Inflammation as a Therapeutic Target after Subarachnoid Hemorrhage: Advances and Challenges

  • Mutsumi Fujii
  • Sheng Chen
  • Damon Klebe
  • Yoshiteru Soejima
  • Alexander Vakhmyanin
  • John H. Zhang
Part of the Springer Series in Translational Stroke Research book series (SSTSR, volume 6)


Subarachnoid hemorrhage (SAH) results from the rupture of an intracranial aneurysm, and the first consequent events are increased intracranial pressure (ICP), reduced cerebral perfusion pressure (CPP), and decreased cerebral blood flow (CBF). The resultant hypoxic state alters autoregulation, ionic homeostasis, and excitotoxicity as well as initiates secondary injuries such as cytotoxic edema, blood-brain barrier (BBB) disruption, inflammation, and apoptotic cell death. Inflammation persists through hemorrhage degradation in the subarachnoid space. Several different aspects of the inflammatory response have been demonstrated in stroke pathogenesis, including cellular response (e.g., leukocyte adherence and microglia activation), expression of adhesion molecules (e.g., selectins, integrins, and immunoglobulin superfamily), production of inflammatory mediators (e.g., cytokines, nitric oxide/nitric oxide synthase (NO/NOS), and free radicals), and accumulation of platelet aggregates. Since all of these inflammatory aspects lead to brain edema and cell death, inflammation could be a particularly important target for designing therapeutic strategies against secondary injuries after SAH. Given these inflammatory contributions could be seen in large vessels, a plethora of research has been intended to reduce cerebral vasospasm (CVS) after SAH. The main research field, however, is moving toward studying early brain injury (EBI) because some human research demonstrated the morphological alleviation of CVS alone might not improve the functional recovery in patients after SAH. This chapter provides the current knowledge of the inflammatory response, translational research, and human clinical trials in SAH as well as discusses emerging opportunities for novel therapeutic strategies for clinical management of SAH.


Nitric Oxide Basilar Artery Cerebral Vasospasm Early Brain Injury Angiographic Vasospasm 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



This study was supports by the National Institutes of Health NS053407 to J.H. Zhang.

Conflict of Interest Statement

We declare that we have no conflicts of interest.


