ reperfusion injury. Stroke 30:134–139PubMedGoogle Scholar
  66. 66.
    Mori E, Del Zoppo GJ, Chambers JD, Copeland BR, Arfors KE (1992) Inhibition of polymorphonuclear leukocyte adherence suppresses no-reflow after focal cerebral ischemia in baboons. Stroke 23:712–718PubMedGoogle Scholar
  67. 67.
    Chen H, Chopp M, Zhang RL, Bodzin G, Chen Q, Rusche JR, Todd RF (1994) Anti-CD11b monoclonal antibody reduces ischemic cell damage after transient focal cerebral ischemia in rat. Ann Neurol 35:458–463PubMedGoogle Scholar
  68. 68.
    Chopp M, Zhang RL, Chen H, Li Y, Jiang N, Rusche JR (1994) Postischemic administration of an anti-Mac-1 antibody reduces ischemic cell damage after transient middle cerebral artery occlusion in rats. Stroke 25:869–875PubMedGoogle Scholar
  69. 69.
    Zhang RL, Chopp M, Jiang N, Tang WX, Prostak J, Manning AM, Anderson DC (1995b) Anti-intercellular adhesion molecule-1 antibody reduces ischemic cell damage after transient but not permanent middle cerebral artery occlusion in the Wistar rat. Stroke 26:1438–1442PubMedGoogle Scholar
  70. 70.
    Hallenbeck JM, Dutka AJ (1990) Background review and current concepts of reperfusion injury. Arch Neurol 47:1245–1254PubMedGoogle Scholar
  71. 71.
    Shyu KG, Chang H, Lin CC (1997) Serum levels of intercellular adhesion molecule-1 and E-selectin in patients with acute ischaemic stroke. J Neurol 244:90–93PubMedGoogle Scholar
  72. 72.
    Stenberg PE, Shuman MA, Levine SP, Bainton DF (1984) Redistribution of alpha-granules and their contents in thrombin-stimulated platelets. J Cell Biol 98:748–760PubMedGoogle Scholar
  73. 73.
    Soriano SG, Lipton SA, Wang YF, Xiao M, Springer TA, Gutierrez-Ramos JC, Hickey PR (1996) Intercellular adhesion molecule-1-deficient mice are less susceptible to cerebral ischemia–reperfusion injury. Ann Neurol 39:618–624PubMedGoogle Scholar
  74. 74.
    Connolly ES Jr, Winfree CJ, Springer TA, Naka Y, Liao H, Yan SD, Stern DM, Solomon RA, Gutierrez-Ramos JC, Pinsky DJ (1996) Cerebral protection in homozygous null ICAM-1 mice after middle cerebral artery occlusion. Role of neutrophil adhesion in the pathogenesis of stroke. J Clin Invest 97:209–216PubMedGoogle Scholar
  75. 75.
    Chopp M, Li Y, Jiang N, Zhang RL, Prostak J (1996) Antibodies against adhesion molecules reduce apoptosis after transient middle cerebral artery occlusion in rat brain. J Cereb Blood Flow Metab 16:578–584PubMedGoogle Scholar
  76. 76.
    Vemuganti R, Dempsey RJ, Bowen KK (2004) Inhibition of intercellular adhesion molecule-1 protein expression by antisense oligonucleotides is neuroprotective after transient middle cerebral artery occlusion in rat. Stroke 35:179–184PubMedGoogle Scholar
  77. 77.
    Antezana DF, Clatterbuck RE, Alkayed NJ, Murphy SJ, Anderson LG, Frazier J, Hurn PD, Traystman RJ, Tamargo RJ (2003) High-dose ibuprofen for reduction of striatal infarcts during middle cerebral artery occlusion in rats. J Neurosurg 98:860–866PubMedGoogle Scholar
  78. 78.
    Becker KJ (2001) Targeting the central nervous system inflammatory response in ischemic stroke. Curr Opin Neurol 14:349–353PubMedGoogle Scholar
  79. 79.
    Del Zoppo G, Ginis I, Hallenbeck JM, Iadecola C, Wang X, Feuerstein GZ (2000) Inflammation and stroke: putative role for cytokines, adhesion molecules and iNOS in brain response to ischemia. Brain Pathol 10:95–112PubMedCrossRefGoogle Scholar
  80. 80.
    Liu T, McDonnell PC, Young PR, White RF, Siren AL, Hallenbeck JM, Barone FC, Feurestein GZ (1993) Interleukin-1 beta mRNA expression in ischemic rat cortex. Stroke 24:1746–1750PubMedGoogle Scholar
  81. 81.
    Buttini M, Sauter A, Boddeke HW (1994) Induction of interleukin-1 beta mRNA after focal cerebral ischaemia in the rat. Brain Res Mol Brain Res 23:126–134PubMedGoogle Scholar
  82. 82.
    Zhang Z, Chopp M, Goussev A, Powers C (1998) Cerebral vessels express interleukin 1beta after focal cerebral ischemia. Brain Res 784:210–217PubMedGoogle Scholar
  83. 83.
    Weller A, Isenmann S, Vestweber D (1992) Cloning of the mouse endothelial selectins. Expression of both E- and P-selectin is inducible by tumor necrosis factor alpha. J Biol Chem 267:15176–15183PubMedGoogle Scholar
  84. 84.
    Yoshimoto T, Houkin K, Tada M, Abe H (1997) Induction of cytokines, chemokines and adhesion molecule mRNA in a rat forebrain reperfusion model. Acta Neuropathol (Berl) 93:154–158Google Scholar
  85. 85.
    Zhang RL, Chopp M, Jiang N, Tang WX, Prostak J, Manning AM, Anderson DC (1995) Anti-intercellular adhesion molecule-1 antibody reduces ischemic cell damage after transient but not permanent middle cerebral artery occlusion in the Wistar rat. Stroke. 26:1438–1442PubMedGoogle Scholar
  86. 86.
    Garcia JH, Liu KF, Relton JK (1995b) Interleukin-1 receptor antagonist decreases the number of necrotic neurons in rats with middle cerebral artery occlusion. Am J Pathol 147:1477–1486PubMedGoogle Scholar
  87. 87.
    Relton JK, Martin D, Thompson RC, Russell DA (1996) Peripheral administration of interleukin-1 receptor antagonist inhibits brain damage after focal cerebral ischemia in the rat. Exp Neurol 138:206–213PubMedGoogle Scholar
  88. 88.
    Liu T, Clark RK, McDonnell PC, Young PR, White RF, Barone FC, Feuerstein GZ (1994) Tumor necrosis factor-alpha expression in ischemic neurons. Stroke 25:1481–1488PubMedGoogle Scholar
  89. 89.
    Zaremba J, Skrobanski P, Losy J (2001) Tumour necrosis factor-alpha is increased in the cerebrospinal fluid and serum of ischaemic stroke patients and correlates with the volume of evolving brain infarct. Biomed Pharmacother 55:258–263PubMedGoogle Scholar
  90. 90.
    Nawashiro H, Martin D, Hallenbeck JM (1997) Neuroprotective effects of TNF binding protein in focal cerebral ischemia. Brain Res 778:265–271PubMedGoogle Scholar
  91. 91.
    Latour LL, Kang DW, Ezzeddine MA, Chalela JA, Warach S (2004) Early blood brain barrier disruption in human focal brain ischemia. Ann Neurol 56:468–477PubMedGoogle Scholar
  92. 92.
    Horstmann S, Kalb P, Koziol J, Gardner H, Wagner S (2003) Profiles of matrix metalloproteinases, their inhibitors, and laminin in stroke patients: influence of different therapies. Stroke 34:2165–2170PubMedGoogle Scholar
  93. 93.
    Gidday JM, Gasche YG, Copin JC, Shah AR, Perez RS, Shapiro SD, Chan PH, Park TS (2005) Leukocyte-derived matrix metalloproteinase-9 mediates blood-brain barrier breakdown and is proinflammatory after transient focal cerebral ischemia. Am J Physiol Heart Circ Physiol 289:H558–H568PubMedGoogle Scholar
  94. 94.
    Wang Q, Tang XN, Yenari MA (2007) The inflammatory response in stroke. J Neuroimmunol 184:53–68PubMedGoogle Scholar
  95. 95.
    Zhang W, Wang X, Narayanan M, Zhang Y, Huo C, Reed JC, Friedlander RM (2003) Fundamental role of the Rip2/caspase-1 pathway in hypoxia and ischemia-induced neuronal cell death. Proc Natl Acad Sci U S A 100:16012–16017PubMedGoogle Scholar
  96. 96.
    Benchoua A, Braudeau J, Reis A, Couriaud C, Onteniente B (2004) Activation of proinflammatory caspases by cathepsin B in focal cerebral ischemia. J Cereb Blood Flow Metab 24:1272–1279PubMedGoogle Scholar
  97. 97.
    Kerr JF, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257PubMedGoogle Scholar
  98. 98.
    Sugawara T, Fujimura M, Noshita N, Kim GW, Saito A, Hayashi T, Narasimhan P, Maier CM, Chan PH (2004) Neuronal death/survival signaling pathways in cerebral ischemia. NeuroRx 1:17–25PubMedGoogle Scholar
  99. 99.
    Li Y, Chopp M, Jiang N, Zhang ZG, Zaloga C (1995) Induction of DNA fragmentation after 10 to 120 minutes of focal cerebral ischemia in rats. Stroke 26:1252–1257PubMedGoogle Scholar
  100. 100.
    Charriaut-Marlangue C, Margaill I, Represa A, Popovici T, Plotkine M, Ben-Ari Y (1996) Apoptosis and necrosis after reversible focal ischemia: an in situ DNA fragmentation analysis. J Cereb Blood Flow Metab 16:186–194PubMedGoogle Scholar
  101. 101.
    Fujimura M, Morita-Fujimura Y, Murakami K, Kawase M, Chan PH (1998) Cytosolic redistribution of cytochrome c after transient focal cerebral ischemia in rats. J Cereb Blood Flow Metab 18:1239–1247PubMedGoogle Scholar
  102. 102.
    Li Y, Chopp M, Powers C, Jiang N (1997) Apoptosis and protein expression after focal cerebral ischemia in rat. Brain Res 765:301–312PubMedGoogle Scholar
  103. 103.
    Li Y, Powers C, Jiang N, Chopp M (1998) Intact, injured, necrotic and apoptotic cells after focal cerebral ischemia in the rat. J Neurol Sci 156:119–132PubMedGoogle Scholar
  104. 104.
    Bredesen DE, Rao RV, Mehlen P (2006) Cell death in the nervous system. Nature 443:796–802PubMedGoogle Scholar
  105. 105.
    Degterev A, Huang Z, Boyce M, Jagtap P, Mizushima N, Cuny GD, Mitchinson TJ, Moskowitz MA, Yuan J (2005) Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol 1:112–119PubMedGoogle Scholar
  106. 106.
    Sastry PS, Rao KS (2000) Apoptosis and the nervous system. J. Neurochem 74:1–20PubMedGoogle Scholar
  107. 107.
    Nitatori T, Sato N, Waguri S, Karasawa Y, Araki H, Shibanai K, Kominami E, Uchiyama Y (1995) Delayed neuronal death in the CA1 pyramidal cell layer of the gerbil hippocampus following transient ischemia is apoptosis. J Neurosci 15:1001–1011PubMedGoogle Scholar
  108. 108.
