Pathophysiology of acute ischaemic stroke: An analysis of common signalling mechanisms and identification of new molecular targets

Pathobiology

Volumn 73, Issue 4, 2006, Pages 159-175

  Mitsios, N ^a   Gaffney, J ^a   Kumar, P ^a   Krupinski, J ^c   Kumar, S ^b   Slevin, M ^a  

^a MANCHESTER METROPOLITAN UNIVERSITY   (United Kingdom)

^b UNIVERSITY OF MANCHESTER   (United Kingdom)

^c HOSPITAL UNIVERSITARI DE BELLVITGE   (Spain)

Author keywords

Angiogenesis; Apoptosis; Cerebral ischaemia; Excitotoxicity; Inflammation; Neuroprotection

Indexed keywords

ANGIOGENESIS; APOPTOSIS; BLOOD CLOT LYSIS; BLOOD VESSEL OCCLUSION; CAUSE OF DEATH; CEREBROVASCULAR ACCIDENT; DISABILITY; DISEASE EXACERBATION; DRUG DESIGN; EVALUATION; EXCITOTOXICITY; GENE TARGETING; HUMAN; INFLAMMATION; NEUROPROTECTION; PATHOPHYSIOLOGY; PRIORITY JOURNAL; PROTEIN ANALYSIS; PROTEIN TARGETING; REVIEW; SIGNAL TRANSDUCTION; TREATMENT PLANNING;

ANIMALS; APOPTOSIS; CEREBROVASCULAR ACCIDENT; CHEMOPREVENTION; DISEASE MODELS, ANIMAL; HUMANS; NERVE DEGENERATION; SIGNAL TRANSDUCTION;

EID: 33751340832     PISSN: 10152008     EISSN: None     Source Type: Journal    
DOI: 10.1159/000096017     Document Type: Review

References (163)

1. Astrup J, Siesjo BK, Symon L: Thresholds in cerebral ischaemia - the ischaemic penumbra. Stroke 1981;12:723-725.
2. Heiss WD: Ischaemic penumbra: evidence from functional imaging in man. J Cereb Blood Flow Metab 2000;20:1276-1293.
3. Mies G, Auer LM, Ebhardt G, Traupe H, Heiss WD: Flow and neuronal density in tissue surrounding chronic infarction. Stroke 1983;14:22-27.
4. Bandera E, Botteri M, Minelli C, Sutton A, Abrams KR, Latronico N: Cerebral blood flow threshold of ischaemic penumbra and infarct core in acute ischaemic stroke. Stroke 2006;37:1334-1339.
5. Kidwell CS, Saver JL, Mattiello J, Starkman S, Vinuela F, Duckwiler G, et al: Thrombolytic reversal of acute human cerebral ischaemic injury shown by diffusion/perfusion magnetic resonance imaging. Ann Neurol 2000;47:462-469.
6. 2O positron emission tomography predicts irreversible ischaemic cortical damage in stroke patients receiving acute thrombolytic therapy. Stroke 2000;31:366-369.
7. Slevin M, Krupinski J, Kumar P, Gaffney J, Kumar S: Gene activation and protein expression following ischemic stroke: strategies towards neuroprotection. J Cell Mol Med 2005;9:85-102.
8. Dirnagl U, Iadecola C, Moskowitz MA: Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 1999;22:391-397.
9. Choi DW: Excitotoxicity, apoptosis and ischemic stroke. J Biochem Mol Biol 2001;34:8-14.
10. Gwag BJ, Won SJ, Kim DY: Excitotoxicity, oxidative stress and apoptosis in ischaemic neuronal death;in Lin RCS (ed): New Concepts in Cerebral Ischaemia. London, CRC Press, 2002, pp 79-112.
11. Leker RL, Shohami E: Cerebral ischaemia and trauma - different aetiologies yet similar mechanisms: neuroprotective opportunities. Brain Res Rev 2002;39:55-73.
12. Oyler GA, Higgins GA, Hart RA, Battenberg ML, Billingsley M, Bloom FE, Wilson WC: The identification of a novel synaptosomal-protein, SNAP-25, differentially expressed by neuronal subpopulations. J Cell Biol 1989;109:3039-3052.
13. Geddes JW, Hess EJ, Hart RA, Kesslak JP, Cotman CW, Wilson MC: Lesions of hippocampal circuitry define synaptosomal-associated protein-25 (SNAP-25) as a novel presynaptic marker. Neuroscience 1990;38:515-525.
14. Marti E, Ferrer I, Ballabriga J, Blasi J: Increase in SNAP-25 immunoreactivity in the mossy fibres following transient forebrain ischaemia in the gerbil. Acta Neuropathol 1998;95:254-260.
15. Ishimaru H, Casamenti F, Ueda K, Maruyama Y, Pepeu G: Changes in presynaptic proteins, SNAP25 and synaptophysin, in the hippocampal CA1 area in ischaemic gerbils. Brain Res 2001;903:94-101.