  1. 1.
    David S, Kroner A (2011) Repertoire of microglial and macrophage responses after spinal cord injury. Nat Rev Neurosci 12:388–99PubMedGoogle Scholar
  2. 2.
    Loane DJ, Byrnes KR (2010) Role of microglia in neurotrauma. Neurotherapeutics 7:366–77PubMedGoogle Scholar
  3. 3.
    Barone FC, Feuerstein GZ (1999) Inflammatory mediators and stroke: new opportunities for novel therapeutics. J Cereb Blood Flow Metab 19:819–34PubMedGoogle Scholar
  4. 4.
    Chamorro A, Hallenbeck J (2006) The harms and benefits of inflammatory and immune responses in vascular disease. Stroke 37:291–3PubMedGoogle Scholar
  5. 5.
    Kleinig TJ, Vink R (2009) Suppression of inflammation in ischemic and hemorrhagic stroke: therapeutic options. Curr Opin Neurol 22:294–301PubMedGoogle Scholar
  6. 6.
    Xia W, Han J, Huang G, Ying W (2010) Inflammation in ischaemic brain injury: current advances and future perspectives. Clin Exp Pharmacol Physiol 37:253–8PubMedGoogle Scholar
  7. 7.
    Aronowski J, Hall CE (2005) New horizons for primary intracerebral hemorrhage treatment: experience from preclinical studies. Neurol Res 27:268–79PubMedGoogle Scholar
  8. 8.
    Ducruet AF, Zacharia BE, Hickman ZL, Grobelny BT, Yeh ML, Sosunov SA et al (2009) The complement cascade as a therapeutic target in intracerebral hemorrhage. Exp Neurol 219:398–403PubMedGoogle Scholar
  9. 9.
    Wang J, Doré S (2007) Inflammation after intracerebral hemorrhage. J Cereb Blood Flow Metab 27:894–908PubMedGoogle Scholar
  10. 10.
    van Gijn J, Kerr RS, Rinkel GJ (2007) Subarachnoid haemorrhage. Lancet 369:306–18PubMedGoogle Scholar
  11. 11.
    King JT Jr (1997) Epidemiology of aneurysmal subarachnoid hemorrhage. Neuroimaging Clin N Am 7:659–68PubMedGoogle Scholar
  12. 12.
    Sehba FA, Hou J, Pluta RM, Zhang JH (2012) The importance of early brain injury after subarachnoid hemorrhage. Prog Neurobiol 97:14–37PubMedGoogle Scholar
  13. 13.
    Wilkins RH (1990) Cerebral vasospasm. Crit Rev Neurobiol 6:51–77PubMedGoogle Scholar
  14. 14.
    Fergusen S, Macdonald RL (2007) Predictors of cerebral infarction in patients with aneurysmal subarachnoid hemorrhage. Neurosurgery 60:658–67PubMedGoogle Scholar
  15. 15.
    Fisher CM, Roberson GH, Ojemann RG (1977) Cerebral vasospasm with ruptured saccular aneurysm–the clinical manifestations. Neurosurgery 1:245–8PubMedGoogle Scholar
  16. 16.
    Rabinstein AA, Friedman JA, Weigand SD, McClelland RL, Fulgham JR, Manno EM et al (2004) Predictors of cerebral infarction in aneurysmal subarachnoid hemorrhage. Stroke 35:1862–6PubMedGoogle Scholar
  17. 17.
    Dorsch NW (1995) Cerebral arterial spasm–a clinical review. Br J Neurosurg 9:403–12PubMedGoogle Scholar
  18. 18.
    Kusaka G, Ishikawa M, Nanda A, Granger DN, Zhang JH (2004) Signaling pathways for early brain injury after subarachnoid hemorrhage. J Cereb Blood Flow Metab 24:916–25PubMedGoogle Scholar
  19. 19.
    Macdonald RL, Kassell NF, Mayer S, Ruefenacht D, Schmiedek P, Weidauer S et al (2008) Clazosentan to overcome neurological ischemia and infarction occurring after subarachnoid hemorrhage (CONSCIOUS-1): randomized, double-blind, placebo-controlled phase 2 dose-finding trial. Stroke 39:3015–21PubMedGoogle Scholar
  20. 20.
    Macdonald RL, Pluta RM, Zhang JH (2007) Cerebral vasospasm after subarachnoid hemorrhage: the emerging revolution. Nat Clin Pract Neurol 3:256–63PubMedGoogle Scholar
  21. 21.
    Pluta RM (2005) Delayed cerebral vasospasm and nitric oxide: review, new hypothesis, and proposed treatment. Pharmacol Ther 105:23–56PubMedGoogle Scholar
  22. 22.
    Broderick JP, Brott TG, Duldner JE, Tomsick T, Leach A (1994) Initial and recurrent bleeding are the major causes of death following subarachnoid hemorrhage. Stroke 25:1342–7PubMedGoogle Scholar
  23. 23.
    Ostrowski RP, Colohan AR, Zhang JH (2006) Molecular mechanisms of early brain injury after subarachnoid hemorrhage. Neurol Res 28:399–414PubMedGoogle Scholar
  24. 24.
    Ostrowski RP, Tang J, Zhang JH (2006) Hyperbaric oxygen suppresses NADPH oxidase in a rat subarachnoid hemorrhage model. Stroke 37:1314–8PubMedGoogle Scholar
  25. 25.
    Grote E, Hassler W (1988) The critical first minutes after subarachnoid hemorrhage. Neurosurgery 22:654–61PubMedGoogle Scholar
  26. 26.
    Cahill J, Calvert JW, Zhang JH (2006) Mechanisms of early brain injury after subarachnoid hemorrhage. J Cereb Blood Flow Metab 26:1341–53PubMedGoogle Scholar
  27. 27.
    Keep RF, Andjelkovic AV, Stamatovic SM, Shakui P, Ennis SR (2005) Ischemia-induced endothelial cell dysfunction. Acta Neurochir Suppl 95:399–402PubMedGoogle Scholar
  28. 28.
    Sehba FA, Pluta RM, Zhang JH (2011) Metamorphosis of subarachnoid hemorrhage research: from delayed vasospasm to early brain injury. Mol Neurobiol 43:27–40PubMedGoogle Scholar
  29. 29.
    Luster AD, Alon R, von Andrian UH (2005) Immune cell migration in inflammation: present and future therapeutic targets. Nat Immunol 6:1182–90PubMedGoogle Scholar