    Chen J, Nagayama T, Jin K, Stetler RA, Zhu RL, Graham SH, Simon RP (1998) Induction of caspase-3-like protease may mediate delayed neuronal death in the hippocampus after transient cerebral ischemia. J Neurosci 18:4914–4928PubMedGoogle Scholar
  109. 109.
    Alnemri ES, Livingston DJ, Nicholson DW, Salvesen G, Thornberry NA, Wong WW, Yuan J (1996) Human ICE/CED-3 protease nomenclature. Cell 87:171PubMedGoogle Scholar
  110. 110.
    Shi Y (2002) Mechanisms of caspase activation and inhibition during apoptosis. Mol Cell 9:459–470PubMedGoogle Scholar
  111. 111.
    Fischer U, Janicke RU, Schulze-Osthoff K (2003) Many cuts to ruin: a comprehensive update of caspase substrates. Cell Death Differ 10:76–100PubMedGoogle Scholar
  112. 112.
    Kuida K, Zheng TS, Na S, Kuan CY, Yang D, Karasuyama H, Rakic P, Flavell RA (1996) Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature 384:368–372PubMedGoogle Scholar
  113. 113.
    Kuida K, Haydar TF, Kuan CY, Gu Y, Taya C, Karasuyama H, Su MSS, Rakic P, Flavell RA (1998) Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell 94:325–337PubMedGoogle Scholar
  114. 114.
    Cecconi F, Alvarez-Bolado G, Meyer BI, Roth KA, Gruss P (1998) Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development. Cell 94:727–737PubMedGoogle Scholar
  115. 115.
    Mattson MP (2007) Mitochondrial regulation of neuronal plasticity. Neurochem Res 32:707–715PubMedGoogle Scholar
  116. 116.
    Kang SJ, Wang S, Hara H, Peterson EP, Namura S, Amin-Hanjani S, Huang Z, Srinivasan A, Tomaselli KJ, Thornberry NA, Moskowitz MA, Yuan J (2000) Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions. J Cell Biol 149(613–622):51Google Scholar
  117. 117.
    Nakagawa T, Zhu H, Morishima N, Li E, Xu J, Yankner BA, Yuan J (2000) Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature 403:98–103PubMedGoogle Scholar
  118. 118.
    Namura S, Zhu J, Fink K, Endres M, Srinivasan A, Tomaselli KJ, Yuan J, Moskowitz MA (1998) Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia. J Neurosci 18:3659–3668PubMedGoogle Scholar
  119. 119.
    Hermann DM, Kilic E, Hata R, Hossmann KA, Mies G (2001) Relationship between metabolic dysfunctions, gene responses and delayed cell death after mild focal cerebral ischemia in mice. Neuroscience 104:947–955PubMedGoogle Scholar
  120. 120.
    Niwa M, Hara, A, Iwai T, Wang S, Hotta K, Mori H, Uematsu T (2001) Caspase activation as an apoptotic evidence in the gerbil hippocampal CA1 pyramidal cells following transient forebrain ischemia. Neurosci Lett 300:103–106PubMedGoogle Scholar
  121. 121.
    Ni B, Wu X, Su Y, Stephenson D, Smalstig EB, Clemens J, Paul SM (1998) Transient global forebrain ischemia induces a prolonged expression of the caspase-3 mRNA in rat hippocampal CA1 pyramidal neurons. J Cereb Blood Flow Metab 18:248–256PubMedGoogle Scholar
  122. 122.
    Davoli MA, Fourtounis J, Tam J, Xanthoudakis S, Nicholson D, Robertson GS, Ng GY, Xu D (2002) Immunohistochemical and biochemical assessment of caspase-3 activation and DNA fragmentation following transient focal ischemia in the rat. Neuroscience 115:125–136PubMedGoogle Scholar
  123. 123.
    Ouyang YB, Tan Y, Comb M, Liu CL, Martone ME, Siesjo BK, Hu BR (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 19:1126–1135PubMedGoogle Scholar
  124. 124.
    Gillardon F, Kiprianova I, Sandkuhler J, Hossmann KA, Spranger M (1999a) Inhibition of caspases prevents cell death of hippocampal CA1 neurons, but not impairment of hippocampal long-term potentiation following global ischemia. Neuroscience 93:1219–1222PubMedGoogle Scholar
  125. 125.
    Gillardon F, Bottiger B, Schmitz B, Zimmermann M, Hossmann KA (1997) Activation of CPP-32 protease in hippocampal neurons following ischemia and epilepsy. Brain Res Mol Brain Res 50:16–22PubMedGoogle Scholar
  126. 126.
    Love S, Barber R, Srinivasan A, Wilcock GK (2000a) Activation of caspase-3 in permanent and transient brain ischaemia in man. Neuro Report 11:2495–2499Google Scholar
  127. 127.
    Love S, Barber R, Wilcock GK (2000b) Neuronal death in brain infarcts in man. Neuropathol Appl Neurobiol 26:2055–2066Google Scholar
  128. 128.
    Zhu C, Wang X, Xu F, Bahr BA, Shibata M, Uchiyama Y, Hagberg H, Blomgren K (2005) The influence of age on apoptotic and other mechanisms of cell death after cerebral hypoxia–ischemia. Cell Death Diff 12:162–176Google Scholar
  129. 129.
    Ota K, Yakovlev AG, Itaya A, Kameoka M, Tanaka Y, Yoshihara K (2002) Alteration of apoptotic protease-activating factor-1 (APAF-1)-dependent apoptotic pathway during development of rat brain and liver. J Biochem (Tokyo) 131:131–135Google Scholar
  130. 130.
    Yakovlev AG, Ota K, Wang G, Movsesyan V, Bao WL, Yoshihara K, Faden AI (2001) Differential expression of apoptotic protease-activating factor-1 and caspase-3 genes and susceptibility to apoptosis during brain development and after traumatic brain injury. J Neurosci 21:7439–7446PubMedGoogle Scholar
  131. 131.
    Vekrellis K, McCarthy MJ, Watson A, Whitfield J, Rubin LL, Ham J (1997) Bax promotes neuronal cell death and is downregulated during the development of the nervous system. Development 124:1239–1249PubMedGoogle Scholar
  132. 132.
    Gill R, Soriano M, Blomgren K, Hagberg H, Wybrecht R, Miss MT, Hoefer S, Adam G, Niederhauser O, Kemp JA, Loetscher H (2002) Role of caspase-3 activation in cerebral ischemia-induced neurodegeneration in adult and neonatal brain. J Cereb Blood Flow Metab 22:420–430PubMedGoogle Scholar
  133. 133.
    Yuan J, Yankner BA (2000) Apoptosis in the nervous system. Nature 407:802–809PubMedGoogle Scholar
  134. 134.
    Merry DE, Korsmeyer SJ (1997) Bcl-2 gene family in the nervous system. Annu Rev Neurosci 20:245–267PubMedGoogle Scholar
  135. 135.
    Michaelidis TM, Sendtner M, Cooper JD, Airaksinen MS, Holtmann B, Meyer M, Thoenen H (1996) Inactivation of bcl-2 results in progressive degeneration of motoneurons, sympathetic and sensory neurons during early postnatal development. Neuron 17:75–89PubMedGoogle Scholar
  136. 136.
    Merry DE, Veis DJ, Hickey WF, Korsmeyer SJ (1994) bcl-2 protein expression is wide spread in the developing nervous system and retained in the adult PNS. Development 120:301–311PubMedGoogle Scholar
  137. 137.
    González-García M, García I, Ding L, O’Shea S, Boise LH, Thompson CB, Núñez G (1995) Bcl-x is expressed in embryonic and postnatal neural tissues and functions to prevent neuronal cell death. Proc Natl Acad Sci U S A 92:4304–4308PubMedGoogle Scholar
  138. 138.
    Motoyama N, Wang F, Roth KA, Sawa H, Nakayama K, Nakayama K, Negishi I, Senju S, Zhang Q, Fujii S et al (1995) Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science 267:1506–1510PubMedGoogle Scholar
  139. 139.
    Middleton G, Wyatt S, Ninkina N, Davies AM (2001) Reciprocal developmental changes in the roles of Bcl-w and Bcl-x(L) in regulating sensory neuron survival. Development 128:447–457PubMedGoogle Scholar
  140. 140.
    Oltvai ZN, Milliman CL, Korsmeyer SJ (1993) Bcl-2 heterodimerizes in vivowith a conserved homolog, Bax, that accelerates programmed cell death. Cell 74:609–619PubMedGoogle Scholar
  141. 141.
    Sedlak TW, Oltvai ZN, Yang E, Wang K, Boise LH, Thompson CB, Korsmeyer SJ (1995) Multiple Bcl-2 family members demonstrate selective dimerizations with Bax. Proc Natl Acad Sci U S A 92:7834–7838PubMedGoogle Scholar
  142. 142.
    Deckwerth TL, Elliott JL, Knudson CM, Johnson EM Jr, Snider WD, Korsmeyer SJ (1996) BAX is required for neuronal death after trophic factor deprivation and during development. Neuron 17:401–411PubMedGoogle Scholar
  143. 143.
    Yuan J, Yankner BA (2000) Apoptosis in the nervous system. Nature 407:802–809PubMedGoogle Scholar
  144. 144.
    Shindler KS, Latham CB, Roth KA (1997) Bax deficiency prevents the increased cell death of immature neurons in bcl-x-deficient mice. J Neurosci 17:3112–3119PubMedGoogle Scholar
  145. 145.
    O’Reilly LA, Print C, Hausmann G, Moriishi K, Cory S, Huang DC, Strasser A (2001) Tissue expression and subcellular localization of the pro-survival molecule Bcl-w. Cell Death Differ 8:486–494PubMedGoogle Scholar
  146. 146.
    Guegan C, Ceballos-Picot I, Nicole A, Kato H, Onteniente SB (1998) Recruitment of several neuroprotective pathways after permanent focal ischemia in mice. Exp Neurol 154:371–380PubMedGoogle Scholar
  147. 147.
    Minami M, Jin KL, Li W, Nagayama T, Henshall DC, Simon RP (2000) Bcl-w expression is increased in brain regions affected by focal cerebral ischemia in the rat. Neurosci Lett 279:193–195PubMedGoogle Scholar
  148. 148.
    Yan C, Chen J, Chen D, Minami M, Pei W, Yin XM, Simon RP (2000) Overexpression of the cell death suppressor Bcl-w in ischemic brain: implications for a neuroprotective role via the mitochondrial pathway. J Cereb Blood Flow Metab 20:620–630PubMedCrossRefGoogle Scholar
  149. 149.
    Ferrer I, Lopez E, Blanco R, Rivera R, Ballabriga J, Pozas E, Marti E (1998) Bcl-2, Bax, and Bcl-x expression in the CA1 area of the hippocampus following transient forebrain ischemia in the adult gerbil. Exp Brain Res 121:167–173PubMedGoogle Scholar
  150. 150.
    Okuno S, Saito A, Hayashi T, Chan PH (2004) The c-Jun N-terminal protein kinase signaling pathway mediates Bax activation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia. J Neurosci 24:7879–7887PubMedGoogle Scholar
  151. 151.
