Targeting astrocytes for stroke therapy.
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Journal: 2011/January - Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
ISSN: 1878-7479
Abstract:
Stroke remains a major health problem and is a leading cause of death and disability. Past research and neurotherapeutic clinical trials have targeted the molecular mechanisms of neuronal cell death during stroke, but this approach has uniformly failed to reduce stroke-induced damage or to improve functional recovery. Beyond the intrinsic molecular mechanisms inducing neuronal death during ischemia, survival and function of astrocytes is absolutely required for neuronal survival and for functional recovery after stroke. Many functions of astrocytes likely improve neuronal viability during stroke. For example, uptake of glutamate and release of neurotrophins enhances neuronal viability during ischemia. Under certain conditions, however, astrocyte function may compromise neuronal viability. For example, astrocytes may produce inflammatory cytokines or toxic mediators, or may release glutamate. The only clinical neurotherapeutic trial for stroke that specifically targeted astrocyte function focused on reducing release of S-100β from astrocytes, which becomes a neurotoxin when present at high levels. Recent work also suggests that astrocytes, beyond their influence on cell survival, also contribute to angiogenesis, neuronal plasticity, and functional recovery in the several days to weeks after stroke. If these delayed functions of astrocytes could be targeted for enhancing stroke recovery, it could contribute importantly to improving stroke recovery. This review focuses on both the positive and the negative influences of astrocytes during stroke, especially as they may be targeted for translation to human trials.
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Neurotherapeutics 7(4): 439-451
PMID: 20880507

Targeting astrocytes for stroke therapy

Summary

Stroke remains a major health problem and is a leading cause of death and disability. Past research and neurotherapeutic clinical trials have targeted the molecular mechanisms of neuronal cell death during stroke, but this approach has uniformly failed to reduce stroke-induced damage or to improve functional recovery. Beyond the intrinsic molecular mechanisms inducing neuronal death during ischemia, survival and function of astrocytes is absolutely required for neuronal survival and for functional recovery after stroke. Many functions of astrocytes likely improve neuronal viability during stroke. For example, uptake of glutamate and release of neurotrophins enhances neuronal viability during ischemia. Under certain conditions, however, astrocyte function may compromise neuronal viability. For example, astrocytes may produce inflammatory cytokines or toxic mediators, or may release glutamate. The only clinical neurotherapeutic trial for stroke that specifically targeted astrocyte function focused on reducing release of S-100β from astrocytes, which becomes a neurotoxin when present at high levels. Recent work also suggests that astrocytes, beyond their influence on cell survival, also contribute to angiogenesis, neuronal plasticity, and functional recovery in the several days to weeks after stroke. If these delayed functions of astrocytes could be targeted for enhancing stroke recovery, it could contribute importantly to improving stroke recovery. This review focuses on both the positive and the negative influences of astrocytes during stroke, especially as they may be targeted for translation to human trials.

Key Words: Astrocyte, stroke, ischemia, glutamate, inflammation, translation
grid.16416.340000000419369174Department of Neurology in the Center for Neural Development and Disease, University of Rochester School of Medicine and Dentistry, 14642 Rochester, New York
David A. Rempe, Email: ude.retsehcor.cmru@epmer_divad.
Corresponding author.
Copyright © Springer 2010

References

  • 1. Guo S, Lo EHDysfunctional cell-cell signaling in the neurovascular unit as a paradigm for central nervous system disease. Stroke. 2009;40(3 Suppl):S4–S7.[Google Scholar]
  • 2. Ransom B, Behar T, Nedergaard MNew roles for astrocytes (stars at last) Trends Neurosci. 2003;26:520–522.[PubMed][Google Scholar]