16. Barone FC, Feuerstein GZ: Inflammatory mediators and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab 1999;19:819-834.
17. Pelidou SH, Kostulas N, Matusevicius D, Kivisakk P, Kostulas V, Link H: High levels of IL-10 secreting cells are present in blood in cerebrovascular diseases. Eur J Neurol 1999;6:437-442.
18. Nathan CF, Prendergast TJ, Wiebe ME, Stanley ER, Platser E, Remold HG, Welte K, Rubin BY, Murray HW: Activation of human macrophages. Comparison of other cytokines with interferon-gamma. J Exp Med 1984;160:600-605.
19. Baadsgaard O, Fisher GJ, Voorhees JJ, Cooper KD: Interactions of epidermal cells and T cells in inflammatory skin diseases. J Am Acad Dermatol 1990;23:1312-1316.
20. Vila N, Castillo J, Davalos A, Chamorro A: Proinflammatory cytokines and early neurological worsening in ischaemic stroke. Stroke 2001;31:2325-2329.
21. Wiessner C, Gehrmann J, Lindholm D, Topper R, Kreutzberg GW, Hossmann KA: Expression of transforming growth factor-beta 1 and interleukin-1 beta mRNA in rat brain following transient forebrain ischemia. Acta Neuropathol 1993;86:439-446.
22. Liu T, Clark RK, McDonnell PC, Young PR, White RF, Barone FC, Feuerstein GZ: Tumour necrosis factor-alpha expression in ischemic neurons. Stroke 1994;25:1481-1488.
23. Wang X, Yue TL, Barone FC, White RF, Gagnon RC, Feuerstein GZ: Concomitant cortical expression of TNF-alpha and IL-1 beta mRNAs follows early response gene expression in transient focal ischemia. Mol Chem Neuropathol 1994;23:103-114.
24. Buttini M, Sauter A, Boddeke HW: Induction of interleukin-1 beta mRNA after focal cerebral ischaemia in the rat. Brain Res Mol Brain Res 1994;23:126-134.
25. Fassbender K, Rossol S, Kammer T, Daffertshefer M, Wirth S, Dollman M, Hennerici M: Proinflammatory cytokines in serum of patients with acute cerebral ischemia: kinetics of secretion and relation to the extent of brain damage and outcome of disease. J Neurol Sci 1994;122:135-139.
26. Botchkina GI, Meistrell ME, Botchkina IL, Tracey KJ: Expression of TNF and TNF receptors (p55 and p75) in the rat brain after focal cerebral ischemia. Mol Med 1997;3:765-781.
27. Wang XK, Barone FC, Aiyar NV, Feuerstein GZ, del Zoppo GJ: Interleukin-1 receptor and receptor antagonist gene expression after focal stroke in rats. Stroke 1997;28:155-162.
28. Hillhouse EW, Kida S, Iannotti F: Middle cerebral artery occlusion in the rat causes a biphasic production of immunoreactive interleukin-1beta in the cerebral cortex. Neurosci Lett 1998;249:177-179.
29. Zhang Z, Chopp M, Goussev A, Powers C: Cerebral vessels express interleukin 1 beta after focal cerebral ischemia. Brain Res 1998;784:210-217.
30. Lawrence CB, Allan SM, Rothwell NJ: Interleukin-1 b and the interleukin-1 receptor antagonist act in the striatum to modify excitotoxic brain damage in the rat. Eur J Neurosci 1998;10:1188-1195.
31. Kostulas N, Pelidou SH, Kivisakk P, Kostulas V, Link H: Increased IL-1beta, IL-8, and IL-17 mRNA expression in blood mononuclear cells observed in a prospective ischemic stroke study. Stroke 1999;30:2174-2179.
32. Ferrarese C, Mascarucci P, Zoia C, Cavarrotta G, Frigo M, Begni B, Sarinella F, Frattola F, De Simoni MG: Increased cytokine release from peripheral blood cells after acute stroke. J Cereb Blood Flow Metab 1999;19:1004-1009.
33. Legos JJ, Whitmore RG, Erhardt JA, Parsons AA, Tuma RF, Barone FC: Quantitative changes in interleukin proteins following focal stroke in the rat. Neurosci Lett 2000;282:189-192.
34. Gregersen R, Lambertsen K, Finsen B: Microglia and macrophages are the major source of tumour necrosis factor in permanent middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 2000;20:53-65.
35. Sairanen TR, Lindsberg PJ, Brenner M, Carpen O, Siren A: Differential cellular expression of tumour necrosis factor-alpha and type I tumour necrosis factor receptor after transient global forebrain ischemia. J Neurol Sci 2001;186:87-99.
36. Zaremba J, Losy J: Early TNF-alpha levels correlate with ischaemic stroke severity. Acta Neurol Scand 2001;104:288-295.
37. Perini F, Morra M, Alecci M, Galloni E, Marchi M, Toso V: Temporal profile of serum anti-inflammatory and pro-inflammatory interleukins in acute ischaemic stroke patients. Neurol Sci 2001;22:289-296.