    Schmidt-Kastner R, Aguirre-Chen C, Kietzmann T, Saul I, Busto R, Ginsberg MD (2004) Nuclear localization of the hypoxia-regulated pro-apoptotic protein BNIP3 after global brain ischemia in the rat hippocampus. Brain Res 1001:133–142PubMedGoogle Scholar
  152. 152.
    Reimertz C, Kögel D, Rami A, Chittenden T, Prehn JH (2003) Gene expression during ER stress-induced apoptosis in neurons: induction of the BH3-only protein Bbc3/PUMA and activation of the mitochondrial apoptosis pathway. J Cell Biol 162:587–597PubMedGoogle Scholar
  153. 153.
    Gibson ME, Han BH, Choi J, Knudson CM, Korsmeyer SJ, Parsadanian M, Holtzman DM (2001) BAX contributes to apoptotic-like death following neonatal hypoxia–ischemia: evidence for distinct apoptosis pathways. Mol Med 7:644–655PubMedGoogle Scholar
  154. 154.
    Kermer P, Digicaylioglu MH, Kaul M, Zapata JM, Krajewska M, Stenner-Liewen F, Takayama S, Krajewski S, Lipton SA, Reed JC (2003) BAG1 over-expression in brain protects against stroke. Brain Pathol 13:495–506PubMedCrossRefGoogle Scholar
  155. 155.
    Conradt B, Horvitz HR (1998) The C. elegans protein EGL-1 is required for programmed cell death and interacts with the Bcl-2-like protein CED-9. Cell 93:519–529PubMedGoogle Scholar
  156. 156.
    Algeciras-Schimnich A, Shen L, Barnhart BC, Murmann AE, Burkhardt JK, Peter ME (2002) Molecular ordering of the initial signaling events of CD95. Mol Cell Biol 22:207–220PubMedGoogle Scholar
  157. 157.
    Ashkenazi A, Dixit VM (1998) Death receptors: signaling and modulation. Science 281:1305–1308PubMedGoogle Scholar
  158. 158.
    Sasaki C, Kitagawa H, Zhang WR, Warita H, Sakai K, Abe K (2000) Temporal profile of cytochrome c and caspase-3 immunoreactivities and TUNEL staining after permanent middle cerebral artery occlusion in rats. Neurol Res 22:223–228PubMedGoogle Scholar
  159. 159.
    Velier JJ, Ellison JA, Kikly KK, Spera PA, Barone FC, Feuerstein GZ (1999) Caspase-8 and caspase-3 are expressed by different populations of cortical neurons undergoing delayed cell death after focal stroke in the rat. J Neurosci 19:5932–5941PubMedGoogle Scholar
  160. 160.
    Rupalla K, Allegrini PR, Sauer D, Wiessner C (1998) Time course of microglia activation and apoptosis in various brain regions after permanent focal cerebral ischemia in mice. Acta Neuropathol (Berl) 96:172–178Google Scholar
  161. 161.
    Botchkina GI, Geimonen E, Bilof ML, Villarreal O, Tracey KJ (1999) Loss of NF-kappaB activity during cerebral ischemia and TNF cytotoxicity. Mol Med 5:372–381PubMedGoogle Scholar
  162. 162.
    Sairanen T, Carpen O, Karjalainen-Lindsberg ML, Paetau A, Turpeinen U, Kaste M, Lindsberg PJ (2001) Evolution of cerebral tumor necrosis factor alpha production during human ischemic stroke. Stroke 32:1750–1758PubMedGoogle Scholar
  163. 163.
    Gross A, Yin XM, Wang K, Wei MC, Jockel J, Milliman C, Erdjument-Bromage H, Tempst P, Korsmeyer SJ (1999) Caspase cleaved BID targets mitochondria and is required for cytochrome c release, while BCL-XL prevents this release but not tumor necrosis factor-R1/Fas death. J Biol Chem 274:1156–1163PubMedGoogle Scholar
  164. 164.
    Krupinski J, Lopez E, Marti E, Ferrer I (2000) Expression of caspases and their substrates in the rat model of focal cerebral ischemia. Neurobiol Dis 7:332–342PubMedGoogle Scholar
  165. 165.
    Li H, Zhu H, Xu CJ, Yuan J (1998) Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis. Cell 94:491–501PubMedGoogle Scholar
  166. 166.
    Luo X, Budihardjo I, Zou H, Slaughter C, Wang X (1998) Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94:481–490PubMedGoogle Scholar
  167. 167.
    Leist M, Single B, Castoldi AF, Kuhnle S, Nicotera P (1997) Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med 185:1481–1486PubMedGoogle Scholar
  168. 168.
    Schinzel AC, Takeuchi O, Huang Z, Fisher JK, Zhou Z, Rubens J, Hetz C, Danial NN, Moskowitz MA, Korsmeyer SJ (2005) Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc Natl Acad Sci U S A 102:12005–12010PubMedGoogle Scholar
  169. 169.
    Cain K, Brown DG, Langlais C, Cohen GM (1999) Caspase activation involves the formation of the aposome, a large (approximately 700 kDa) caspase activating complex. J Biol Chem 274:22686–22692PubMedGoogle Scholar
  170. 170.
    Kim HE, Du F, Fang M, Wang X (2005) Formation of apoptosome is initiated by cytochrome c-induced dATP hydrolysis and subsequent nucleotide exchange on Apaf-1. Proc Natl Acad Sci U S A 102:17545–17550PubMedGoogle Scholar
  171. 171.
    Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, Wang X (1997) Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91:479–489PubMedGoogle Scholar
  172. 172.
    Fujimura M, Morita-Fujimura Y, Murakami K, Kawase M, Chan PH (1998) Cytosolic redistribution of cytochrome c after transient focal cerebral ischemia in rats. J Cereb Blood Flow Metab 18:1239–1247PubMedGoogle Scholar
  173. 173.
    Perez-Pinzon MA, Xu GP, Born J, Lorenzo J, Busto R, Rosenthal M, Sick TJ (1999) Cytochrome C is released from mitochondria into the cytosol after cerebral anoxia or ischemia. J Cereb Blood Flow Metab 19:39–43PubMedGoogle Scholar
  174. 174.
    Cao G, Minami M, Pei W, Yan C, Chen D, O’Horo C, Graham SH, Chen J (2001) Intracellular Bax translocation after transient cerebral ischemia: implications for a role of the mitochondrial apoptotic signaling pathway in ischemic neuronal death. J Cereb Blood Flow Metab 21:321–333PubMedGoogle Scholar
  175. 175.
    Sugawara T, Fujimura M, Morita-Fujimura Y, Kawase M, Chan PH (1999) Mitochondrial release of cytochrome c corresponds to the selective vulnerability of hippocampal CA1 neurons in rats after transient forebrain ischemia. J Neurosci 19:RC39PubMedGoogle Scholar
  176. 176.
    Krajewski S, Krajewska M, Ellerby LM, Welsh K, Xie Z, Deveraux QL, Salvesen GS, Bredesen DE, Rosenthal RE, Fiskum G, Reed JC (1999) Release of caspase-9 from mitochondria during neuronal apoptosis and cerebral ischemia. Proc Natl Acad Sci U S A 96:5752–575PubMedGoogle Scholar
  177. 177.
    Cao G, Luo Y, Nagayama T, Pei W, Stetler RA, Graham SH, Chen J (2002) Cloning and characterization of rat caspase-9: implications for a role in mediating caspase-3 activation and hippocampal cell death after transient cerebral ischemia. J Cereb Blood Flow Metab 22:534–546PubMedGoogle Scholar
  178. 178.
    Mouw G, Zechel JL, Zhou Y, Lust WD, Selman WR, Ratcheson RA (2002) Caspase-9 inhibition after focal cerebral ischemia improves outcome following reversible focal ischemia. Metab Brain Dis 17:143–151PubMedGoogle Scholar
  179. 179.
    MacManus JP, Hill IE, Preston E, Rasquinha I, Walker T, Buchan AM (1995) Differences in DNA fragmentation following transient cerebral or decapitation ischemia in rats. J Cereb Blood Flow Metab 15:728–737PubMedGoogle Scholar
  180. 180.
    Chen J, Jin K, Chen M, Pei W, Kawaguchi K, Greenberg DA, Simon RP (1997) Early detection of DNA strand breaks in the brain after transient focal ischemia: implications for the role of DNA damage in apoptosis and neuronal cell death. J Neurochem 69:232–245PubMedCrossRefGoogle Scholar
  181. 181.
    Kihara S, Shiraishi T, Nakagawa S, Toda K, Tabuchi K (1994) Visualization of DNA double strand breaks in the gerbil hippocampal CA1 following transient ischemia. Neurosci Lett 175:133–136PubMedGoogle Scholar
  182. 182.
    Graham SH, Chen J (2001) Programmed cell death in cerebral ischemia. J Cereb Blood Flow Metab 21:99–109PubMedGoogle Scholar
  183. 183.
    Enari M, Sakahira H, Yokoyama H, Okawa K, Iwamatsu A, Nagata S (1998) A caspase-activated DNase that degrades DNA during apoptosis, and its inhibitor ICAD. Nature 391:43–50PubMedGoogle Scholar
  184. 184.
    Luo Y, Cao G, Pei W, O, Horo C, Graham SH, Chen J (2002) Induction of caspase-activated deoxyribonuclease activity after focal cerebral ischemia and reperfusion. J Cereb Blood Flow Metab 22:15–20PubMedGoogle Scholar
  185. 185.
    Sugawara T, Noshita N, Lewe’n A, Gasche Y, Ferrand-Drake M, Fujimura M, Morita-Fujimura Y, Chan PH (2002) Overexpression of copper/zinc superoxide dismutase in transgenic rats protects vulnerable neurons against ischemic damage by blocking the mitochondrial pathway of caspase activation. J Neurosci 22:209–217PubMedGoogle Scholar
  186. 186.
    Krajewski S, Mai JK, Krajewska M, Sikorska M, Mossakowski MJ, Reed JC (1995) Upregulation of bax protein levels in neurons following cerebral ischemia. J Neurosci 15:6364–6376PubMedGoogle Scholar
  187. 187.
    Putcha GV, Deshmukh M, Johnson EM Jr (1999) BAX translocation is a critical event in neuronal apoptosis: regulation by neuroprotectants, BCL-2, and caspases. J Neurosci 19:7476–7485PubMedGoogle Scholar
  188. 188.
    Sulejczak D, Czarkowska-Bauch J, Macias M, Skup M (2004) Bcl-2 and Bax proteins are increased in neocortical but not in thalamic apoptosis following devascularizing lesion of the cerebral cortex in the rat: an immunohistochemical study. Brain Res 1006:133–149PubMedGoogle Scholar
  189. 189.
    Linnik MD, Zahos P, Geschwind MD, Federoff HJ (1995) Expression of bcl-2 from a defective herpes simplex virus-1 vector limits neuronal death in focal cerebral ischemia. Stroke 26:1670–1674PubMedGoogle Scholar
  190. 190.