  • 3. Iadecola C, Nedergaard MGlial regulation of the cerebral microvasculature. Nat Neurosci. 2007;10:1369–1376.[PubMed][Google Scholar]
  • 4. Chen Y, Swanson RAAstrocytes and brain injury. J Cereb Blood Flow Metab. 2003;23:137–149.[PubMed][Google Scholar]
  • 5. Kimelberg HKAstrocytic swelling in cerebral ischemia as a possible cause of injury and target for therapy. Glia. 2005;50:389–397.[PubMed][Google Scholar]
  • 6. Anderson CM, Nedergaard MAstrocyte-mediated control of cerebral microcirculation. Trends Neurosci. 2003;26:340–344.[PubMed][Google Scholar]
  • 7. Trendelenburg G, Dimagl UNeuroprotective role of astrocytes in cerebral ischemia: focus on ischemic preconditioning. Glia. 2005;50:307–320.[PubMed][Google Scholar]
  • 8. Chesler MFailure and function of intracellular pH regulation in acute hypoxic-ischemic injury of astrocytes. Glia. 2005;50:398–406.[PubMed][Google Scholar]
  • 9. Dienel GA, Hertz LAstrocytic contributions to bioenergetics of cerebral ischemia. Glia. 2005;50:362–388.[PubMed][Google Scholar]
  • 10. Nedergaard M, Dirnagl URole of glial cells in cerebral ischemia. Glia. 2005;50:281–286.[PubMed][Google Scholar]
  • 11. Giffard RG, Swanson RAIschemia-induced programmed cell death in astrocytes. Glia. 2005;50:299–306.[PubMed][Google Scholar]
  • 12. Rossi DJ, Brady JD, Mohr CAstrocyte metabolism and signaling during brain ischemia. Nat Neurosci. 2007;10:1377–1386.[PubMed][Google Scholar]
  • 13. Asano T, Mori T, Shimoda T, et al Arundic acid (ONO-2506) ameliorates delayed ischemic brain damage by preventing astrocytic overproduction of S100B. Curr Drug Targets CNS Neurol Disord. 2005;4:127–142.[PubMed][Google Scholar]
  • 14. Sofroniew MVReactive astrocytes in neural repair and protection. Neuroscientist. 2005;11:400–407.[PubMed][Google Scholar]
  • 15. Eroglu CThe role of astrocyte-secreted matricellular proteins in central nervous system development and function. J Cell Commun Signal. 2009;3:167–176.[Google Scholar]
  • 16. Panickar KS, Norenberg MDAstrocytes in cerebral ischemic injury: morphological and general considerations. Glia. 2005;50:287–298.[PubMed][Google Scholar]
  • 17. Almeida A, Delgado-Esteban M, Bolaños JP, Medina JMOxygen and glucose deprivation induces mitochondrial dysfunction and oxidative stress in neurones but not in astrocytes in primary culture. J Neurochem. 2002;81:207–217.[PubMed][Google Scholar]
  • 18. Vangeison G, Carr D, Federoff HJ, Rempe DAThe good, the bad, and the cell type-specific roles of hypoxia inducible factor-1α in neurons and astrocytes. J Neurosci. 2008;28:1988–1993.[Google Scholar]
  • 19. Swanson RA, Farrell K, Stein BAAstrocyte energetics, function, and death under conditions of incomplete ischemia: a mechanism of glial death in the penumbra. Glia. 1997;21:142–153.[PubMed][Google Scholar]
  • 20. Giffard RG, Monyer H, Choi DWSelective vulnerability of cultured cortical glia to injury by extracellular acidosis. Brain Res. 1990;530:138–141.[PubMed][Google Scholar]
  • 21. Giffard RG, Papadopoulos MC, van Hooft JA, Xu L, Giuffrida R, Monyer HThe electrogenic sodium bicarbonate cotransporter: developmental expression in rat brain and possible role in acid vulnerability. J Neurosci. 2000;20:1001–1008.[Google Scholar]
  • 22. Liu D, Smith CL, Barone FC, et al Astrocytic demise precedes delayed neuronal death in focal ischemic rat brain. Brain Res Mol Brain Res. 1999;68:29–41.[PubMed][Google Scholar]
  • 23. Garcia JH, Yoshida Y, Chen H, et al Progression from ischemic injury to infarct following middle cerebral artery occlusion in the rat. Am J Pathol. 1993;142:623–635.[Google Scholar]
  • 24. Lukaszevicz AC, Sampaïo N, Guégan C, et al High sensitivity of protoplasmic cortical astroglia to focal ischemia. J Cereb Blood Flow Metab. 2002;22:289–298.[PubMed][Google Scholar]
  • 25. Gürer G, Gursoy-Ozdemir Y, Erdemli E, Can A, Dalkara TAstrocytes are more resistant to focal cerebral ischemia than neurons and die by a delayed necrosis. Brain Pathol. 2009;19:630–641.[PubMed][Google Scholar]
  • 26. Barrett KM, Ding YH, Wagner DP, Kallmes DF, Johnston KC. ASAP Investigators. Change in diffusion-weighted imaging infarct volume predicts neurologic outcome at 90 days: results of the Acute Stroke Accurate Prediction (ASAP) trial serial imaging substudy. Stroke. 2009;40:2422–2427.
