Cerebral ischemia is one of the strongest stimuli for gene induction in the brain. Hundreds of genes have been found to be induced by brain ischemia. Many genes are involved in neurodestructive functions such as excitotoxicity, inflammatory response and neuronal apoptosis. However, cerebral ischemia is also a powerful reformatting and reprogramming stimulus for the brain through neuroprotective gene expression. Several genes may participate in both cellular responses. Thus, isolation of candidate genes for neuroprotection strategies and interpretation of expression changes have been proven difficult. Nevertheless, many studies are being carried out to improve the knowledge of the gene activation and protein expression following ischemic stroke, as well as in the development of new therapies that modify biochemical, molecular and genetic changes underlying cerebral ischemia. Owing to the complexity of the process involving numerous critical genes expressed differentially in time, space and concentration, ongoing therapeutic efforts should be based on multiple interventions at different levels. By modification of the acute gene expression induced by ischemia or the apoptotic gene program, gene therapy is a promising treatment but is still in a very experimental phase. Some hurdles will have to be overcome before these therapies can be introduced into human clinical stroke trials.

Keywords:
Gene expression, Cerebral ischemia, Apoptosis, Neuroprotection, Angiogenesis
1.
Hachinski V: Stroke: the next 30 years. Stroke 2002;33:1–4.
2.
King HC, Sinha AA: Gene expression profile analysis by DNA microarrays. JAMA 2001;286:2280–2288.
3.
Read SJ, Parsons AA, Harrison DC, Philpott K, Kabnick K, O’Brien S, et al: Stroke genomics: approaches to identify, validate, and understand ischemic stroke gene expression. J Cereb Blood Flow Metab 2001;21:755–778.
4.
Pulsinelli W: Pathophysiology of acute ischemic stroke. Lancet 1992;339:533–536.
5.
Akins PT, Liu PK, Hsu CY: Immediate early gene expression in response to cerebral ischemia: friend or foe? Stroke 1996;27:1682–1687.
6.
Ginsberg MD: Adventures in the pathophysiology of brain ischemia: penumbra, gene expression, neuroprotection. The 2002 Thomas Willis Lecture. Stroke 2003;34:214–223.
7.
Slevin M, Krupinski J, Kumar P, Gaffney J, Kumar S: Gene activation and protein expression following ischaemic stroke: strategies towards neuroprotection. J Cell Mol Med 2005;9:85–102.
8.
May Lu XC, Williams AJ, Yao C, Berti R, Hartings JA, Whipple R, et al: 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.
9.
Hong H, Liu GC: Current status and perspectives on the development of neuroprotectants for ischemic vascular disease. Drugs Today (Barc) 2003:39:213–222.
10.
Heiss WD, Graf R: The ischemic penumbra. Curr Opin Neurol 1994;7:11–19.
11.
Ginsberg MD: Injury mechanisms in the ischemic penumbra. Approaches to neuroprotection in acute ischemic stroke. Cerebrovasc Dis 1997;7(suppl 2):7–12.
12.
Legos JJ, Tuma RF, Barone FC: Pharmacological interventions for stroke: failures and future. Expert Opin Invest Drugs 2002;11:603–614.
13.
Rossi DJ, Oshima T, Atwell D: Glutamate release in severe brain ischemia is mainly by reserved uptake. Nature 2000;403:316–321.
14.
Boscia F, Gala R, Pignataro G, de Bartolomeis A, Cicale M, Ambesi-Impiombato A, et al: Permanent focal brain ischemia induces isoform-dependent changes in the pattern of Na+/Ca2+ exchanger gene expression in the ischemic core, periinfarct area, an intact brain regions. J Cereb Blood Flow Metab 2005 (Epub ahead of print).
15.
Schwartz-Bloom RD, Sah R: Gamma-aminobutyric acid A neurotransmission and cerebral ischemia. J Neurochem 2001;77:353–371.
16.
Castillo J, Rodríguez I: Biochemical changes and inflammatory response as markers of brain ischaemia: molecular markers of diagnostic utility and prognosis in human practice. Cerebrovasc Dis 2004;17:7–18.
17.