    Asoh S, Ohsawa I, Mori T, Katsura K, Hiraide T, Katayama Y, Kimura M, Ozaki D, Yamagata K, Ohta S (2002) Protection against ischemic brain injury by protein therapeutics. Proc Natl Acad Sci U S A 99:17107–17112PubMedGoogle Scholar
  191. 191.
    Zhao H, Yenari MA, Cheng D, Sapolsky RM, Steinberg GK (2003) Bcl-2 overexpression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochrome c translocation and caspase-3 activity. J Neurochem 85:1026–1036PubMedCrossRefGoogle Scholar
  192. 192.
    Poppe M, Reimertz C, Düssmann H, Krohn AJ, Luetjens CM, Böckelmann D, Nieminen AL, Kögel D, Prehn JH (2001) Dissipation of potassium and proton gradients inhibits mitochondrial hyperpolarization and cytochrome c release during neural apoptosis. J Neurosci 21:4551–4563PubMedGoogle Scholar
  193. 193.
    Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14–3–3, not Bcl-xL. Cell 87:619–628PubMedGoogle Scholar
  194. 194.
    Datta SR, Katsov A, Hu L, Petros A, Fesik SW, Yaffe MB, Greenberg ME (2000) 14–3–3 proteins and survival kinases cooperate to inactivate BAD by BH3 domain phosphorylation. Mol Cell 6:41–51PubMedGoogle Scholar
  195. 195.
    Zhang L, Chen J, Fu H (1999) Suppression of apoptosis signal-regulating kinase 1-induced cell death by 14–3–3 proteins. Proc Natl Acad Sci U S A 96:8511–8515PubMedGoogle Scholar
  196. 196.
    Hsu YT, Youle RJ (1997) Nonionic detergents induce dimerization among members of the Bcl-2 family. J Biol Chem 272:13829–13834PubMedGoogle Scholar
  197. 197.
    Saito A, Hayashi T, Okuno S, Ferrand-Drake M, Chan PH (2003) 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. J Neurosci 23:1710–1718PubMedGoogle Scholar
  198. 198.
    Zhu Y, Yang GY, Ahlemeyer B, Pang L, Che XM, Culmsee C, Klumpp S, Krieglstein J (2002) Transforming growth factor-beta 1 increases bad phosphorylation and protects neurons against damage. J Neurosci 22:3898–3909PubMedGoogle Scholar
  199. 199.
    Chan PH (2005) Mitochondrial dysfunction and oxidative stress as determinants of cell death/survival in stroke. Ann Acad Sci 1042:203–209Google Scholar
  200. 200.
    Kamada H, Nito C, Endo H, Chan PH (2007) Bad as a converging signaling molecule between survival PI3-K/Akt and death JNK in neurons after transient focal cerebral ischemia in rats. J Cereb Blood Flow Metab 27:521–533PubMedGoogle Scholar
  201. 201.
    Shiraishi H, Okamoto H, Yoshimura A, Yoshida H (2006) ER stress-induced apoptosis and caspase-12activation occurs downstream of mitochondrial apoptosis involving Apaf-1. J Cell Sci 119:3958–3966PubMedGoogle Scholar
  202. 202.
    Paschen W, Doutheil J (1999) Disturbances of the functioning of endoplasmic reticulum: a key mechanism underlying neuronal cell injury? J Cereb Blood Flow Metab 19:1–18PubMedGoogle Scholar
  203. 203.
    Ma Y, Hendershot LM (2001) The unfolding tale of the unfolded protein response. Cell 107:827–830PubMedGoogle Scholar
  204. 204.
    DeGracia DJ, Kumar R, Owen CR, Krause GS, White BC (2002) Molecular pathways of protein synthesis inhibition during brain reperfusion: implications for neuronal survival or death. J Cereb Blood Flow Metab 22:127–141PubMedGoogle Scholar
  205. 205.
    Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D (2000) Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol 2:326–332PubMedGoogle Scholar
  206. 206.
    Shen J, Chen X, Hendershot L, Prywes R (2002) ER stress regulation of ATF6 localization by dissociation of BiP/GRP78 binding and unmasking of Golgi localization signals. Dev Cell 3:99–111PubMedGoogle Scholar
  207. 207.
    Degracia DJ, Montie HL (2004) Cerebral ischemia and the unfolded protein response. J Neurochem 91:1–8PubMedGoogle Scholar
  208. 208.
    Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT, Remotti H, Stevens JL, Ron D (1998) CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 12:982–995PubMedGoogle Scholar
  209. 209.
    Oyadomari S, Mori M (2004) Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ 11:381–389PubMedGoogle Scholar
  210. 210.
    Hayashi T, Saito A, Okuno S, Ferrand-Drake M, Doddand RL, Chan PK (2005) Damage to the endoplasmic reticulum and activation of apoptotic machinery by oxidative stress in ischemic neurons. J Cereb Blood Flow Metab 25:41–53PubMedGoogle Scholar
  211. 211.
    Haze K, Yoshida H, Yanagi H, Yura T, Mori K (1999) Mammalian transcription factor ATF6 is synthesized as a transmembrane protein and activated by proteolysis in response to endoplasmic reticulum stress. Mol Biol Cell 10:3787–3799PubMedGoogle Scholar
  212. 212.
    Roy B, Lee AS (1999) The mammalian endoplasmic reticulum stress response element consists of an evolutionarily conserved tripartite structure and interacts with a novel stress-inducible complex. Nucleic Acids Res 27:1437–1443PubMedGoogle Scholar
  213. 213.
    Wang S, Longo FM, Chen J, Butman M, Graham SH, Haglid KG, Sharp FR (1993) Induction of glucose regulated protein (grp78) and inducible heat shock protein (hsp70) mRNAs in rat brain after kainic acid seizures and focal ischemia. Neurochem Int 23:575–582PubMedGoogle Scholar
  214. 214.
    Yoneda T, Imaizumi K, Oono K, Yui D, Gomi F, Katayama T, Tohyama M (2001) Activation of caspase-12, an endoplastic reticulum (ER) resident caspase, through tumor necrosis factor receptor-associated factor 2-dependent mechanism in response to the ER stress. J Biol Chem 276:13935–13940PubMedGoogle Scholar
  215. 215.
    Paschen W (1996) Disturbances of calcium homeostasis within the endoplasmic reticulum may contribute to the development of ischemic-cell damage. Med Hypotheses 47:283–288PubMedGoogle Scholar
  216. 216.
    Hu BR, Martone ME, Jones YZ, Liu CL (2000) Protein aggregation after transient cerebral ischemia. J Neurosci 20:3191–3199PubMedGoogle Scholar
  217. 217.
    Althausen S, Mengesdorf T, Mies G, Olah L, Nairn AC, Proud CG, Paschen W (2001) Changes in the phosphorylation of initiation factor eIF- 2alpha, elongation factor eEF-2 and p70 S6 kinase after transient focal cerebral ischaemia in mice. J Neurochem 78:779–787PubMedGoogle Scholar
  218. 218.
    Kumar R, Azam S, Sullivan JM, Owen C, Cavener DR, Zhang P, Ron D, Harding HP, Chen JJ, Han A, White BC, Krause GS, DeGracia DJ (2001) Brain ischemia and reperfusion activates the eukaryotic initiation factor 2alpha kinase, PERK. J Neurochem 77:1418–1421PubMedGoogle Scholar
  219. 219.
    Nowak TS Jr, Fried RL, Lust WD, Passonneau JV (1985) Changes in brain energy metabolism and protein synthesis following transient bilateral ischemia in the gerbil. J Neurochem 44:487–494PubMedGoogle Scholar
  220. 220.
    Paschen W, Gissel C, Linden T, Althausen S, Doutheil J (1998) Activation of gadd153 expression through transient cerebral ischemia: evidence that ischemia causes endoplasmic reticulum dysfunction. Brain Res Mol Brain Res 60:115–122PubMedGoogle Scholar
  221. 221.
    Mouw G, Zechel JL, Gamboa J, Lust WD, Selman WR, Ratcheson RA (2003) Activation of caspase-12, an endoplasmic reticulum resident caspase, after permanent focal ischemia in rat. Neuroreport 14:183–186PubMedGoogle Scholar
  222. 222.
    Shibata M, Hattori H, Sasaki T, Gotoh J, Hamada J, Fukuuchi Y (2003) Activation of caspase-12 by endoplasmic reticulum stress induced by transient middle cerebral artery occlusion in mice. Neuroscience 118:491–499PubMedGoogle Scholar
  223. 223.
    Szegezdi E, Fitzgerald U, Samali A (2003) Caspase-12 and ER-stress-mediated apoptosis: the story so far. Ann N Y Acad Sci 1010:186–194PubMedGoogle Scholar
  224. 224.
    Hetz C, Russelakis-Carneiro M, Maundrell K, Castilla J, Soto C (2003) Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein. EMBO J 22:5435–5445PubMedGoogle Scholar
  225. 225.
    Hitomi J, Katayama T, Eguchi Y, Kudo T, Taniguchi M, Koyama Y, Manabe T, Yamagishi S, Bando Y, Imaizumi K, Tsujimoto Y, Tohyama M (2004) Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Aβ-induced cell death. J Cell Biol 165:347–356PubMedGoogle Scholar
  226. 226.
    McCullough KD, Martindale JL, Klotz LO, Aw T, Holbrook NJ (2001) Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol 21:1249–1259PubMedGoogle Scholar
  227. 227.
    Zinszner H, Kuroda M, Wang X, Batchvarova N, Lightfoot RT, Remotti H, Stevens JL, Ron D (1998) CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev 12:982–995PubMedGoogle Scholar
  228. 228.
    Xu C, Bailly-Maitre B, Reed JC (2005) Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest 115:2656–2664PubMedGoogle Scholar
  229. 229.
    Tajiri S, Oyadomari S, Yano S, Morioka M, Gotoh T, Hamada J-I, Ushio Y, Mori M (2004) Ischemia-induced neuronal cell death is mediated by the endoplasmic reticulum stress pathway involving CHOP. Cell Death Differ 11:403–415PubMedGoogle Scholar
  230. 230.
    Putney JW Jr, Ribeiro CM (2000) Signaling pathways between the plasma membrane and endoplasmic reticulum calcium stores. Cell Mol Life Sci 57:1272–1286PubMedGoogle Scholar
  231. 231.
    Rutter GA, Rizzuto R (2000) Regulation of mitochondrial metabolism by ER Ca2+ release: an intimate connection. Trends Biochem Sci 25:215–221PubMedGoogle Scholar
  232. 232.
    Hacki J, Egger L, Monney L, Conus S, Rosse T, Fellay I, Borner C (2000) Apoptotic crosstalk between the endoplasmic reticulum and mitochondria controlled by Bcl-2. Oncogene 19:2286–2295PubMedGoogle Scholar
  233. 233.
    Boehning D, Patterson RL, Sedaghat L, Glebova NO, Kurosaki T, Snyder SH (2003) Cytochrome c binds to inositol (1,4,5) trisphosphate receptors, amplifying calcium-dependent apoptosis. Nat Cell Biol 5:1051–1061PubMedGoogle Scholar
  234. 234.
    Beresewicz M, Kowalczyk JE, Zablocka B (2006) Cytochrome c binds to inositol (1,4,5) trisphosphate and ryanodine receptors in vivo after transient brain ischemia in gerbils. Neurochem Int 48:568–571PubMedGoogle Scholar
  235. 235.