  • 27. Du C, Hu R, Csernansky CA, Hsu CY, Choi DWVery delayed infarction after mild focal cerebral ischemia: a role for apoptosis? J Cereb Blood Flow Metab. 1996;16:195–201.[PubMed][Google Scholar]
  • 28. Zhao BQ, Wang S, Kim HY, et al Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med. 2006;12:441–445.[PubMed][Google Scholar]
  • 29. Baranova O, Miranda LF, Pichiule P, Dragatsis I, Johnson RS, Chavez JCNeuron-specific inactivation of the hypoxia inducible factor 1 α increases brain injury in a mouse model of transient focal cerebral ischemia. J Neurosci. 2007;27:6320–6332.[Google Scholar]
  • 30. Smith JM, Bradley DP, James MF, Huang CLPhysiological studies of cortical spreading depression. Biol Rev Camb Philos Soc. 2006;81:457–481.[PubMed][Google Scholar]
  • 31. Shin HK, Dunn AK, Jones PB, Boas DA, Moskowitz MA, Ayata CVasoconstrictive neurovascular coupling during focal ischemic depolarizations. J Cereb Blood Flow Metab. 2006;26:1018–1030.[PubMed][Google Scholar]
  • 32. Mies G, Iijima T, Hossmann KACorrelation between peri-infarct DC shifts and ischaemic neuronal damage in rat. Neuroreport. 1993;4:709–711.[PubMed][Google Scholar]
  • 33. Iadecola C, Alexander MCerebral ischemia and inflammation. Curr Opin Neurol. 2001;14:89–94.[PubMed][Google Scholar]
  • 34. Iadecola C, Niwa K, Nogawa S, et al Reduced susceptibility to ischemic brain injury and N-methyl-d-aspartate-mediated neurotoxicity in cyclooxygenase-2-deficient mice. Proc Natl Acad Sci U S A. 2001;98:1294–1299.[Google Scholar]
  • 35. Iadecola C, Zhang F, Casey R, Nagayama M, Ross MEDelayed reduction of ischemic brain injury and neurological deficits in mice lacking the inducible nitric oxide synthase gene. J Neurosci. 1997;17:9157–9164.[Google Scholar]
  • 36. Endoh M, Maiese K, Wagner JExpression of the inducible form of nitric oxide synthase by reactive astrocytes after transient global ischemia. Brain Res. 1994;651:92–100.[PubMed][Google Scholar]
  • 37. Iadecola C, Zhang F, Xu S, Casey R, Ross MEInducible nitric oxide synthase gene expression in brain following cerebral ischemia. J Cereb Blood Flow Metab. 1995;15:378–384.[PubMed][Google Scholar]
  • 38. Semenza GLRegulation of oxygen homeostasis by hypoxia-inducible factor 1. Physiology (Bethesda) 2009;24:97–106.[PubMed][Google Scholar]
  • 39. Chavez JC, Baranova O, Lin J, Pichiule PThe transcriptional activator hypoxia inducible factor 2 (HIF-2/EPAS-1) regulates the oxygen-dependent expression of erythropoietin in cortical astrocytes. J Neurosci. 2006;26:9471–9481.[Google Scholar]
  • 40. Jelkmann W, Wagner KBeneficial and ominous aspects of the pleiotropic action of erythropoietin. Ann Hematol. 2004;83:673–686.[PubMed][Google Scholar]
  • 41. Zhang ZG, Zhang L, Jiang Q, et al VEGF enhances angiogenesis and promotes blood-brain barrier leakage in the ischemic brain. J Clin Invest. 2000;106:829–838.[Google Scholar]
  • 42. Harvey BK, Chang CF, Chiang YH, et al HSV amplicon delivery of glial cell line-derived neurotrophic factor is neuroprotective against ischemic injury. Exp Neurol. 2003;183:47–55.[PubMed][Google Scholar]
  • 43. Hermann DM, Kilic E, Kügler S, Isenmann S, Bahr MAdenovirus-mediated GDNF and CNTF pretreatment protects against striatal injury following transient middle cerebral artery occlusion in mice. Neurobiol Dis. 2001;8:655–666.[PubMed][Google Scholar]
  • 44. Kitagawa H, Sasaki C, Sakai K, et al Adenovirus-mediated gene transfer of glial cell line-derived neurotrophic factor prevents ischemic brain injury after transient middle cerebral artery occlusion in rats. J Cereb Blood Flow Metab. 1999;19:1336–1344.[PubMed][Google Scholar]
  • 45. Vahedi K, Hofmeijer J, Juettler E, et al. DECIMAL, DESTINY, and HAMLET investigators. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol. 2007;5:215–222.[PubMed]
  • 46. Papadopoulos MC, Verkman ASPotential utility of aquaporin modulators for therapy of brain disorders. Prog Brain Res. 2008;170:589–601.[Google Scholar]
  • 47. Zador Z, Stiver S, Wang V, Manley GT. Role of aquaporin-4 in cerebral edema and stroke. Handb Exp Pharmacol 2009;(190): 159–170.