38. Intiso D, Zarrelli MM, Lagioia G, Di Rienzo F, De Ambrosio CC, Simone P, Tonali P, Cioffi RP: Tumour necrosis factor alpha serum levels and inflammatory response in acute ischemic stroke patients. Neurol Sci 2004;24:390-396.
39. Pana W, Dinga Y, Yua Y, Ohtakib H, Nakamachib T, Kastina AJ: Stroke upregulates TNFαtransport across the blood-brain barrier. Exp Neurol 2006;198:222-233.
40. Wang XK, Yue TL, Barone FC, Feuerstein GZ: Monocyte chemoattractant protein-1 messenger RNA expression in rat ischaemic cortex. Stroke 1995;26:661-665.
41. Matsumoto T, Ikeda K, Mukaida N, Harada A, Matsumoto Y, Yamashita J, Matsushima K: Prevention of cerebral oedema and infarct in cerebral reperfusion injury by an antibody to interleukin-8. Lab Invest 1997;77:119-125.
42. Che X, Ye W, Panga L, Wu DC, Yang GY: Monocyte chemoattractant protein-1 expressed in neurons and astrocytes during focal ischemia in mice. Brain Res 2001;902:171-177.
43. Hughes PM, Allegrini PR, Rudin M, Perry VH, Mir AK, Wiessner C: Monocyte chemoattractant protein-1 deficiency is protective in a murine stroke model. J Cereb Blood Flow Metab 2002;22:308-317.
44. Clark WM, Coull BM, Briley DP, Mainolfi E, Rothlein R: Circulating intercellular adhesion molecule-1 levels and neutrophil adhesion in stroke. J Neuroimmunol 1993;44:123-125.
45. Matsuo Y, Onodera H, Shiga Y, et al: Role of cell adhesion molecules in brain injury after transient middle cerebral artery occlusion in the rat. Brain Res 1994;656:344-352.
46. Wang X, Siren AL, Liu Y, Yue TL, Barone FC, Feuerstein GZ: Upregulation of intercellular adhesion molecule 1 (ICAM-1) on brain microvascular endothelial cells in rat ischemic cortex. Brain Res Mol Brain Res 1994;26:61-68.
47. Fassbender K, Mossner R, Motsch L, Kischka U, Grau A, Hennerici M: Circulating selectin-and immunoglobulin-type adhesion molecules in acute ischemic stroke. Stroke 1995;26:1361-1364.
48. Connolly ES, Winfree CJ, Prestigiacomo CJ, et al: Exacerbation of cerebral injury in mice that express the P-selectin gene: identification of P-selectin blockade as a new target for the treatment of stroke. Circ Res 1997;81:304-310.
49. Bitsch A, Klene W, Murtada L, Prange H, Rieckmann P: A longitudinal prospective study of soluble adhesion molecules in acute stroke. Stroke 1998;29:2129-2135.
50. Ge H, Wen Y, Yang G, Betz AL: Increased expression of intercellular adhesion molecule-1 in mouse focal cerebral ischemia model. Chin Med J 2000;113:75-79.
51. Zhang RL, Chopp M, Jiang N, Tang WX, Prostak J, Manning AM, Anderson DC: Anti-intracellular adhesion molecule-1 antibody reduces ischaemic cell damage after transient but not permanent middle cerebral artery occlusion in the Wistar rat. Stroke 1995;26:1438-1442.
52. Suzuki H, Hayashi T, Tojo SJ, Kitagawa H, Kimura K, Mizugaki M, Itoyama Y, Abe K: Anti-P-selectin antibody attenuates rat brain ischaemic injury. Neurosci Lett 1999;265:163-166.
53. Huang J, Choundhri TF, Winfree CJ, McTaggart RA, Kiss S, Mocco J, Kim LJ, Protopsaltis TS, Zhang Y, Pinsky DJ, Connolly ES: Postischemic cerebrovascular E-selectin expression mediates tissue injury in murine stroke. Stroke 2000;31:3047-3053.
54. Vemuganti R, Dempsey RJ, Bowen KK: Inhibition of intracellular adhesion molecule-1 protein expression by antisense oligonucleotides is neuroprotective after transient middle cerebral artery occlusion in rat. Stroke 2004;35:179-184.
55. Toyoda T, Suzuki S, Kassell NF, Lee KS: Intraischaemic hypothermia attenuates neutrophil infiltration in the rat neocortex after focal ischaemia-reperfusion injury. Neurosurgery 1996;39:1200-1205.
56. Dawson J, Hurtenbach U, MacKenzie A: Cyclosporin A inhibits the in vivo production of interleukin-1 beta and tumour necrosis factor alpha, but not interleukin-6, by a T-cell-independent mechanism. Cytokine 1996;8:882-888.
57. Spera PA, Ellison JA, Feuerstein GZ, Barone FC: IL-10 reduces rat brain injury following focal stroke. Neurosci Lett 1998;251:189-192.