    Sanges D, Marigo V (2006) Cross-talk between two apoptotic pathways activated by endoplasmic reticulum stress: differential contribution of caspase-12 and AIF. Apoptosis 11:1629–1641PubMedGoogle Scholar
  236. 236.
    Chan SL, Mattson MP (1999) Caspase and calpain substrates: roles in synaptic plasticity and cell death. J Neurosci Res 58:167–190PubMedGoogle Scholar
  237. 237.
    Orrenius S, Zhivotovsky B, Nicotera P (2003) Regulation of cell death: the calcium-apoptosis link. Nat Rev Mol Cell Biol 4:552–565PubMedGoogle Scholar
  238. 238.
    Nakagawa T, Yuan J (2000) Cross-talk between two cysteine protease families: activation of caspase-12 by calpain in apoptosis. J Cell Biol 50:887–894Google Scholar
  239. 239.
    Raynaud F, Marcilhac A (2006) Implication of calpain in neuronal apoptosis. FEBS J 273:3437–3443PubMedGoogle Scholar
  240. 240.
    Garcıa-Bonilla L, Burda J, Pineiro D, Ayuso I, Gomez-Calcerrada M, Salinas M (2006) Calpain-induced proteolysis after transient global cerebral ischemia and ischemic tolerance in a rat model. Neurochem Res 31:1433–1441PubMedGoogle Scholar
  241. 241.
    Renolleau S, Benjelloun N, Ben-Ari Y, Charriaut-Marlangue C (1997) Regulation of apoptosis-associated proteins in cell death following transient focal ischemia in rat pups. Apoptosis 2:368–376PubMedGoogle Scholar
  242. 242.
    McGahan L, Hakim AM, Robertson GS (1998) Hippocampal Myc and p53 expression following transient global ischemia. Brain Res Mol Brain Res 56:133–145PubMedGoogle Scholar
  243. 243.
    Fortin A, Sean P, Jason C, MacLaurin G, Kushwaha N, Hickman ES, Thompson CS, Hakim A, Albert PR, Cecconi F, Helin K, Park DS, Slack RS (2001) APAF1 is a key transcriptional target for p53 in the regulation of neuronal cell death. J Cell Biol 155:207–216PubMedGoogle Scholar
  244. 244.
    Cheng T, Liu D, Griffin JH, Fernández JA, Castellino F, Rosen ED, Fukudome K, Zlokovic BV (2003) Activated protein C blocks p53-mediated apoptosis in ischemic human brain endothelium and is neuroprotective. Nat Med 9:338–342PubMedGoogle Scholar
  245. 245.
    Leker RR, Aharonowiz M, Greig NH, Ovadia H (2004) The role of p53-induced apoptosis in cerebral ischemia: effects of the p53 inhibitor pifithrinά. Exp Neurol 187:478–486PubMedGoogle Scholar
  246. 246.
    Endo H, Kamada H, Nito C, Nishi T, Chan PH (2006) Mitochondrial translocation of p53 mediates release of cytochrome c and hippocampal CA1 neuronal death after transient global cerebral ischemia in rats. J Neurosci 26:7974–7983PubMedGoogle Scholar
  247. 247.
    Susin SA, Lorenzo HK, Zamzami N, Marzo I, Snow BE, Brothers GM, Mangion J, Jacotot E, Costantini P, Loeffler M, Larochette N, Goodlett DR, Aebersold R, Siderovski DP, Penninger JM, Kroemer G (1999) Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397:441–446PubMedGoogle Scholar
  248. 248.
    Daugas E, Susin SA, Zamzami N, Ferri KF, Irinopoulou T, Larochette N, Prevost MC, Leber B, Andrews D, Penninger J, Kroemer G (2000) Mitochondrio-nuclear translocation of AIF in apoptosis and necrosis. FASEB J 14:729–739PubMedGoogle Scholar
  249. 249.
    Wang H, Yu SW, Koh DW, Lew J, Coombs C, Bowers W, Federoff HJ, Poirier GG, Dawson TM, Dawson VL (2004) Apoptosis-inducing factor substitutes for caspase executioners in NMDA-triggered excitotoxic neuronal death. J Neurosci 24:10963–10973PubMedGoogle Scholar
  250. 250.
    Cao G, Clark RS, Pei W, Yin W, Zhang F, Sun FY, Graham SH, Chen J (2003) Translocation of apoptosis-inducing factor in vulnerable neurons after transient cerebral ischemia and in neuronal cultures after oxygen-glucose deprivation. J Cereb Blood Flow Metab 23:1137–1150PubMedGoogle Scholar
  251. 251.
    Komjati K, Mabley JG, Virag L, Southan GJ, Salzman AL, Szabo C (2004) Poly (ADP-ribose) polymerase inhibition protect neurons and the white matter and regulates the translocation of apoptosisinducing factor in stroke. Int J Mol Med 13:373–382PubMedGoogle Scholar
  252. 252.
    Zhu C, Qiu L, Wang X, Hallin U, Cande C, Kroemer G, Hagberg H, Blomgren K (2003) Involvement of apoptosis-inducing factor in neuronal death after hypoxia–ischemia in the neonatal rat brain. J Neurochem 86:306–317PubMedGoogle Scholar
  253. 253.
    Matsumori Y, Hong SM, Aoyama K, Fan Y, Kayama T, Sheldon RA, Vexler ZS, Ferriero DM, Weinstein PR, Liu J (2005) Hsp70 overexpression sequesters AIF and reduces neonatal hypoxic/ischemic brain injury. J Cereb Blood Flow Metab 25:899–910PubMedGoogle Scholar
  254. 254.
    Plesnila N, Zhu C, Culmsee C, Groger M, Moskowitz MA, Blomgren K (2004) Nuclear translocation of apoptosis-inducing factor after focal cerebral ischemia. J Cereb Blood Flow Metab 24:458–466PubMedGoogle Scholar
  255. 255.
    Cande C, Vahsen N, Garrido C, Kroemer G (2004) Apoptosis-inducing factor (AIF): caspase-independent after all. Cell Death Differ 11:591–595PubMedGoogle Scholar
  256. 256.
    Zhao H, Yenari MA, Cheng D, Barreto-Chang OL, Sapolsky RM, Steinberg GK (2004) Bcl-2 transfection via herpes simplex virus blocks apoptosis-inducing factor translocation after focal ischemia in the rat. J Cereb Blood Flow Metab 24:681–692PubMedGoogle Scholar
  257. 257.
    Culmsee C, Zhu C, Landshamer S, Becattini B, Wagner E, Pellechia M, Blomgren K, Plesnila N (2005) Apoptosis-inducing factor triggered by poly (ADP-ribose) polymerase and Bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia. J Neurosci 25:10262–10272PubMedGoogle Scholar
  258. 258.
    Yu SW, Wang H, Poitras MF, Coombs C, Bowers WJ, Federoff HJ, Poirier GG, Dawson TM, Dawson VL (2002) Mediation of poly (adp-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor. Science 297:259–263PubMedGoogle Scholar
  259. 259.
    Endres M, Wang ZQ, Namura S, Waeber C, Moskowitz MA (1997) Ischemic brain injury is mediated by the activation of poly(ADP-ribose)polymerase. J Cereb Blood Flow Metab 17:1143–1151PubMedGoogle Scholar
  260. 260.
    Eliasson MJ, Sampei K, Mandir AS, Hurn PD, Traystman RJ, Bao J, Pieper A, Wang ZQ, Dawson TM, Snyder SH (1997) Poly(ADP-ribose) polymerase gene disruption renders mice resistant to cerebral ischemia. Nat Med 3:1089–1095PubMedGoogle Scholar
  261. 261.
    Johnson GL, Lapadat R (2002) Mitogen-activated protein kinase pathways mediated by erk, jnk, and p38 protein kinases. Science 298:1911–1912PubMedGoogle Scholar
  262. 262.
    Cheung ECC, Slack RS (2004) Emerging role for erk as a key regulator of neuronal apoptosis. Science`s stke. 251:PE45Google Scholar
  263. 263.
    Alessandrini A, Namura S, Moskowitz MA, Bonventre JV (1999) MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia. Proc Natl Acad Sci U S A 96:12866–12869PubMedGoogle Scholar
  264. 264.
    Zhuang S, Schnellmann RG (2006) A death-promoting role for extracellular signal-regulated kinase. J Pharmacol Exp Ther 319:991–997PubMedGoogle Scholar
  265. 265.
    Subramaniam S, Zirrgiebel U, Von Bohlen Und Halbach O, Strelau J, Laliberte C, Kaplan DR, Unsicker K (2004) ERK activation promotes neuronal degeneration predominantly through plasma membrane damage and independently of caspase-3. J Cell Biol 165:357–369PubMedGoogle Scholar
  266. 266.
    Irving EA, Barone FC, Reith AD, Hadingham SJ, Parsons AA (2000) Differential activation of MAPK/ERK and p38/SAPK in neurones and glia following focal cerebral ischaemia in the rat. Brain Res Mol Brain Res 77:65–75PubMedGoogle Scholar
  267. 267.
    Namura S, Iihara K, Takami S, Nagata I, Kikuchi H, Matsushita K, Moskowitz MA, Bonventre JV, Alessandrini A (2001) Intravenous administration of MEK inhibitor U0126 affords brain protection against forebrain ischemia and focal cerebral ischemia. Proc Natl Acad Sci U S A 98:11569–11574PubMedGoogle Scholar
  268. 268.
    Hetman M, Gozaz A (2004) Role of extracellular signal regulated kinases 1 and 2 in neuronal survival. Eur J Biochem 271:050–2055Google Scholar
  269. 269.
    Noshita N, Sugawara T, Hayashi T, Lewén A, Omar G, Chan PH (2002) Copper/zinc superoxide dismutase attenuates neuronal cell death by preventing extracellular signal-regulated kinase activation after transient focal cerebral ischemia in mice. J Neurosci 22:923–7930Google Scholar
  270. 270.
    Irving EA, Bamford M (2002) Role of mitogen- and stress-activated kinases in ischemic injury. J Cereb Blood Flow Metab 22:631–647PubMedGoogle Scholar
  271. 271.
    Gao Y, Signore AP, Yin W, Cao G, Yin X, Sun F, Luo Y, Graham SH, Chen J (2005) Neuroprotection against focal ischemic brain injury by inhibition of c-Jun N-terminal kinase and attenuation of the mitochondrial apoptosis-signaling pathway. J Cereb Blood Flow Metab 25:694–712PubMedGoogle Scholar
  272. 272.
    Shackelford DA, Yeh RY (2006) Modulation of ERK and JNK activity by transient forebrain ischemia in rats. J Neurosci Res 83:476–488PubMedGoogle Scholar
  273. 273.
    Kuan C-Y, Whitnarsh A, Yang DD, Lioa G, Schloemer A, Dong C, Bao J, Banasiak K, Haddad GG, Flavell RA, Davis R, Rakic P (2003) A critical role of neural-specific JNK3 for ischemic apoptosis. Proc Natl Acad Sci U S A 100:15184–15189PubMedGoogle Scholar
  274. 274.