  • 48. Nielsen S, Nagelhus EA, Amiry-Moghaddam M, Bourque C, Agre P, Ottersen OPSpecialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci. 1997;17:171–180.[Google Scholar]
  • 49. Manley GT, Fujimura M, Ma T, et al Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med. 2000;6:159–163.[PubMed][Google Scholar]
  • 50. Benfenati V, Nicchia GP, Svelto M, Rapisarda C, Frigeri A, Ferroni SFunctional down-regulation of volume-regulated anion channels in AQP4 knockdown cultured rat cortical astrocytes. J Neurochem. 2007;100:87–104.[PubMed][Google Scholar]
  • 51. Feustel PJ, Jin Y, Kimelberg HKVolume-regulated anion channels are the predominant contributors to release of excitatory amino acids in the ischemic cortical penumbra. Stroke. 2004;35:1164–1168.[PubMed][Google Scholar]
  • 52. Zhang Y, Jin Y, Behr MJ, Feustel PJ, Morrison JP, Kimelberg HKBehavioral and histological neuroprotection by tamoxifen after reversible focal cerebral ischemia. Exp Neurol. 2005;196:41–46.[PubMed][Google Scholar]
  • 53. Zhang Y, Milatovic D, Aschner M, Feustel PJ, Kimelberg HKNeuroprotection by tamoxifen in focal cerebral ischemia is not mediated by an agonist action at estrogen receptors but is associated with antioxidant activity. Exp Neurol. 2007;204:819–827.[Google Scholar]
  • 54. Lakhan SE, Kirchgessner A, Hofer MInflammatory mechanisms in ischemic stroke: therapeutic approaches. J Transl Med. 2009;7:97–97.[Google Scholar]
  • 55. Wang Q, Tang XN, Yenari MAThe inflammatory response in stroke. J Neuroimmunol. 2007;184:53–68.[Google Scholar]
  • 56. Bezzi P, Domercq M, Brambilla L, et al CXCR4-activated astrocyte glutamate release via TNFα: amplification by microglia triggers neurotoxicity. Nat Neurosci. 2001;4:702–710.[PubMed][Google Scholar]
  • 57. Anderson CM, Swanson RAAstrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia. 2000;32:1–14.[PubMed][Google Scholar]
  • 58. Rothstein JD, Dykes-Hoberg M, Pardo CA, et al Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate. Neuron. 1996;16:675–686.[PubMed][Google Scholar]
  • 59. Boycott HE, Dallas M, Boyle JP, Pearson HA, Peers CHypoxia suppresses astrocyte glutamate transport independently of amyloid formation. Biochem Biophys Res Commun. 2007;364:100–104.[PubMed][Google Scholar]
  • 60. Dallas M, Boycott HE, Atkinson L, et al Hypoxia suppresses glutamate transport in astrocytes. J Neurosci. 2007;27:3946–3955.[Google Scholar]
  • 61. Taylor CT, Cummins EPThe role of NF-κB in hypoxia-induced gene expression. Ann N Y Acad Sci. 2009;1177:178–184.[PubMed][Google Scholar]
  • 62. Taylor CTInterdependent roles for hypoxia inducible factor and nuclear factor-κB in hypoxic inflammation. J Physiol. 2008;586:4055–4059.[Google Scholar]
  • 63. Boycott HE, Wilkinson JA, Boyle JP, Pearson HA, Peers CDifferential involvement of TNFα in hypoxic suppression of astrocyte glutamate transporters. Glia. 2008;56:998–1004.[PubMed][Google Scholar]
  • 64. Rothstein JD, Patel S, Regan MR, et al β-Lactam antibiotics offer neuroprotection by increasing glutamate transporter expression. Nature. 2005;433:73–77.[PubMed][Google Scholar]
  • 65. Chu K, Lee ST, Sinn DI, et al Pharmacological induction of ischemic tolerance by glutamate transporter-1 (EAAT2) upregulation. Stroke. 2007;38:177–182.[PubMed][Google Scholar]
  • 66. Lee SG, Su ZZ, Emdad L, et al Mechanism of ceftriaxone induction of excitatory amino acid transporter-2 expression and glutamate uptake in primary human astrocytes. J Biol Chem. 2008;283:13116–13123.[Google Scholar]
  • 67. Lewerenz J, Albrecht P, Tien ML, et al Induction of Nrf2 and xCT are involved in the action of the neuroprotective antibiotic ceftriaxone in vitro. J Neurochem. 2009;111:332–343.[PubMed][Google Scholar]
  • 68. Yang GY, Zhao YJ, Davidson BL, Betz ALOverexpression of interleukin-l receptor antagonist in the mouse brain reduces ischemic brain injury. Brain Res. 1997;751:181–188.[PubMed][Google Scholar]
  • 69. Fogal B, Li J, Lobner D, McCullough LD, Hewett SJSystem xc activity and astrocytes are necessary for interleukin-lβ-mediated hypoxic neuronal injury. J Neurosci. 2007;27:10094–10105.[Google Scholar]