58. Dietrich WD, Busto R, Bethea JR: Postischaemic hypothermia and IL-10 treatment provide long-lasting neuroprotection of CA1 hippocampus following transient global ischaemia in rats. Exp Neurol 1999;158:444-450.
59. Vila N, Castillo J, Davalos A, Esteve A, Planas AM, Chamorro A: Levels of anti-inflammatory cytokines and neurological worsening in acute ischaemic stroke. Stroke 2003;34:671-675.
60. Ooboshi H, Ibayashi S, Shichita T, Kumai Y, Takada J, Ago T, Arakawa S, Sugimori H, Kamouchi M, Kitazono T, Iida M: Postischaemic gene transfer of interleukin-10 protects against both focal and global brain ischaemia. Circulation 2005;111:913-919.
61. Hirschberg DL, Yoles E, Belkin M, Schwartz M: Inflammation after axonal injury has conflicting consequences for recovery of function: rescue of spared axons is impaired but regeneration is supported. J Neuroimmunol 1994;50:9-16.
62. Bruce AJ, Boling W, Kindy MS, Peschon J, Kraemer PJ, Carpenter MK, Holtsberg FW, Mattson MP: Altered neuronal and microglial responses to excitotoxic and ischaemic brain injury in mice lacking TNF receptors. Nat Med 1996;2:788-794.
63. Gusev E, Skvortsova VI: Microglial activation, cytokine production and local inflammation in focal brain ischaemia;in Brain Ischaemia. Dordrecht, Kluwer Academic Publishers, 2003, pp 115-145.
64. Martin-Villalba A, Hahne M, Kleber S, Vogel J, Falk W, Schenkel J, Krammer PH: Therapeutic neutralization of CD95-ligand and TNF attenuates brain damage in stroke. Cell Death Differ 2001;8:679-686.
65. Shohami E, Ginis I, Hallenbeck JM: Dual role of tumour necrosis factor alpha in brain injury. Cytokine Growth Factor Rev 1999;10:119-130.
66. Boutin H, LeFeuvre RA, Horai R, Asano M, Iwakura Y, Rothwell NJ: Role of IL-1 alpha and IL-1 beta in ischaemic brain damage. J Neurosci 2001;21:5528-5534.
67. Touzani O, Boutin H, Chuquet J, Rothwell N: Potential mechanisms of interleukin-1 involvement in cerebral ischaemia. J Neuroimmunol 1999;100:203-215.
68. Li JH, Wang HC, Mason JM, Levine J, Yu M, Ulloa L, Czura C, Tracey KJ, Yang H: Recombinant HMGB1 with cytokine-stimulating activity. J Immunol Methods 2004;289:211-223.
69. Kalinina N, Agrotis A, Antropova Y, DiVitto G, Kanellakis P, Kostolias G, Ilyinskaya O, Tararak E, Bobik A: Increased expression of the DNA-binding cytokine HMGB1 in human atherosclerotic lesions - role of activated macrophages and cytokines. Arterioscler Thromb Vasc Biol 2004;24:2320-2325.
70. Degryse B, Bonaldi T, Scaffidi P, Muller S, Resnati M, Sanvito F, Arrigoni G: The HMG boxes of the nuclear protein HMG1 induce chemotaxis and cytoskeleton reorganization in rat smooth muscle cells. J Cell Biol 2001;152:1197-1206.
71. Czura CJ, Yang H, Tracey KJ: High mobility group box-1 as a therapeutic target downstream of tumour necrosis factor. J Infect Dis 2003;187:S391-S396.
72. Cheung RTF, Diab T, Cechetto DF: Time-course of neuropeptide changes in peri-ischaemic zone and amygdale following focal ischaemia in rats. J Comp Neurol 1995;360:101-120.
73. Cheung RT, Cechetto DF: Neuropeptide changes following excitotoxic lesion of the insular cortex in rats. J Comp Neurol 1995;362:535-550.
74. Chen SH, Cheung RTF: Peripheral and central administration of neuropeptide Y in a rat middle cerebral artery occlusion stroke model reduces cerebral blood flow and increases infarct volume. Brain Res 2002;927:138-143.
75. Chen SH, Cheung RTF: Neuropeptide Y and its analogs differentially modulate the immunoreactivity for neuronal or endothelial nitric oxide synthase in the rat brain following focal ischaemia with reperfusion. J Biomed Sci 2005;12:267-278.
76. Ivacko J, Szaflarski J, Malinak C, Flory C, Warren JS, Silverstein FS: Hypoxic-ischaemic injury induces monocyte chemoattractant protein-1 expression in neonatal rat brain. J Cereb Blood Flow Metab 1997;17:759-770.
77. Yamagami S, Tamura M, Hayashi M, Endo N, Tanabe H, Katsuura Y: Differential production of MCP-1 and cytokine-induced neutrophil chemoattractant in the ischaemic brain after transient focal ischaemia in rats. J Leukoc Biol 1999;65:744-749.
78. Che XM: Monocyte chemoattractant protein-1 expressed in neurons and astrocytes during focal ischaemia in mice. Brain Res 2001;902:171-177.