Vallet P, Charnay Y, Steger K, Ogier-Denis E, Kovari E, Herrmann F, et al: Neuronal expression of the NADPH oxidase NOX4, and its regulation in mouse experimental brain ischemia. Neuroscience 2005;132:233–238.
18.
Castillo J, Rama R, Dávalos A: Nitric oxide-related brain damage in acute ischemic stroke. Stroke 2000;31:852–857.
19.
Ikonomidou C, Turski L: Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury? Lancet Neurol 2002;i:383–386.
20.
Yao C, Williams AJ, Lu XC, Price RA, Cunningham BS, Berti R, et al: The sodium channel blocker RS100642 reverses down-regulation of the sodium channel α-subunit Na(v) 1.1 expression caused by transient ischemic brain injury in rats. Neurotox Res 2003;5:245–254.
21.
Yasuda H, Shichinohe H, Kuroda S, Ishikawa T, Iwasaki Y: Neuroprotective effect of a heat shock protein inducer, geranylgeranylacetone, in permanent focal cerebral ischemia. Brain Res 2005;1032:176–182.
22.
Rothstein JD, Pastel S, Regan MR, Haenggeli C, Huang YH, Bergles DE, et al: Beta-lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature 2005;433:73–77.
23.
Vila N, Castillo J, Dávalos A, Chamorro A: Proinflammatory cytokines and early stroke progression. Stroke 2000;31:2325–2329.
24.
Iadecola C, Alexander M: Cerebral ischemia and inflammation. Curr Opin Neurol 2001;14:89–94.
25.
Danton GH, Dietrich WD: Inflammatory mechanisms after ischemia and stroke. J Neuropath Exp Neurol 2003;62:127–136.
26.
Takagi Y, Harada J, Chiarugi A, Moskowitz MA: STAT1 is activated in neurons after ischaemia and contributes to ischaemic brain injury. J Cereb Blood Flow Metab 2002;22:1311–1318.
27.
Castellanos M, Leira R, Serena J, Pumar JM, Lizasoain I, Castillo J, et al: Plasma metalloproteinase-9 concentration predicts hemorrhagic transformation in acute ischemic stroke. Stroke 2003;34:40–46.
28.
Montaner J, Alvarez-Sabín J, Molina CA, Anglés A, Abilleira S, Arenillas JF, et al: Matrix metalloproteinase expression after human cardioembolic stroke: temporal profile and relation to neurological impairment. Stroke 2001;32:1759–1766.
29.
Berti R, Williams AJ, Velarde LC, Moffett JR, Elliot PJ, Adams J, et al: Effect of the proteasome inhibitor MLN519 on the expression of inflammatory molecules following middle cerebral artery occlusion and reperfusion in rat. Neurotox Res 2002;5:505–514.
30.
Vemuganti R, Dempsey RJ, Bowen KK: Inhibition of intercellular adhesion molecule-1 protein expression by antisense oligonucleotides is neuroprotective after transient middle cerebral artery occlusion in rat. Stroke 2004;35:179–184.
31.
Wang X, Feuerstein GZ, Xu L, Wang H, Schumacher WA, Ogletree ML: Inhibition of tumor necrosis factor-α-converting enzyme by a selective antagonist protects brain from focal ischemic injury in rats. Mol Pharmacol 2004;65:890–896.
32.
Choi DW: Excitotoxicity, apoptosis and ischemic stroke. J Biochem Mol Biol 2001;34:8–14.
33.
MacManus JP, Linnik MD: Gene expression induced by cerebral ischemia: an apoptotic perspective. J Cereb Blood Flow Metab 1997;17:815–852.
34.
Ferrer I, Planas AM: Signaling of cell death and cell survival following focal cerebral ischaemia: life and death struggle in the penumbra. J Neuropath Exp Neurol 2003;62:329–339.
35.
Sedarous M, Keramaris E, O’Hare M: Calpains mediate p53 activation and neuronal death evoked by DNA damage. J Biol Chem 2003;278:26031–26038.
36.
Harper SJ, LoGrasso P: Signalling for survival and death in neurones. The role of the stress-activated kinases, JNK and p38. Cell Signal 2001;13:299–310.
37.
Guan QH, Pei DS, Zhang QG, Hao ZB, Xu TL, Zhang GY: The neuroprotective action of SP600125, a new inhibitor of JNK, on transient brain ischemia/reperfusion-induced neuronal death in rat hippocampal CA1 via nuclear and non-nuclear pathways. Brain Res 2005;1035:51–59.