  • 70. Hara H, Friedlander RM, Gagliardini V, et al Inhibition of interleukin 1β converting enzyme family proteases reduces ischemic and excitotoxic neuronal damage. Proc Natl Acad Sci U S A. 1997;94:2007–2012.[Google Scholar]
  • 71. Ohtaki H, Takaki A, Yin L, et al Suppression of oxidative stress after transient focal ischemia in interleukin-l knock out mice. Acta Neurochir Suppl. 2003;86:191–194.[PubMed][Google Scholar]
  • 72. Mulcahy NJ, Ross J, Rothwell NJ, Loddick SADelayed administration of interleukin-1 receptor antagonist protects against transient cerebral ischaemia in the rat. Br J Pharmacol. 2003;140:471–476.[Google Scholar]
  • 73. Rothwell NInterleukin-1 and neuronal injury: mechanisms, modification, and therapeutic potential. Brain Behav Immun. 2003;17:152–157.[PubMed][Google Scholar]
  • 74. Emsley HC, Smith CJ, Georgiou RF, et al A randomised phase II study of interleukin-1 receptor antagonist in acute stroke patients. J Neurol Neurosurg Psychiatry. 2005;76:1366–1372.[Google Scholar]
  • 75. Matsui T, Mori T, Tateishi N, et al. Astrocytic activation and delayed infarct expansion after permanent focal ischemia in rats. Part I: enhanced astrocytic synthesis of S-100β in the periinfarct area precedes delayed infarct expansion. J Cereb Blood Flow Metab. 2002;22:711–722.[PubMed]
  • 76. Hu J, Ferreira A, Van Eldik LJS100β induces neuronal cell death through nitric oxide release from astrocytes. J Neurochem. 1997;69:2294–2301.[PubMed][Google Scholar]
  • 77. Tateishi N, Mori T, Kagamiishi Y, et al. Astrocytic activation and delayed infarct expansion after permanent focal ischemia in rats. Part II: suppression of astrocytic activation by a novel agent (R)-(-)-2-propyloctanoic acid (ONO-2506) leads to mitigation of delayed infarct expansion and early improvement of neurologic deficits. J Cereb Blood Flow Metab. 2002;22:723–734.[PubMed]
  • 78. Pettigrew LC, Kasner SE, Gorman M, Atkinson RP, Funakoshi Y, Ishibashi H. Arundic Acid (ONO-2506) Stroke Study Group. Effect of arundic acid on serum S-100β in ischemic stroke. J Neurol Sci. 2006;251:57–61.[PubMed]
  • 79. Pettigrew LC, Kasner SE, Albers GW, et al. Arundic Acid (ONO-2506) Stroke Study Group. Safety and tolerability of arundic acid in acute ischemic stroke. J Neurol Sci. 2006;251:50–56.[PubMed]
  • 80. Sorensen AG, Buonanno FS, Gonzalez RG, et al Hyperacute stroke: evaluation with combined multisection diffusion-weighted and he-modynamically weighted echo-planar MR imaging. Radiology. 1996;199:391–401.[PubMed][Google Scholar]
  • 81. Beaulieu C, de Crespigny A, Tong DC, Moseley ME, Albers GW, Marks MPLongitudinal magnetic resonance imaging study of perfusion and diffusion in stroke: evolution of lesion volume and correlation with clinical outcome. Ann Neurol. 1999;46:568–578.[PubMed][Google Scholar]
  • 82. Olivot JM, Marks MPMagnetic resonance imaging in the evaluation of acute stroke. Top Magn Reson Imaging. 2008;19:225–230.[PubMed][Google Scholar]
  • 83. Schwamm LH, Koroshetz WJ, Sorensen AG, et al Time course of lesion development in patients with acute stroke: serial diffusion- and hemodynamic-weighted magnetic resonance imaging. Stroke. 1998;29:2268–2276.[PubMed][Google Scholar]
  • 84. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581–1587.[PubMed]
  • 85. Marti HH, Gassmann M, Wenger RH, et al Detection of eryth-ropoietin in human liquor: intrinsic erythropoietin production in the brain. Kidney Int. 1997;51:416–418.[PubMed][Google Scholar]
  • 86. Ruscher K, Freyer D, Karsch M, et al Erythropoietin is a paracrine mediator of ischemic tolerance in the brain: evidence from an in vitro model. J Neurosci. 2002;22:10291–10301.[Google Scholar]
  • 87. Prass K, Scharff A, Ruscher K, et al Hypoxia-induced stroke tolerance in the mouse is mediated by erythropoietin. Stroke. 2003;34:1981–1986.[PubMed][Google Scholar]
  • 88. Masuda S, Okano M, Yamagishi K, Nagao M, Ueda M, Sasaki R. A novel site of erythropoietin production. Oxygen-dependent production in cultured rat astrocytes. J Biol Chem. 1994;269:19488–19493.[PubMed]
  • 89. Gruber M, Hu CJ, Johnson RS, Brown EJ, Keith B, Simon MCAcute postnatal ablation of Hif-2α results in anemia. Proc Natl Acad Sci U S A. 2007;104:2301–2306.[Google Scholar]