79. Losy J, Zaremba J: Monocyte chemoattractant protein-1 is increased in the cerebrospinal fluid of patients with ischaemic stroke. Stroke 2001;32:2695-2696.
80. Sanchez-Moreno C, Dashe JF, Scott T, Thaler D, Folstein MF, Martin A: Decreased levels of plasma vitamin C and increased levels of inflammatory and oxidative stress markers after stroke. Stroke 2004;35:163-168.
81. Chen Y, Hallenbeck JM, Ruetzler C, Bol D, Thomas K, Berman NE, Vogel SN: Over-expression of MCP-1 in brain exacerbates ischaemic injury and is associated with recruitment of inflammatory cells. J Cereb Blood Flow Metab 2003;23:748-755.
82. Strle K, Zhou JH, Shen WH, Broussard SR, Johnson RW, Freund GG, Dantzer R, Kelley KW: Interleukin-10 in the brain. Crit Rev Immunol 2001;21:427-449.
83. Zhai QH, Futrell N, Chen FJ: Gene expression of IL-10 in relationship to TNF-α, IL-1β and IL-2 in the rat brain following middle cerebral artery occlusion. J Neurol Sci 1997;152:119-124.
84. Lee JL, Zipfel GJ, Choi DW: The changing landscapes of ischaemic brain injury mechanisms. Nature 1999;399(suppl):A7-A14.
85. Choi DW: Ischaemia-induced neuronal apoptosis. Curr Opin Neurobiol 1996;6:667-672.
86. Le DA, Wu YQ, Huang ZH, Matsushita K, Plesnila N, Augustinack JC, Hyman BT, Yuan JY, Kuida K, Flavell RA, Moskowitz MA: Caspase activation and neuroprotection in caspase-3-deficient mice after in vivo cerebral ischaemia and in vitro oxygen glucose deprivation. Proc Natl Acad Sci USA 2002;99:15188-15193.
87. Joza N, Susin SA, Daugas E, Stanford WL, Cho SK, Li CY, Sasaki T, Elia AJ, Cheng HY, Ravagnan L, Ferri KF, Zamzami N, Wakeham A, Hakem R, Yoshida HH, Kong YY, Mak TW, Zuniga-Pflucker JC, Kroemer G, Penninger JM: Essential role of the mitochondrial apoptosis-inducing factor in programmed cell death. Nature 2001;401:549-554.
88. Eldadah BA, Faden AI: Caspase pathways, neuronal apoptosis, and CNS injury. J Neurotrauma 2000;17:811-829.
89. Gillardon F, Kiprianova I, Sandkuhler J, Hossmann KA, Spranger M: Inhibition of caspases prevents cell death of hippocampal CA1 neurons but not impairment of longterm potentiation following global ischaemia. Neuroscience 1999;93;1219-1222.
90. Miyashita T, Krajewski S, Krajewska M, Wang HG, Lin HK, Liebermann DA, Hoffman Reed JC: Tumour suppressor p53 is a regulator of bcl-2 and bax gene expression in vitro and in vivo. Oncogene 1994;9:1799-1805.
91. Mihara M, Erster S, Zaika A, Petrenko O, Chittenden T, Pancoska P, Moll UM: P53 has a direct apoptogenic role at the mitochondria. Mol Cell 2003;11:577-590.
92. Li Y, Chopp M, Zhang Z, Zaloga C, Niewenhuis L, Gautam S: P53 immunoreactive protein and mRNA expression after transient MCAO in rats. Stroke 1994;23:849-855.
93. Tomasevic G, Kamme F, Stubberod P, Wieloch M, Wieloch T: The tumour suppressor p53 and its response gene p21 are not markers of neuronal death following transient global cerebral ischaemia. Neuroscience 1999;90:781-792.
94. Culmsee C, Zhu XX, Yu QS, Chan SL, Camandola S, Guo ZH, Greig NH, Mattson MP: A synthetic inhibitor of p53 protects neurons against death induced by ischaemic and excitotoxic insults, and amyloid β-peptide. J Neurochem 2001;77:220-228.
95. Gupta S, Campbell D, Derijard B, Davis RJ: Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science 1995;267:389-393.
96. Okuno S, Saito A, Hayashi T, Chan PH: The c-jun N-terminal protein kinase signalling pathway mediates bax activation and subsequent neuronal apoptosis through interaction with bim after transient cerebral ischaemia. J Neurosci 2004;24:7879-7887.
97. Hayashi T, Sakai K, Sasaki C, Zhang WR, Warita H, Abe K: JNK and JIP response in rat brain after transient MCAO. Neurosci Lett 2000;284:195-199.
98. Shackelford DA, Yeh RY: Differential effects of ischaemia and reperfusion on c-Jun N-terminal kinase isoform protein and activity. Mol Brain Res 2001;94:178-192.