    Cheng A, Chan SL, Milhavet O, Wang S, Mattson MP (2001) p38 map kinase mediates nitric oxide-induced apoptosis of neural progenitor cells. J Biol Chem 276:43320–43327PubMedGoogle Scholar
  275. 275.
    Xia Z, Dickens M, Raingeaud J, Davis RJ, Greenberg ME (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270:1326–1331PubMedGoogle Scholar
  276. 276.
    Clem RJ, Fechheimer M, Miller LK (1991) Prevention of apoptosis by a baculovirus gene during infection of insect cells. Science 254:1388–1390PubMedGoogle Scholar
  277. 277.
    Wilkinson JC, Wilkinson AS, Scott FL, Csomos RA, Salvesen GS, Duckett CS (2004) Neutralization of Smac/Diablo by inhibitors of apoptosis (IAPs). J Biol Chem 279:51082–51090PubMedGoogle Scholar
  278. 278.
    Fan T, Han L, Cong R, Liang J (2005) Caspase family proteases and apoptosis. Acta Biochimica et Biophysica Sinica 37:719–727PubMedGoogle Scholar
  279. 279.
    Yang Y, Fang S, Jensen JP, Weissman AM, Ashwell JD (2000) Ubiquitin protein ligase activity of IAPs and their degradation in proteasomes in response to apoptotic stimuli. Science 288:874–877PubMedGoogle Scholar
  280. 280.
    Eberhardt O, Coelln RV, Kugler S, Lindenau J, Rathke-Hartlieb S, Gerhardt E, Haid S, Isenmann S, Gravel C, Srinivasan A, Bahr M, Weller M, Dichgans J, Schulz JB (2000) Protection by synergistic effects of adenovirus-mediated x-chromosome-linked inhibitor of apoptosis and glial cell line-derived neurotrophic factor gene transfer in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson’s disease. J Neurosci 15:9126–9134Google Scholar
  281. 281.
    Simons M, Beinroth S, Gleichmann M, Liston P, Korneluk RG, MacKenzie AE, Bahr M, Klockgether T, Robertson GS, Weller M, Schulz JB (1999) Adenovirus-mediated gene transfer of IAPs delays apoptosis of cerebellar granule neurons. J Neurochem 72:292–301PubMedGoogle Scholar
  282. 282.
    Siegelin MD, Kossatz LS, Winckler J, Rami A (2005) Regulation of XIAP and Smac/DIABLO in the rat hippocampus following transient forebrain ischemia. Neurochem Int 46:41–51PubMedGoogle Scholar
  283. 283.
    Vaux DL, Silke J (2003) Mammalian mitochondrial IAP binding proteins. Biochem Biophys Res Commun 304:499–504PubMedGoogle Scholar
  284. 284.
    Costantini P, Bruey JM, Castedo M, Métivier D, Loeffler M, Susin SA, Ravagnan L, Zamzami N, Garrido C, Kroemer G (2002) Pre-processed caspase-9 contained in mitochondria participates in apoptosis. Cell Death Differ 9:82–88PubMedGoogle Scholar
  285. 285.
    Saito A, Hayashi T, Okuno S, Nishi T, Chan PH (2004) Oxidative stress is associated with xiap and Smac/Diablo signaling pathways in mouse brains after transient focal cerebral ischemia. Stroke 35:1443–1448PubMedGoogle Scholar
  286. 286.
    Siegelin M, Touzani O, Toutain J, Liston P, Ramia A (2005) Induction and redistribution of XAF1, a new antagonist of XIAP in the rat brain after transient focal ischemia. Neurobiol Dis 20:509–518PubMedGoogle Scholar
  287. 287.
    Wang X, Zhu C, Wang X, Hagberg H, Korhonen L, Sandberg M, Lindholm D, Blomgren K (2004) X-linked inhibitor of apoptosis (XIAP) protein protects against caspase activation and tissue loss after neonatal hypoxia–ischemia. Neurobiol Dis 16:179–189PubMedGoogle Scholar
  288. 288.
    Faccio L, Fusco C, Chen A, Martinotti S, Bonventre JV, Zervos AS (2000) Characterization of a novel human serine protease that has extensive homology to bacterial heat shock endoprotease htra and is regulated by kidney ischemia. J Biol Chem 275:2581–2588PubMedGoogle Scholar
  289. 289.
    Savopoulos JW, Carter PS, Turconi S, Pettman GR, Karran EH, Gray CW, Ward RV, Jenkins O, Creasy CL (2000) Expression, purification, and functional analysis of the human serine protease HtrA2. Protein Expr Purif 19:227–234PubMedGoogle Scholar
  290. 290.
    Yang Q, Church-Hajduk R, Ren J, Newton ML, Du C (2003) Omi/HtrA2 catalytic cleavage of inhibitor of apoptosis (IAP) irreversibly inactivates IAPs and facilitates caspase activity in apoptosis. Genes Dev 17:1487–1496PubMedGoogle Scholar
  291. 291.
    Saito A, Hayashi T, Okuno S, Nishi T, Chan PH (2004) Modulation of the Omi/HtrA2 signaling pathway after transient focal cerebral ischemia in mouse brains that over express SOD1. Mol Brain Res 127:89–95PubMedGoogle Scholar
  292. 292.
    Althaus J, Siegelin MD, Dehghani F, Cilenti L, Zervos AS, Rami A (2007) The serine protease Omi/HtrA2 is involved in XIAP cleavage and in neuronal cell death following focal cerebral ischemia/reperfusion. Neurochem Intl 50:172–180Google Scholar
  293. 293.
    Nowak TS Jr (1993) Synthesis of heat shock/stress proteins during cellular injury. Ann NY Acad Sci 679:142–156PubMedGoogle Scholar
  294. 294.
    Sharp FR, Kinouchi H, Koistinaho J, Chan PH, Sagar SM (1993) HSP70 heat shock gene regulation during ischemia. Stroke 24:I72–175PubMedGoogle Scholar
  295. 295.
    Yenari MA, Giffard RG, Sapolsky RM, Steinberg GK (1999) The neuroprotective potential of heat shock protein 70 (HSP70). Mol Med Today 5:525–531PubMedGoogle Scholar
  296. 296.
    Weinstein PR, Hong S, Sharp FR (2004) Molecular identification of the ischemic penumbra. Stroke 35:2666–2670PubMedGoogle Scholar
  297. 297.
    Rajdev S, Hara K, Kokubo Y, Mestril R, Dillmann W, Weinstein PR, Sharp FR (2000) Mice overexpressing rat heat shock protein 70 are protected against cerebral infarction. Ann Neurol 47:782–791PubMedGoogle Scholar
  298. 298.
    Van der Weerd L, Lythgoe MF, Badin RA, Valentim LM, Akbar MT, de Belleroche JS, Latchman DS, Gadian DG (2005) Neuroprotective effects of HSP70 overexpression after cerebral ischaemia-An MRI study. Exp Neurol 195:257–266PubMedGoogle Scholar
  299. 299.
    Tsuchiya D, Hong S, Matsumori Y, Shiina H, Kayama T, Swanson RA, Dillman WH, Liu J, Panter SS, Weinstein PR (2003) Overexpression of rat heat shock protein 70 is associated with reduction of early mitochondrial cytochrome c release and subsequent DNA fragmentation after permanent focal ischemia. J Cereb Blood Flow Metab 23:718–727PubMedGoogle Scholar
  300. 300.
    Lee SH, Kwon HM, Kim YJ, Lee KM, Kim M, Yoon BW (2004) Effects of Hsp70.1 gene knockout on the mitochondrial apoptotic pathway after focal cerebral ischemia. Stroke 35:2195–2199PubMedGoogle Scholar
  301. 301.
    Matsumori Y, Hong SM, Aoyama K, Fan Y, Kayama T, Sheldon RA, Vexler ZS, Ferriero DM, Weinstein PR, Liu J (2005) Hsp70 overexpression sequesters AIF and reduces neonatal hypoxic/ischemic brain injury. J Cereb Blood Flow Metab 25:899–910PubMedGoogle Scholar
  302. 302.
    Park HS, Lee JS, Huh SH, Seo JS, Choi EJ (2001) Hsp72 functions as a natural inhibitory protein of c-Jun N-terminal kinase. EMBO J 20:446–456PubMedGoogle Scholar
  303. 303.
    Meriin AB, Yaglom JA, Gabai VL, Zon L, Ganiatsas S, Mosser DD, Zon L, Sherman MY (1999) Protein-damaging stresses activate c-Jun N-terminal kinase via inhibition of its dephosphorylation: a novel pathway controlled by HSP72. Mol Cell Biol 19:2547–2555PubMedGoogle Scholar
  304. 304.
    Klionsky DJ, Emr SD (2000) Autophagy as a regulated pathway of cellular degradation. Science 290:1717–1721PubMedGoogle Scholar
  305. 305.
    Tsujimoto Y, Shimizu S (2005) Another way to die: autophagic programmed cell death. Cell Death Differ 12:528–1534Google Scholar
  306. 306.
    Yuan J, Lipinski M, Degterev A (2003) Diversity in the mechanisms of neuronal cell death. Neuron 40:401–413PubMedGoogle Scholar
  307. 307.
    Eskelinen EL, Jekyll D, Hyde M (2005) Autophagy can promote both cell survival and cell death. Cell Death Differ 12:1468–1472PubMedGoogle Scholar
  308. 308.
    Ogata M, Hino S, Saito A, Morikawa K, Kondo S, Kanemoto S, Murakami T, Taniguchi M, Tanii I, Yoshinaga K, Shiosaka S, Hammarback JA, Urano F, Imaizumi K (2006) Autophagy is activated for cell survival after endoplasmic reticulum stress. Mol Cell Biol 26:9220–9231PubMedGoogle Scholar
  309. 309.
    Adhami F, Schloemer A, Kuan C (2007) The roles of Autophagy in cerebral ischemia. Autophagy 3:42–44PubMedGoogle Scholar
  310. 310.
    Hamacher-Brady A, Brady NR, Gottlieb RA (2006) The interplay between pro-death and pro-survival signaling pathways in myocardial ischemia/reperfusion injury: apoptosis meets autophagy. Cardiovasc Drugs Ther 20:445–462PubMedGoogle Scholar
  311. 311.
    Levine B, Yuan J (2005) Autophagy in cell death: an innocent convict? J Clin Invest 115:2679–2688PubMedGoogle Scholar
  312. 312.
    Lebeurrier N, Vivien D, Ali C (2004) The complexity of tissue-type plasminogen activator: can serine protease inhibitors help in stroke management? Expert Opin Ther Targets 8:309–320PubMedGoogle Scholar
  313. 313.
    Montaner J, Molina CA, Monasterio J, Abilleira S, Arenillas JF, Ribo M, Quintana M, Alvarez-Sabin J (2003) Matrix metalloproteinase-9 pretreatment level predicts intracranial hemorrhagic complications after thrombolysis in human stroke. Circulation 107:598–603PubMedGoogle Scholar
  314. 314.
    Wang X, Lee SR, Arai K, Lee SR, Tsuji K, Rebeck GW, Lo EH (2003) Lipoprotein receptor-mediated induction of matrix metalloproteinase by tissue plasminogen activator. Nat Med 9:1313–1317PubMedGoogle Scholar
  315. 315.