  • 90. Weidemann A, et al The glial cell response is an essential component of hypoxia-induced erythropoiesis in mice. J Clin Invest. 2009;119:3373–3383.[Google Scholar]
  • 91. Morishita E, Masuda S, Nagao M, Yasuda Y, Sasaki RErythropoietin receptor is expressed in rat hippocampal and cerebral cortical neurons, and erythropoietin prevents in vitro glutamate-induced neuronal death. Neuroscience. 1997;76:105–116.[PubMed][Google Scholar]
  • 92. Sakanaka M, Wen TC, Matsuda S, et al In vivo evidence that erythropoietin protects neurons from ischemic damage. Proc Natl Acad Sci U S A. 1998;95:4635–4640.[Google Scholar]
  • 93. Liu J, Narasimhan P, Song YS, et al Epo protects SOD2-deficient mouse astrocytes from damage by oxidative stress. Glia. 2006;53:360–365.[PubMed][Google Scholar]
  • 94. Diaz Z, Assaraf MI, Miller WH, Schipper HMAstroglial cytoprotection by erythropoietin pre-conditioning: implications for ischemic and degenerative CNS disorders. J Neurochem. 2005;93:392–402.[PubMed][Google Scholar]
  • 95. Bernaudin M, Marti HH, Roussel S, et al A potential role for erythropoietin in focal permanent cerebral ischemia in mice. J Cereb Blood Flow Metab. 1999;19:643–651.[PubMed][Google Scholar]
  • 96. Sirén AL, Fratelli M, Brines M, et al Erythropoietin prevents neuronal apoptosis after cerebral ischemia and metabolic stress. Proc Natl Acad Sci U S A. 2001;98:4044–4049.[Google Scholar]
  • 97. Gonzalez FF, Abel R, Almli CR, Mu D, Wendland M, Ferriero DMErythropoietin sustains cognitive function and brain volume after neonatal stroke. Dev Neurosci. 2009;31:403–411.[Google Scholar]
  • 98. Sola A, Wen TC, Hamrick SE, Ferriero DMPotential for protection and repair following injury to the developing brain: a role for erythropoietin? Pediatr Res. 2005;57:110R–117R.[PubMed][Google Scholar]
  • 99. Ehrenreich H, Hasselblatt M, Dembowski C, et al Erythropoietin therapy for acute stroke is both safe and beneficial. Mol Med. 2002;8:495–505.[Google Scholar]
  • 100. Ehrenreich H, Weissenborn K, Prange H, et al. EPO Stroke Trial Group. Recombinant human erythropoietin in the treatment of acute ischemic stroke. Stroke. 2009;40:e647–e656.[PubMed]
  • 101. Shingo T, Sorokan ST, Shimazaki T, Weiss SErythropoietin regulates the in vitro and in vivo production of neuronal progenitors by mammalian forebrain neural stem cells. J Neurosci. 2001;21:9733–9743.[Google Scholar]
  • 102. Sirén AL, Fasshauer T, Bartels C, Ehrenreich HTherapeutic potential of erythropoietin and its structural or functional variants in the nervous system. Neurotherapeutics. 2009;6:108–127.[Google Scholar]
  • 103. Byts N, Sirén ALErythropoietin: a multimodal neuroprotective agent. Exp Transi Stroke Med. 2009;1:4–4.[Google Scholar]
  • 104. Siddiq A, Ayoub IA, Chavez JC, et al Hypoxia-inducible factor prolyl 4-hydroxylase inhibition: a target for neuroprotection in the central nervous system. J Biol Chem. 2005;280:41732–41743.[Google Scholar]
  • 105. Rempe DA, Lelli KM, Vangeison G, Johnson RS, Federoff HJIn cultured astrocytes, p53 and MDM2 do not alter hypoxia-inducible factor-1α function regardless of the presence of DNA damage. J Biol Chem. 2007;282:16187–16201.[PubMed][Google Scholar]
  • 106. Lee MY, Ju WK, Cha JH, et al Expression of vascular endothelial growth factor mRNA following transient forebrain ischemia in rats. Neurosci Lett. 1999;265:107–110.[PubMed][Google Scholar]
  • 107. Sinor AD, Irvin SM, Cobbs CS, Chen J, Graham SH, Greenberg DAHypoxic induction of vascular endothelial growth factor (VEGF) protein in astroglial cultures. Brain Res. 1998;812:289–291.[PubMed][Google Scholar]
  • 108. Beck H, Plate KHAngiogenesis after cerebral ischemia. Acta Neuropathol. 2009;117:481–496.[PubMed][Google Scholar]
  • 109. Jin KL, Mao XO, Greenberg DAVascular endothelial growth factor: direct neuroprotective effect in in vitro ischemia. Proc Natl Acad Sci U S A. 2000;97:10242–10247.[Google Scholar]
  • 110. Wick A, Wick W, Waltenberger J, Weller M, Dichgans J, Schulz JBNeuroprotection by hypoxic preconditioning requires sequential activation of vascular endothelial growth factor receptor and Akt. J Neurosci. 2002;22:6401–6407.[Google Scholar]