99. Krupinski J, Slevin M, Marti E, Catena E, Rubio F, Gaffney J: Time-course phosphorylation of the MAP kinase group of signalling proteins and related molecules following MCAO in the rats. Neuropathol Appl Neurobiol 2003;29:114-158.
100. + channels. Neuron 2004;41:351-365.
101. Borsello T, Clarke PGH, Hirt L, Vercelli A, Repici M, Schorderet DF, Bogousslavsky J, Bonny C: A peptide inhibitor of JNK protects against excitotoxicity and cerebral ischaemia. Nat Med 2003;9:1180-1186.
102. Zhu Y, Sun Y, Xie L, Jin K, Sheibani N, Greenberg DA: Hypoxic induction of endoglin via mitogen-activated protein kinases in mouse brain micro-vascular endothelial cells. Stroke 2003;34:2483-2488.
103. Duff SE, Li CG, Garland JM, Kumar S: CD105 is important for angiogenesis: evidence and potential applications. FASEB J 2003;17:984-992.
104. Yoshizumi M, Fujita Y, Izawa Y, Suzaki Y, Kyaw M, Ali N, Tsuchiya K, Kagami S, Yano S, Sone S, Tamaki T: Ebselen inhibits TNFα-induced JNK activation and adhesion molecule expression in endothelial cells. Exp Cell Res 2004;292:1-10.
105. Herdegen T, Claret FX, Kallunki T, Martin-Villalba A, Winter C, Hunter T, Karin M: Lasting N-terminal phosphorylation of c-Jun N-terminal kinases after neuronal injury. J Neurosci 1998;18:5124-5135.
106. Behrens A, Sibilia M, Wagner EF: Amino-terminal phosphorylation of c-jun regulates stress-induced apoptosis and cellular proliferation. Nat Genet 1999;21:326-329.
107. Barone FC, Parsons AA: Therapeutic potential of anti-inflammatory drugs in focal stroke. Expert Opin Investig Drugs 2000;9:2281-2306.
108. Cao J, Semenova MM, Solovyan VT, Han J, Coffey ET, Courtney MJ: Distinct requirements for p38αand c-jun n-terminal kinase stress-activated protein kinases in different forms of apoptotic neuronal death. J Biol Chem 2004;279:35903-35913.
109. Irving A, Barone FC, Reith AD, Hadingham SJ, Parsons AA: Differential activation of MAPK/ERK and p38/SAPK in neurons and glia following focal cerebral ischaemia in the rat. Mol Brain Res 2000;77:65-75.
110. Budihardjo I: Pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol 1999;15:269-290.
111. Ekshyyan O, Aw TY: Apoptosis in neurodegenerative disorders. Curr Neurovasc Res 2004;1:355-371.
112. Velier JJ, Ellison JA, Kikly KK, Spera PA, Barone FC, Feuerstein GZ: Caspase-8 and -3 expressed by different populations of cortical neurons undergoing delayed cell death after stroke in rat. J Neurosci 1999;19:5932-5941.
113. Krupinski J, Lopez E, Marti E, Ferrer I: Expression of caspases and their substrates in the rat model of focal cerebral ischaemia. Neurobiol Dis 2000;7:332-342.
114. Namura S, Zhu J, Fink K, Endres M, Srinivasan A, Tomaselli KJ, Yuan J, Moskowitz MA: Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischaemia. J Neurosci 1998;18:3659-3668.
115. Loetscher H, Niederhauser O, Kemp J, Gill R: Is caspase-3 inhibition a valid therapeutic strategy in cerebral ischaemia? Drug Discov Today 2001;6:671-680.
116. Love S, Barber R, Wilcock GK: Neuronal death in brain infarcts in man. Neuropathol Appl Neurobiol 2000;26:55-66.
117. Love S: Neuronal expression of cell-cycle related proteins after brain ischaemia in man. Neurosci Lett 2003;353:29-32.
118. Weishaupt JH, Neusch C, Bahr M: Cyclin-dependent kinase 5 (CDK5) and neuronal cell death. Cell Tissue Res 2003;312:1-8.
119. Green SL, Kulp KS, Vulliet R: Cyclin-dependent kinase 5 activity increases in rat brain following ischaemia. Neurochem Int 1997;31:617-623.
120. Hayashi T, Warita H, Abe K, Itoyama Y: Expression of CDK5 and its activator in rat brain after middle cerebral artery occlusion. Neurosci Lett 1999;265:37-40.
121. Wang J, Liu SH, Fu YP, Wang JH, Lu YM: CDK5 activation induces hippocampal CA1 cell death by directly phosphorylating NMDA receptors. Nat Neurosci 2003;6:1039-1047.
122. Weishaupt JH, Kussmaul L, Grotsch P, Heckel A, Rohde G, Romig H, Bahr M, Gillardon F: Inhibition of CDK5 is protective in necrotic and apoptotic paradigms of neuronal cell death and prevents mitochondrial dysfunction. Mol Cell Neurosci 2003;24:489-502.