    Pfefferkon T, Rosenberg GA (2003) Closure of the blood–brain barrier by matrix metalloproteinase inhibition reduces rtPA-mediated mortality in cerebral ischemia with delayed reperfusion. Stroke 34:2025–2030Google Scholar
  316. 316.
    Reddrop C, Moldrich RX, Beart PM, Farso M, Liberatore GT, Howells DW, Petersen KU, Schleuning WD, Medcalf RL (2005) Vampire bat salivary plasminogen activator (desmoteplase) inhibits tissue-type plasminogen activator-induced potentiation of excitotoxic injury. Stroke 36:1241–1246PubMedGoogle Scholar
  317. 317.
    Hacke W, Albers G, Al-Rawi Y, Bogousslavsky J, Davalos A, Eliasziw M, Fischer M, Furlan A, Kaste M, Lees KR, Soehngen M, Warach S (2005) The desmoteplase in Acute Ischemic Stroke Trial (DIAS): a phase II MRI-based 9-hour window acute stroke thrombolysis trial with intravenous desmoteplase. DIAS Study Group Stroke 36:66–73PubMedGoogle Scholar
  318. 318.
    Furlan AJ, Eyding D, Albers GW, Al-Rawi Y, Lees KR, Rowley HA, Sachara C, Soehngen M, Warach S, Hacke W (2006) Dose escalation of desmoteplase for acute ischemic stroke (DEDAS) evidence of safety and efficacy 3 to 9 hours after stroke onset. Stroke 37:1227–1231PubMedGoogle Scholar
  319. 319.
    Suzuki Y, Chen F, Ni Y, Marchal G, Collen D, Nagai N (2004) Microplasmin reduces ischemic brain damage and improves neurological function in a rat stroke model monitored with MRI. Stroke 35:2402–2406PubMedGoogle Scholar
  320. 320.
    Chen F, Suzuki Y, Nagai N, Sun X, Wang H, Yu J, Marchal G, Ni Y (2007) Microplasmin and tissue plasminogen activator: comparison of therapeutic effects in rat stroke model at multiparametric MR imaging. Radiology 244:429–438PubMedGoogle Scholar
  321. 321.
    Watanabe T, Yuki S, Egawa M, Nishi H (1994) Protective effects of MCI-186 on cerebral ischemia: possible involvement of free radical scavenging and antioxidant actions. J Pharmacol Exp Ther 268:1597–1604PubMedGoogle Scholar
  322. 322.
    The Edaravone Acute Brain Infarction Study Group (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 15:222–229Google Scholar
  323. 323.
    Watanabe T, Morita I, Nishi H, Murota S (1988) Preventive effect of MCI-186 on 15-HPETE induced vascular endothelial cell injury in vitro. Prostaglandins Leukot Essent Fat Acids 33:81–87Google Scholar
  324. 324.
    Abe K, Yuki S, Kogure K (1988) Strong attenuation of ischemic and postischemic brain edema in rats by a novel free radical scavenger. Stroke 19:480–485PubMedGoogle Scholar
  325. 325.
    Yamamoto T, Yuki S, Watanabe T, Mitsuka M, Saito K, Kogure K (1997) Delayed neuronal death prevented by inhibition of increased hydroxyl radical formation in a transient cerebral ischemia. Brain Res 762:240–242PubMedGoogle Scholar
  326. 326.
    Toyoda K, Fujii K, Kamouchia M, Nakane H, Arihiro S, Okada Y, Ibayashi S, Iida M (2004) Free radical scavenger, edaravone, in stroke with internal carotid artery occlusion. J Neurol Sci 221:11–17PubMedGoogle Scholar
  327. 327.
    Qi X, Okuma Y, Hosoi T, Nomura Y (2004) Edaravone protects against hypoxia/ischemia-induced endoplasmic reticulum dysfunction. J Pharmacol Exp Ther 311:388–393PubMedGoogle Scholar
  328. 328.
    Mizuno A, Umemura K, Nakashima M (1998) Inhibitory effect of MCI-186, a free radical scavenger, on cerebral ischemia following rat middle cerebral artery occlusion. Gen Pharmacol 30:575–578PubMedGoogle Scholar
  329. 329.
    Lees KR, Zivin JA, Ashwood T, Davalos A, Davis SM, Diener H, Grotta J, Lyden P, Shuaib A, Hardemark H, Wasiewski WW (2006) NXY-059 for acute ischemic stroke. N Engl J Med 354:588–600PubMedGoogle Scholar
  330. 330.
    Fisher M (2007) Advances in stroke 2006. Stroke 38:214–215Google Scholar
  331. 331.
    Iadecola C, Zhang F, Xu X (1995) Inhibition of inducible nitric oxide synthase ameliorates cerebral ischemic damage. Am J Physiol 268:R286–R292PubMedGoogle Scholar
  332. 332.
    Zhao X, Haensel C, Araki E, Ross ME, Iadecola C (2000) Gene-dosing effect and persistence of reduction in ischemic brain injury in mice lacking inducible nitric oxide synthase. Brain Res 872:215–218PubMedGoogle Scholar
  333. 333.
    Coughlan T, Gibson C, Murphy S (2005) Modulatory effects of progesterone on inducible nitric oxide synthase expression in vivo and in vitro. J Neurochem 93:932–942PubMedGoogle Scholar
  334. 334.
    Park EM, Cho S, Frys KA, Glickstein SB, Zhou P, Anrather J, Ross ME, Iadecola C (2006) Inducible nitric oxide synthase contributes to gender differences in ischemic brain injury. J Cereb Blood Flow Metab 26:392–401PubMedGoogle Scholar
  335. 335.
    Kawano T, Anrather J, Zhou P, Park L, Wang G, Frys KA, Kunz A, Cho S, Orio M, Iadecola C (2006) Prostaglandin E2 EP1 receptors: downstream effectors of COX-2 neurotoxicity. Nat Med 12:225–229PubMedGoogle Scholar
  336. 336.
    Ruehl ML, Orozco JA, Stoker MB, McDonagh PF, Coull BM, Ritter LS (2002) Protective effects of inhibiting both blood and vascular selectins after stroke and reperfusion. Neurol Res 24:226–232PubMedGoogle Scholar
  337. 337.
    Mulcahy NJ, Ross J, Rothwell NJ, Loddick SA (2003) Delayed administration of interleukin-1 receptor antagonist protects against transient cerebral ischaemia in the rat. Br J Pharmacol 140:471–476PubMedGoogle Scholar
  338. 338.
    Yang GY, Zhao YJ, Davidson BL, Betz AL (1997) Overexpression of interleukin-1 receptor antagonist in the mouse brain reduces ischemic brain injury. Brain Res 751:181–188PubMedGoogle Scholar
  339. 339.
    Pinteaux E, Rothwell NJ, Boutin H (2006) Neuroprotective actions of endogenous interleukin-1 receptor antagonist (IL-1ra) are mediated by glia. Glia 53:551–556PubMedGoogle Scholar
  340. 340.
    Vemuganti R, Dempsey RJ, Bowen KK (2004) Inhibition of intercellular adhesion molecule-1 protein expression by antisense oligonucleotides is neuroprotective after transient middle cerebral artery occlusion in rat. Stroke 35:179–184PubMedGoogle Scholar
  341. 341.
    Mayne M, Ni W, Yan HJ, Xue M, Johnston JB, Del Bigio MR, Peeling J, Power C (2001) Antisense oligodeoxynucleotide inhibition of tumor necrosis factor-alpha expression is neuroprotective after intracerebral hemorrhage. Stroke 32:240–248PubMedGoogle Scholar
  342. 342.
    Luo Y, Yin W, Signore AP, Zhang F, Hong Z, Wang S, Graham SH, Chen J (2006) Neuroprotection against focal ischemic brain injury by the peroxisome proliferator-activated receptor-g agonist rosiglitazone. J Neurochem 97:435–448PubMedGoogle Scholar
  343. 343.
    Tureyen K, Kapadia R, Bowen KK, Satriotomo I, Liang J, Feinstein DL, Vemuganti R (2007) Peroxisome proliferator-activated receptor-gamma agonists induce neuroprotection following transient focal ischemia in normotensive, normoglycemic as well as hypertensive and type-2 diabetic rodents. J Neurochem 101:41–45PubMedGoogle Scholar
  344. 344.
    Park SW, Yi JH, Miranpuri G, Satriotoma I, Bowen K, Resnick DK, Vemuganti R (2007) Thiazolidinedione class of peroxisome proliferator-activated receptor gamma agonists prevents neuronal damage, motor dysfunction, myelin loss, neuropathic pain, and inflammation after spinal cord injury in adult rats. J Pharmacol Exp Ther 320:1002–1012PubMedGoogle Scholar
  345. 345.
    Deplanque D, Gelé P, Pétrault O, Six I, Furman C, Bouly M, Nion S, Dupuis B, Leys D, Fruchart JC, Cecchelli R, Staels B, Duriez P, Bordet R (2003) Peroxisome proliferator-activated receptor-alpha activation as a mechanism of preventive neuroprotection induced by chronic fenofibrate treatment. J Neurosci 23:6264–6271PubMedGoogle Scholar
  346. 346.
    Iwashita A, Muramatsu Y, Yamazaki T, Muramoto M, Kita Y, Yamazaki S, Mihara K, Moriguchi A, Matsuoka N (2007) Neuroprotective efficacy of the peroxisome proliferator-activated receptor delta-selective agonists in vitro and in vivo. J Pharmacol Exp Ther 320:1087–1096PubMedGoogle Scholar
  347. 347.
    Romera C, Hurtado O, Mallolas J, Pereira MP, Morales JR, Romera A, Serena J, Vivancos J, Nombela F, Lorenzo P, Lizasoain I, Moro MA (2007) Ischemic preconditioning reveals that GLT1/EAAT2 glutamate transporter is a novel PPAR gamma target gene involved in neuroprotection. J Cereb Blood Flow Metab 27:1327–1338PubMedGoogle Scholar
  348. 348.
    Koh SH, Chang D-I, Kim H-T, Kim J, Kim M-H, Kim KS, Bae I, Kim H, Kim DW, Kim SH (2005) Effect of 3-aminobenzamide, PARP inhibitor, on matrix metalloproteinase-9 level in plasma and brain of ischemic stroke model. Toxicol 214:131–139Google Scholar
  349. 349.
    Loddick SA, MacKenzie A, Rothwell NJ (1996) An ICE inhibitor, z-VAD-DCB attenuates ischaemic brain damage in the rat. NeuroReport 7:1465–1468PubMedGoogle Scholar
  350. 350.
    Hara H, Friedlander RM, Gagliardini V, Ayata C, Fink K, Huang Z, Shimizu-Sasamata M, Yuan J, Moskowitz MA (1997) Inhibition of interleukin 1 β-converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc Natl Acad Sci U S A 94:2007–2012PubMedGoogle Scholar
  351. 351.
    Endres M, Namura S, Shimizu-Sasamata M, Waeber C, Zhang L, Gómez-Isla T, Hyman BT, Moskowitz MA (1998) Attenuation of delayed neuronal death after mild focal ischemia in mice by inhibition of the caspase family. J Cereb Blood Flow Metab 18:238–247PubMedGoogle Scholar
  352. 352.