  • 111. Bernaudin M, Nedelec AS, Divoux D, MacKenzie ET, Petit E, Schumann-Bard PNormobaric hypoxia induces tolerance to focal permanent cerebral ischemia in association with an increased expression of hypoxia-inducible factor-1 and its target genes, erythropoietin and VEGF, in the adult mouse brain. J Cereb Blood Flow Metab. 2002;22:393–403.[PubMed][Google Scholar]
  • 112. Plate KH, Beck H, Danner S, Allegrini PR, Wiessner CCell type specific upregulation of vascular endothelial growth factor in an MCA-occlusion model of cerebral infarct. J Neuropathol Exp Neurol. 1999;58:654–666.[PubMed][Google Scholar]
  • 113. Jian Liu K, Rosenberg GAMatrix metalloproteinases and free radicals in cerebral ischemia. Free Radie Biol Med. 2005;39:71–80.[PubMed][Google Scholar]
  • 114. Cunningham LA, Wetzel M, Rosenberg GAMultiple roles for MMPs and TIMPs in cerebral ischemia. Glia. 2005;50:329–339.[PubMed][Google Scholar]
  • 115. Asahi M, Asahi K, Jung JC, del Zoppo GJ, Fini ME, Lo EHRole for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J Cereb Blood Flow Metab. 2000;20:1681–1689.[PubMed][Google Scholar]
  • 116. Wardas JNeuroprotective role of adenosine in the CNS. Pol J Pharmacol. 2002;54:313–326.[PubMed][Google Scholar]
  • 117. Heurteaux C, Lauritzen I, Widmann C, Lazdunski MEssential role of adenosine, adenosine A1 receptors, and ATP-sensitive K channels in cerebral ischemic preconditioning. Proc Natl Acad Sci U S A. 1995;92:4666–4670.[Google Scholar]
  • 118. Lin JH, Lou N, Kang N, et al A central role of connexin 43 in hypoxic preconditioning. J Neurosci. 2008;28:681–695.[Google Scholar]
  • 119. Williams-Kamesky RL, Stenzel-Poore MPAdenosine and stroke: maximizing the therapeutic potential of adenosine as a prophylactic and acute neuroprotectant. Curr Neuropharmacol. 2009;7:217–227.[Google Scholar]
  • 120. Kang J, Kang N, Lovatt D, et al Connexin 43 hemichannels are permeable to ATP. J Neurosci. 2008;28:4702–4711.[Google Scholar]
  • 121. Robson SC, Sévigny J, Zimmermann HThe E-NTPDase family of ectonucleotidases: structure function relationships and pathophysiological significance. Purinergic Signal. 2006;2:409–430.[Google Scholar]
  • 122. Boison DAdenosine kinase, epilepsy and stroke: mechanisms and therapies. Trends Pharmacol Sci. 2006;27:652–658.[PubMed][Google Scholar]
  • 123. Boison DAdenosine and epilepsy: from therapeutic rationale to new therapeutic strategies. Neuroscientist. 2005;11:25–36.[PubMed][Google Scholar]
  • 124. Grenz A, Zhang H, Hermes M, et al Contribution of E-NTP-Dasel (CD39) to renal protection from ischemia-reperfusion injury. FASEB J. 2007;21:2863–2873.[PubMed][Google Scholar]
  • 125. Köhler D, Eckle T, Faigle M, et al CD39/ectonucleoside triphosphate diphosphohydrolase 1 provides myocardial protection during cardiac ischemia/reperfusion injury [Erratum in: Circulation 2007;116:e514.] Circulation. 2007;116:1784–1794.[PubMed][Google Scholar]
  • 126. Kochanek PM, Vagni VA, Janesko KL, et al Adenosine A1 receptor knockout mice develop lethal status epilepticus after experimental traumatic brain injury. J Cereb Blood Flow Metab. 2006;26:565–575.[PubMed][Google Scholar]
  • 127. Pignataro G, Simon RP, Boison DTransgenic overexpression of adenosine kinase aggravates cell death in ischemia. J Cereb Blood Flow Metab. 2007;27:1–5.[PubMed][Google Scholar]
  • 128. Olsson T, Cronberg T, Rytter A, et al Deletion of the adenosine A1 receptor gene does not alter neuronal damage following ischaemia in vivo or in vitro. Eur J Neurosci. 2004;20:1197–1204.[PubMed][Google Scholar]
  • 129. von Lubitz DKAdenosine and cerebral ischemia: therapeutic future or death of a brave concept? Eur J Pharmacol. 1999;371:85–102.[PubMed][Google Scholar]
  • 130. Chen JF, Huang Z, Ma J, et al A2A adenosine receptor deficiency attenuates brain injury induced by transient focal ischemia in mice. J Neurosci. 1999;19:9192–9200.[Google Scholar]
  • 131. O’Regan MH, Simpson RE, Perkins LM, Phillis JWThe selective A2 adenosine receptor agonist CGS 21680 enhances excitatory transmitter amino acid release from the ischemic rat cerebral cortex. Neurosci Lett. 1992;138:169–172.[PubMed][Google Scholar]
  • 132. Popoli P, Betto P, Reggio R, Ricciarello GAdenosine A2A receptor stimulation enhances striatal extracellular glutamate levels in rats. Eur J Pharmacol. 1995;287:215–217.[PubMed][Google Scholar]