123. Sharma MR, Tuszynski GP, Sharma MC: Angiostatin-induced inhibition of endothelial cell proliferation/apoptosis is associated with the downregulation of cell cycle regulatory protein CDK5. J Cell Biochem 2004;91:398-409.
124. Abe K, Kawagoe J, Aoki M, Kogure K, Itoyama Y: Stress protein inductions after brain ischaemia. Cell Mol Neurobiol 1998;18:709-719.
125. Giffard RG, Yenari MA: Many mechanisms for HSP70 protection from cerebral ischaemia. J Neurosurg Anesthesiol 2004;16:53-61.
126. Yasuda H, Shichinohe H, Kuroda S, Ishikawa T, Iwasaki Y: Neuroprotective effect of a heat shock protein inducer, geranylgeranylacetone in permanent focal cerebral ischaemia. Brain Res 2005;1032:176-182.
127. Yenari MA, Liu ZL, Zheng Z, Vexler ZS, Lee JE, Giffard RG: Antiapoptotic and anti-inflammatory mechanisms of heat-shock protein protection. Ann NY Acad Sci 2005;1053:74-83.
128. Emsley HCA, Smith CJ, Georgiou RF, Vail A, Hopkins SJ, Rothwell NJ, Tyrrell PJ: A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry 2005;76:1366-1372.
129. Hsu CY, An G, Liu JS, Xue JJ, He YY, Lin TN: Expression of IEG and growth factor mRNAs in a focal cerebral ischaemia model in the rat. Stroke 1993;24:178-188.
130. Kaplan DR, Miller FD: Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol 2000;10:381-391.
131. Schabitz WR, Kollmar R, Schwaninger M, Juettler E, Bardutzky J, Scholzke MN, Sommer C, Schwab S: Neuroprotective effect of granulocyte colony-stimulating factor after focal ischaemia. Stroke 2003;34:745-751.
132. Schneider A, Kruger 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, Schabitz WR: The haematopoietic factor G-CSF is a neuronal ligand that counteracts programmed cell death and drives neurogenesis. J Clin Invest 2005;115:2083-2098.
133. Jung KH, Chu K, Lee ST, Kang L, Kim SU, Kim M, Roh JK: G-CSF protects human cerebral hybrid neurons against in vitro ischaemia. Neurosci Lett 2006;394:168-173.
134. Hu XL, Olsson T, Johansson IM, Brannstrom T, Wester P: Dynamic changes of the anti-and pro-apoptotic proteins Bcl-w, Bcl-2 and Bax with Smac/Diablo mitochondrial release after photo-thrombotic ring stroke in rats. Eur J Neurosci 2004;20:1177-1188.
135. Thomenius MJ, Wang NS, Reineks EZ, Wang Z, Distelhorst CW: Bcl-2 on the endoplasmic reticulum regulates bax activity by binding to BH3-only proteins. J Biol Chem 2003;278:6243-6250.
136. Saito N, Yamamoto T, Watanabe T, Abe Y, Kumagai T: Implications of p53 protein expression in experimental spinal cord injury. J Neurotrauma 2000;17:173-182.
137. Zhao H, Yenari MA, Cheng D, Sapolsky RM, Steinberg GK: Bcl-2 over-expression protects against neuron loss within the ischaemic margin following stroke and inhibits cytochrome c and caspase-3 activity. J Neurochem 2003;85:1026-1036.
138. Clark RS, Kochanek PM, Chen M, Watkins SC, Marion DW, Chen J, Hamilton RL, Loeffert JE, Graham SH: Increases in Bcl-2 and cleavage of caspase-1 and caspase-3 in human brain after head injury. Fed Am Soc Exp Biol J 1999;13:813-821.
139. Tarkowski E, Rosengren L, Blomstrand C, Jensen C, Ekholm S, Tarkowski A: Intrathecal expression of proteins regulating apoptosis in acute stroke. Stroke 1999;30:321-327.
140. Roucou X, Gains M, LeBlanc AC: Neuroprotective functions of prion protein. J Neurosci Res 2004;75:153-161.
141. Bounhar Y, Zhang Y, Goodyer CG, LeBlanc A: Prion protein protects human neurons against Bax-mediated apoptosis. J Biol Chem 2001;276:39145-39149.
142. McLennan NF, Brennan PM, McNeil A, Davies I, Fotheringham A, Rennison KA, Ritchie D, Brannan F, Head MW, Ironside JW, Williams A, Bell JE: PrP accumulation and neuroprotection in hypoxic brain damage. Am J Pathol 2004;165:227-235.
143. Weise J, Crome O, Sandau R, Schulz-Schaeffer W, Bahr M, Zerr I: Upregulation of cellular prion protein (PrPc) after focal cerebral ischaemia and influence of lesion severity. Neurosci Lett 2004;372:146-150.
144. Weise J, Sandau R, Schwarting S, Crome O, Wrede A, Schulz-Schaeffer W, Zerr I, Bahr M: Deletion of cellular prion protein results in reduced Akt activation, enhanced postischaemic caspase-3 activation, and exacerbation of ischaemic brain injury. Stroke 2006;37:1296-1300.