    Cheng Y, Deshmukh M, D, Costa A, Demaro JA, Gidday JM, Shah A, Sun Y, Jacquin MF, Johnson EM, Holtzman DM (1998) Caspase inhibitor affords neuroprotection with delayed administration in a rat model of neonatal hypoxic-ischemic brain injury. J Clin Investig 101:1992–1999PubMedGoogle Scholar
  353. 353.
    Li H, Colbourne F, Sun P, Zhao Z, Buchan AM (2000) Caspase inhibitors reduce neuronal injury after focal but not global cerebral ischemia in rats. Stroke 31:176–182PubMedGoogle Scholar
  354. 354.
    Inoue S, Davis DP, Drummond JC, Cole DJ, Patel PM (2006) The combination of isoflurane and caspase 8 inhibition results in sustained neuroprotection in rats subject to focal cerebral ischemia. Anesth Analg 102:1548–1555PubMedGoogle Scholar
  355. 355.
    Frankel AD, Pabo CO (1988) Cellular uptake of the tat protein from human immunodeficiency virus. Cell 55:1189–1193PubMedGoogle Scholar
  356. 356.
    Green M, Loewenstein PM (1988) Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein. Cell 55:1179–1188PubMedGoogle Scholar
  357. 357.
    Fawell S, Seery J, Daikh Y, Moore C, Chen LL, Pepinsky B, Barsoum J (1994) Tat-mediated delivery of heterologous proteins into cells. Proc Natl Acad Sci U S A 91:664–668PubMedGoogle Scholar
  358. 358.
    Schwarze SR, Ho A, Vocero-Akbani A, Dowdy SF (1999) In vivo protein transduction: delivery of a biologically active protein into the mouse. Science 285:1569–1572PubMedGoogle Scholar
  359. 359.
    Kilic U, Kilic E, Dietz GP, Bahr M (2003) Intravenous TAT-GDNF is protective after focal cerebral ischemia in mice. Stroke 34:1304–1310PubMedGoogle Scholar
  360. 360.
    Kilic E, Dietz GP, Hermann DM, Bahr M (2002) Intravenous TAT-Bcl-xL is protective after middle cerebral artery occlusion in mice. Ann Neurol 52:617–622PubMedGoogle Scholar
  361. 361.
    Guegan C, Braudeau J, Couriaud C, Dietz GP, Lacombe P, Bahr M, Nosten-Bertrand M, Onteniente B (2006) PTD-XIAP protects against cerebral ischemia by anti-apoptotic and transcriptional regulatory mechanisms. Neurobiol Dis 22:177–186PubMedGoogle Scholar
  362. 362.
    Fan YF, Lu CZ, Xie J, Zhao YX, Yang GY (2006) Apoptosis inhibition in ischemic brain by intraperitoneal PTD-BIR3-RING (XIAP). Neurochem Int 48:50–59PubMedGoogle Scholar
  363. 363.
    Cao YJ, Shibata T, Rainov NG (2002) Liposome-mediated transfer of the bcl-2 gene results in neuroprotection after in vivo transient focal cerebral ischemia in an animal model. Gene Ther 9:415–419PubMedGoogle Scholar
  364. 364.
    Hong KW, Kim KY, Lee JH, Shin HK, Kwak YG, Kim SO, Lim H, Yoo SE (2002) Neuroprotective effect of (2S,3S,4R)-N″-cyano-N-(6-amino-3, 4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N′-benzylguanidine(KR-31378), a benzopyran analog, against focal ischemic brain damage in rats. J Pharmacol Exp Ther 301:210–216PubMedGoogle Scholar
  365. 365.
    Kim KY, Lee JH, Park JH, Yoo MA, Kwak YG, Kim SO, Yoo SE, Hong KW (2004) Anti-apoptotic action of (2S,3S,4R)-N″-cyano-N-(6-amino-3,4-dihydro-3-hydroxy-2-methyl-2-dimethoxymethyl-2H-benzopyran-4-yl)-N′-benzylguanidine (KR-31378) by suppression of the phosphatase and tensin homolog deleted from chromosome 10 phosphorylation and increased phosphorylation of casein kinase2/Akt/ cyclic AMP response element binding protein via maxi-K channel opening in neuronal cells. Eur J Pharmacol 497:267–277PubMedGoogle Scholar
  366. 366.
    Choi JM, Shin HK, Kim KY, Lee JH, Hong KW (2002) Neuroprotective effect of cilostazol against focal cerebral ischemia via antiapoptotic action in rats. J Pharmacol Exp Ther 300:787–793PubMedGoogle Scholar
  367. 367.
    Scott CW, Sobotka-Briner C, Wilkins DE, Jacobs RT, Folmer JJ, Frazee WJ, Bhat RV, Ghanekar SV, Aharony D (2003) Novel small molecule inhibitors of caspase-3 block cellular and biochemical features of apoptosis. J Pharmacol ExpTher 304:433–440Google Scholar
  368. 368.
    D’Mello SR, Chin PC (2005) Treating neurodegenerative conditions through the understanding of neuronal apoptosis. Curr Drug Targets CNS Neurol Disord 4:3–23PubMedGoogle Scholar
  369. 369.
    Jiang ZG, Lu XC, Nelson V, Yang X, Pan W, Chen RW, Lebowitz MS, Almassian B, Tortella FC, Brady RO, Ghanbari HA (2006) A multifunctional cytoprotective agent that reduces neurodegeneration after ischemia. Proc Natl Acad Sci U S A 103:1581–1586PubMedGoogle Scholar
  370. 370.
    Belayev L, Liu Y, Zhao W, Busto R, Ginsberg MD (2001) Human albumin therapy of acute ischemic stroke: marked neuroprotective efficacy at moderate doses and with a broad therapeutic window. Stroke 32:553–560PubMedGoogle Scholar
  371. 371.
    Belayev L, Pinard E, Nallet H, Seylaz J, Liu Y, Riyamongkol P, Zhao W, Busto R, Ginsberg MD (2002) Albumin therapy of transient focal cerebral ischemia: in vivo analysis of dynamic microvascular responses. Stroke 33:1077–1084PubMedGoogle Scholar
  372. 372.
    Ginsberg MD, Hill MD, Palesch YY, Ryckborst KJ, Tamariz D (2006) The ALIAS pilot trial. A ose-escalation and safety study of albumin therapy for acute ischemic stroke-I: physiological responses and safety results. Stroke 37:2100–2106PubMedGoogle Scholar
  373. 373.
    Palesch YY, Hill MD, Ryckborst KJ, Tamariz D, Ginsberg MD (2006) The ALIAS pilot trial. A dose-escalation and safety study of albumin therapy for acute ischemic stroke-II: neurological outcome and efficiency analysis. Stroke 37:2107–2114PubMedGoogle Scholar
  374. 374.
    Belayev L, Marcheselli VL, Khoutorova L, Rodriguez de Turco EB, Busto R, Ginsberg MD, Bazan NG (2005) Docosahexaenoic acid complexed to albumin elicits high-grade ischemic neuroprotection. Stroke 36:118–123PubMedGoogle Scholar
  375. 375.
    Bazan NG (2005) Synaptic signaling by lipids in the life and death of neurons. Mol Neurobiol 31:219–230PubMedGoogle Scholar
  376. 376.
    Marcheselli VL, Hong S, Lukiw WJ, Tian XH, Gronert K, Musto A, Hardy M, Gimenez JM, Chiang N, Serhan CN, Bazan NG (2003) Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J Biol Chem 278:43807–43817PubMedGoogle Scholar
  377. 377.
    Nelson PT, Kondziolka D, Wechsler L, Goldstein S, Gebel J, DeCesare S, Elder EM, Zhang PJ, Jacobs A, McGrogan M, Lee VM, Trojanowski JQ (2002) Clonal human (hNT) neuron grafts for stroke therapy: neuropathology in a patient 27 months after implantation. Am J Pathol 160:1201–1206PubMedGoogle Scholar
  378. 378.
    Gilman S (2006) Pharmacologic management of ischemic stroke: relevance to stem cell therapy. Exp Neurol 199:28–33PubMedGoogle Scholar
  379. 379.
    Zhang R, Zhang Z, Wang L, Wang Y, Gousev A, Zhang L, Ho KL, Morshead C, Chopp M (2004) Activated neural stem cells contribute to stroke-induced neurogenesis and neuroblast migration toward the infarct boundary in adult rats. J Cereb Blood Flow Metab 24:441–448PubMedGoogle Scholar
  380. 380.
    Schäbitz WR, Kollmar R, Schwaninger M, Juettler E, Bardutzky J, Schölzke MN, Sommer C, Schwab S (2003) Neuroprotective effect of granulocyte colony-stimulating factor after focal cerebral ischemia. Stroke 34:745–751PubMedGoogle Scholar
  381. 381.
    Schneider A, Krüger C, Steigleder T, Weber D, Pitzer C, Laage R, Aronowski J, Maurer MH, Gassler N, Mier W, Hasselblatt M, Kollmar R, Schwab S, Sommer C, Bach A, Kuhn HG, Schäbitz WR (2005) The hematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest 115:2083–2098PubMedGoogle Scholar
  382. 382.
    Siren AL, Fratelli M, Brines M, Goemans C, Casagrande S, Lewczuk P, Keenan S, Gleiter C, Pasquali C, Capobianco A (2001) Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci U S A 98:4044–4049PubMedGoogle Scholar
  383. 383.
    Wang L, Zhang Z, Wang Y, Zhang R, Chopp M (2004) Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in Rats. Stroke 35:1732–1737PubMedGoogle Scholar
  384. 384.
    Villa P, Van Beek J, Larsen AK, Gerwien J, Christensen S, Cerami A, Brines M, Leist M, Ghezzi P, Torup L (2007) Reduced functional deficits, neuroinflammation, and secondary tissue damage after treatment of stroke by nonerythropoietic erythropoietin derivatives. J Cereb Blood Flow Metab 27:552–563PubMedGoogle Scholar
  385. 385.
    Leist M, Ghezzi P, Grasso G, Bianchi R, Villa P, Fratelli M, Savino C, Bianchi M, Nielsen J, Gerwien J, Kallunki P, Larsen AK, Helboe L, Christensen S, Pedersen LO, Nielsen M, Torup L, Sager T, Sfacteria A, Erbayraktar S, Erbayraktar Z, Gokmen N, Yilmaz O, Cerami-Hand C, Xie QW, Coleman T, Cerami A, Brines M (2004) Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 305:239–242PubMedGoogle Scholar
  386. 386.
    Zhang R, Wang Y, Zhang L, Zhang Z, Tsang W, Lu M, Chopp M (2002) Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke 33:2675–2680PubMedGoogle Scholar
  387. 387.
    Zhang RL, Zhang Z, Zhang L, Wang Y, Zhang C, Chopp M (2006) Delayed treatment with sildenafil enhances neurogenesis and improves functional recovery in aged rats after focal cerebral ischemia. J Neurosci Res 83:1213–1219PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Venkata Prasuja Nakka
    • 1
  • Anchal Gusain
    • 1
  • Suresh L. Mehta
    • 1
  • Ram Raghubir
    • 1
  1. 1.Division of PharmacologyCentral Drug Research InstituteLucknowIndia

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