  • 133. Stone TW, Ceruti S, Abbracchio MP. Adenosine receptors and neurological disease: neuroprotection and neurodegeneration. Handb Exp Pharmacol 2009;(193):535–587. [[PubMed]
  • 134. Farahani R, Pina-Benabou MH, Kyrozis A, et al Alterations in metabolism and gap junction expression may determine the role of astrocytes as “good Samaritans” or executioners. Glia. 2005;50:351–361.[PubMed][Google Scholar]
  • 135. Juszczak GR, Swiergiel AHProperties of gap junction blockers and their behavioural, cognitive and electrophysiological effects: animal and human studies. Prog Neuropsychopharmacol Biol Psychiatry. 2009;33:181–198.[PubMed][Google Scholar]
  • 136. de Pina-Benabou MH, Szostak V, Kyrozis A, et al Blockade of gap junctions in vivo provides neuroprotection after perinatal global ischemia. Stroke. 2005;36:2232–2237.[PubMed][Google Scholar]
  • 137. Vakili A, Hosseinzadeh SA, Khorasani MZPeripheral administration of carbenoxolone reduces ischemic reperfusion injury in transient model of cerebral ischemia. J Stroke Cerebrovasc Dis. 2009;18:81–85.[PubMed][Google Scholar]
  • 138. Perez Velazquez JL, Kokarovtseva L, Sarbaziha R, Jeyapalan Z, Leshchenko YRole of gap junctional coupling in astrocytic networks in the determination of global ischaemia-induced oxidative stress and hippocampal damage. Eur J Neurosci. 2006;23:1–10.[PubMed][Google Scholar]
  • 139. Turpie AG, Thomson TJCarbenoxolone sodium in the treatment of gastric ulcer with special reference to side-effects. Gut. 1965;6:591–594.[Google Scholar]
  • 140. Nakase T, Söhl G, Theis M, Willecke K, Naus CCIncreased apoptosis and inflammation after focal brain ischemia in mice lacking connexin43 in astrocytes. Am J Pathol. 2004;164:2067–2075.[Google Scholar]
  • 141. Nudo RJPostinfarct cortical plasticity and behavioral recovery. Stroke. 2007;38:840–845.[PubMed][Google Scholar]
  • 142. Carmichael STPlasticity of cortical projections after stroke. Neuroscientist. 2003;9:64–75.[PubMed][Google Scholar]
  • 143. Hamilton NB, Attwell DDo astrocytes really exocytose neuro-transmitters? Nat Rev Neurosci. 2010;11:227–238.[PubMed][Google Scholar]
  • 144. Barker AJ, Ullian EMAstrocytes and synaptic plasticity. Neuroscientist. 2010;16:40–50.[PubMed][Google Scholar]
  • 145. Liauw J, Hoang S, Choi M, et al Thrombospondins 1 and 2 are necessary for synaptic plasticity and functional recovery after stroke. J Cereb Blood Flow Metab. 2008;28:1722–1732.[PubMed][Google Scholar]
  • 146. Christopherson KS, Ullian EM, Stokes CC, et al Thrombospondins are astrocyte-secreted proteins that promote CNS synaptogenesis. Cell. 2005;120:421–433.[PubMed][Google Scholar]
  • 147. Kyriakides TR, MacLauchlan SThe role of thrombospondins in wound healing, ischemia, and the foreign body reaction. J Cell Commun Signal. 2009;3:215–225.[Google Scholar]
  • 148. Eroglu C, Allen NJ, Susman MW, et al Gabapentin receptor α2δ-1 is a neuronal thrombospondin receptor responsible for excitatory CNS synaptogenesis. Cell. 2009;139:380–392.[Google Scholar]
  • 149. Li Y, Chopp MMarrow stromal cell transplantation in stroke and traumatic brain injury. Neurosci Lett. 2009;456:120–123.[Google Scholar]
  • 150. Chopp M, Li YTreatment of neural injury with marrow stromal cells. Lancet Neurol. 2002;1:92–100.[PubMed][Google Scholar]
  • 151. Liu Z, Li Y, Zhang ZG, et al Bone marrow stromal cells enhance inter- and intracortical axonal connections after ischemic stroke in adult rats. J Cereb Blood Flow Metab. 2010;30:1288–1295.[Google Scholar]
  • 152. Gao Q, Li Y, Chopp MBone marrow stromal cells increase astrocyte survival via upregulation of phosphoinositide 3-kinase/ threonine protein kinase and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase pathways and stimulate astrocyte trophic factor gene expression after anaerobic insult. Neuroscience. 2005;136:123–134.[PubMed][Google Scholar]
  • 153. Xin H, Li Y, Shen LH, et al Increasing tPA activity in astrocytes induced by multipotent mesenchymal stromal cells facilitate neurite outgrowth after stroke in the mouse. PLoS ONE. 2010;5:e9027–e9027.[Google Scholar]
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