38.
Cao G, Pei W, Ge H, Liang Q, Luo Y, Sharp FR, et al: In vivo delivery of a Bcl-xl fusion protein containing the TAT protein transduction domain protects against ischemic brain injury and neuronal apoptosis. J Neurosci 2002;22:5423–5431.
39.
Krupinski J, Ferrer I, Barrachina M, Secades JJ, Mercadal J, Lozano R: CDP-choline reduces pro-caspase and cleaved caspase-3 expression, nuclear DNA fragmentation, and specific PARP-cleaved products of caspase artery occlusion in the rat. Neuropharmacology 2002;42:846–854.
40.
Culmsee C, Gerling N, Lehmnan M, Nikolova-Karakashian M, Prehn JHM, Mattson MP, et al: Nerve growth factor survival signalling in cultured hippocampal neurons is mediated through TRKA and requires the common neurotrophin receptor p75. Neuroscience 2002;115:1089–1108.
41.
Fujiwara K, Date I, Shingo T, Yoshida H, Kobayashi K, Takeuchi A, et al: Reduction of infarct volume and apoptosis by grafting of encapsulated basic fibroblast growth factor-secreting cells in a model of middle cerebral artery occlusion in rats. J Neurosurg 2003;99:1053–1062.
42.
Ijichi A, Sakuma S, Tofilon PJ. Hypoxia-induced vascular endothelial growth factor expression in normal rat astrocyte cultures. Glia 1995;14:87–93.
43.
Krupinski J, Kaluza J, Kumar P: Role of angiogenesis in patients with cerebral ischaemic stroke. Stroke 1994;25:1794–1798.
44.
Krupinski J, Stroemer P, Slevin M: Three-dimensional structure of newly-formed blood vessels after focal cerebral ischemia in rat. Neuroreport 2003;14:1171–1176.
45.
Croll SD, Wiegand SJ: Vascular growth factors in cerebral ischemia. Mol Neurobiol 2001;23:121–135.
46.
Sun Y, Jin K, Xie L, et al: VEGF-induced neuroprotection, neurogenesis and angiogenesis after focal cerebral ischaemia. J Clin Invest 2003;111:1843–1851.
47.
Sun FY, Guo X: Molecular and cellular mechanisms of neuroprotection by vascular endothelial growth factor. J Neurosci Res 2005;79:180–184.
48.
Ay H, Ay I, Koroshetz WJ, et al.: Potential usefulness of basic fibroblast growth factor as a treatment for stroke. Cerebrovasc Dis 2000;9:131–135.
49.
Watanabe T, Okuda Y, Nonoguchi N, Zhao MZ, Kajimoto Y, Furutama D, et al: Postischemic intraventricular administration of FGF-2 expressing adenoviral vectors improves neurologic outcome and reduces infarct volume after transient focal cerebral ischemia in rats. J Cereb Blood Flow Metab 2004;24:1205–1213.
50.
Shimamura M, Sato N, Oshima K, et al: Novel therapeutic strategy to treat brain ischaemia: overexpression of hepatocyte growth factor gene reduced ischaemic injury without cerebral edema in rat model. Circulation 2004;109:424–431.
51.
Xu Z, Ford GD, Croslan DR, Jiang J, Gates A, Allen R, et al: Neuroprotection by neuroregulin-1 following focal stroke is associated with the attenuation of ischemia-induced pro-inflammatory and stress gene expression. Neurobiol Dis 2005;19:461–470.
52.
Heistad DD, Faraci F: Gene therapy for cerebrovascular disease. Stroke 1996;27:1688–1693.
53.
Sapolsky RM, Steinberg GK: Gene therapy using viral vectors for acute neurologic insults. Neurology 1999;53:1922–1931.
54.
Vila N: A genetic approach to ischemic stroke therapy. Cerebrovasc Dis 2004;17(suppl 1): 63–69.
55.
Ooboshi H, Ibayashi S, Takada J, Yao H, Kitazono T, Fujishima M: Adenovirus-mediated gene transfer to ischemic brain. Stroke 2001;32:1043–1047.
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2006
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