145. Lindvall O, Ernfors P, Bengzon J, Kokaia Z, Smith ML, Siesjo NK, Persson H: Differential regulation of messenger RNAs for nerve growth-factor, brain-derived neurotrophic factor, and neurotrophin-3 in the adult rat brain following cerebral ischaemia and hypoglycaemic coma. Proc Natl Acad Sci USA 1992;89:648-652.
146. Yang JT, Chang CN, Lee TH, Hsu JC, Lin TN, Wu JH: Dexamethasone inhibits ischaemia-induced transient reduction of neurotrophin-3 mRNA in rat hippocampus neurons. Neuroreport 1998;9:3477-3480.
147. Tokumine J, Kakinohana O, Cizkova D, Smith DW, Marsala M: Changes in spinal NT-3 expression after transient ischaemia in the rat. J Neurosci Res 2003;74:552-561.
148. Bates B, Hirt L, Thomas SS, Akbarian S, Le D, Amin-Hanjani S, Whalen M, Jaenisch R, Moskowitz MA: Nt-3 promotes cell death induced in cerebral ischaemia, oxygen-glucose deprivation and oxidative stress. Neurobiol Dis 2002;9:24-37.
149. Galvin KA, Oorschot DE: Continuous low-dose treatment with neurotrophin-3 protects striatal medium spiny neurons from mild neonatal hypoxia/ischaemia. Neuroscience 2003;118:1023-1032.
150. Krupinski J, Kaluza J, Kumar P, Kumar S, Wang JM: Role of angiogenesis in patients with cerebral ischaemic stroke. Stroke 1994;25:1794-1798.
151. Issa R, Krupinski J, Bujny T, Kumar S, Kaluza J, Kumar P: Vascular endothelial growth factor and its receptor, KDR, in human brain tissue after ischemic stroke. Lab Invest 1999;79:417-425.
152. Issa R, AlQteishat A, Mitsios N, Saka M, Krupinski J, Tarkowski E, Gaffney J, Slevin M, Kumar S, Kumar P: Expression of basic fibroblast growth factor mRNA and protein in the human brain following ischemic stroke. Angiogenesis 2005;8:53-62.
153. Wang L, Zhang Z, Wang Y, Zhang RL, Chopp M: Treatment of stroke with erythropoietin enhances neurogenesis and angiogenesis and improves neurological function in rats. Stroke 2004;35:1732-1737.
154. Soriano MA, Tessier M, Certa U, Gill R: Parallel gene expression monitoring using oligonucleotide probe arrays of multiple transcripts with an animal model of focal ischaemia. J Cereb Blood Flow Metab 2000;20:1045-1055.
155. Jin K, Mao XO, Eshoo MW, Nagayama T, Minami M, Simon RP, Greenberg DA: Microarray analysis of hippocampal gene expression in global cerebral ischaemia. Ann Neurol 2001;50:93-103.
156. Kim YD, Sohn NW, Kang C, Soh Y: DNA array reveals altered gene expression in response to focal cerebral ischaemia. Brain Res Bull 2002;58:491-498.
157. Rao VLR, Bowen KK, Dhodda VK, Song G, Franklin JL, Gavva NR, Dempsey RJ: Gene expression analysis of spontaneously hypertensive rat cerebral cortex following transient focal cerebral ischaemia. J Neurochem 2002;83:1072-1086.
158. Schmidt-Kastner R, Zhang B, Belayev L, Khoutorova L, Amin R, Busto R, Ginsberg MD: DNA microarray analysis of cortical gene expression during early recirculation after focal brain ischaemia in rat. Mol Brain Res 2002;108:81-93.
159. Roth A, Gill R, Certa U: Temporal and spatial gene expression patterns after experimental stroke in a rat model and characterization of PC4, a potential regulator of transcription. Mol Cell Neurosci 2003;22:353-364.
160. Kim JB, Piao CS, Lee KW, Han PL, Ahn JI, Lee YS, Lee JK: Delayed genomic responses to transient middle cerebral artery occlusion in the rat. J Neurochem 2004;89:1271-1282.
161. Lu XCM, Williams AJ, Yao C, Berti R, Hartings JA, Whipple R, Vahey MT, Polavarapu RG, Woller KL, Tortella FC, Dave JR: Microarray analysis of acute and delayed gene expression profile in rats after focal ischemic brain injury and reperfusion. J Neurosci Res 2004;77:843-857.
162. Ford G, Xu Z, Gates A, Jiang J, Ford BD: Expression Analysis Systematic Explorer (EASE) analysis reveals differential gene expression in permanent and transient focal stroke rat models. Brain Res 2006;1071:226-236.
163. Moore DF, Li H, Jeffries N, Wright V, Cooper RA, Elkahloun A, Gelderman MP, Zudaire E, Blevins G, Yu H, Goldin E, Baird AE: Using peripheral blood mononuclear cells to determine a gene expression profile of acute ischaemic stroke. Circulation 2005;111:212-221.