  30. 30.
    Friedrich V, Flores R, Muller A, Bi W, Peerschke EI, Sehba FA (2011) Reduction of neutrophil activity decreases early microvascular injury after subarachnoid haemorrhage. J Neuroinflammation 8:103PubMedGoogle Scholar
  31. 31.
    Dumont AS, Dumont RJ, Chow MM, Lin CL, Calisaneller T, Ley KF et al (2003) Cerebral vasospasm after subarachnoid hemorrhage: putative role of inflammation. Neurosurgery 53:123–35PubMedGoogle Scholar
  32. 32.
    Provencio JJ, Fu X, Siu A, Rasmussen PA, Hazen SL, Ransohoff RM (2010) CSF neutrophils are implicated in the development of vasospasm in subarachnoid hemorrhage. Neurocrit Care 12:244–51PubMedGoogle Scholar
  33. 33.
    Wang Q, Tang XN, Yenari MA (2007) The inflammatory response in stroke. J Neuroimmunol 184:53–68PubMedGoogle Scholar
  34. 34.
    Wang Y, Zhong M, Tan XX, Yang YJ, Chen WJ, Liu W et al (2007) Expression change of interleukin-8 gene in rabbit basilar artery after subarachnoid hemorrhage. Neurosci Bull 23:151–5PubMedGoogle Scholar
  35. 35.
    Matz P, Turner C, Weinstein PR, Massa SM, Panter SS, Sharp FR (1996) Heme-oxygenase-1 induction in glia throughout rat brain following experimental subarachnoid hemorrhage. Brain Res 713:211–22PubMedGoogle Scholar
  36. 36.
    Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ et al (2000) Immunobiology of dendritic cells. Annu Rev Immunol 1(8):767–811Google Scholar
  37. 37.
    Theoharides TC, Alysandratos KD, Angelidou A, Delivanis DA, Sismanopoulos N, Zhang B et al (2012) Mast cells and inflammation. Biochim Biophys Acta 2012:21–33Google Scholar
  38. 38.
    Liesz A, Suri-Payer E, Veltkamp C, Doerr H, Sommer C, Rivest S et al (2009) Regulatory T cells are key cerebroprotective immunomodulators in acute experimental stroke. Nat Med 15:192–9PubMedGoogle Scholar
  39. 39.
    Rossi B, Constantin G (2008) Anti-selectin therapy for the treatment of inflammatory diseases. Inflamm Allergy Drug Targets 7:85–93PubMedGoogle Scholar
  40. 40.
    Moore KL (1998) Structure and function of P-selectin glycoprotein ligand-1. Leuk Lymphoma 29:1–15PubMedGoogle Scholar
  41. 41.
    McEver RP (2002) Selectins: lectins that initiate cell adhesion under flow. Curr Opin Cell Biol 14:581–6PubMedGoogle Scholar
  42. 42.
    Sperandio M, Smith ML, Forlow SB, Olson TS, Xia L, McEver RP et al (2003) P-selectin glycoprotein ligand-1 mediates L-selectin-dependent leukocyte rolling in venules. J Exp Med 197:1355–63PubMedGoogle Scholar
  43. 43.
    Hynes RO (2002) Integrins: bidirectional, allosteric signaling machines. Cell 110:673–87PubMedGoogle Scholar
  44. 44.
    Springer TA, Dustin ML, Kishimoto TK, Marlin SD (1987) The lymphocyte function-associated LFA-1, CD2, and LFA-3 molecules: cell adhesion receptors of the immune system. Annu Rev Immunol 5:223–52PubMedGoogle Scholar
  45. 45.
    Miller LJ, Schwarting R, Springer TA (1986) Regulated expression of the Mac-1, LFA-1, p150, 95 glycoprotein family during leukocyte differentiation. J Immunol 137:2891–900PubMedGoogle Scholar
  46. 46.
    Pradilla G, Wang PP, Legnani FG, Ogata L, Dietsch GN, Tamargo RJ (2004) Prevention of vasospasm by anti-CD11/CD18 monoclonal antibody therapy following subarachnoid hemorrhage in rabbits. J Neurosurg 101:88–92PubMedGoogle Scholar
  47. 47.
    Clatterbuck RE, Oshiro EM, Hoffman PA, Dietsch GN, Pardoll DM, Tamargo RJ (2002) Inhibition of vasospasm with lymphocyte function-associated antigen-1 monoclonal antibody in a femoral artery model in rats. J Neurosurg 97:676–82PubMedGoogle Scholar
  48. 48.
    Handa Y, Kubota T, Kaneko M, Tsuchida A, Kobayashi H, Kawano H et al (1995) Expression of intercellular adhesion molecule 1 (ICAM-1) on the cerebral artery following subarachnoid haemorrhage in rats. Acta Neurochir (Wien) 132:92–7PubMedGoogle Scholar
  49. 49.
    Gallia GL, Tamargo RJ (2006) Leukocyte-endothelial cell interactions in chronic vasospasm after subarachnoid hemorrhage. Neurol Res 28:750–8PubMedGoogle Scholar
  50. 50.
    Oshiro EM, Hoffman PA, Dietsch GN, Watts MC, Pardoll DM, Tamargo RJ (1997) Inhibition of experimental vasospasm with anti-intercellular adhesion molecule-1 monoclonal antibody in rats. Stroke 28:2031–8PubMedGoogle Scholar
  51. 51.
    Sills AK Jr, Clatterbuck RE, Thompson RC, Cohen PL, Tamargo RJ (1997) Endothelial cell expression of intercellular adhesion molecule 1 in experimental posthemorrhagic vasospasm. Neurosurgery 41:453–61PubMedGoogle Scholar
  52. 52.
    Mack WJ, Mocco J, Hoh DJ, Huang J, Choudhri TF, Kreiter KT et al (2002) Outcome prediction with serum intercellular adhesion molecule-1 levels after aneurysmal subarachnoid hemorrhage. J Neurosurg 96:71–5PubMedGoogle Scholar
  53. 53.
    Polin RS, Bavbek M, Shaffrey ME, Billups K, Bogaev CA, Kassell NF et al (1998) Detection of soluble E-selectin, ICAM-1, VCAM-1, and L-selectin in the cerebrospinal fluid of patients after subarachnoid hemorrhage. J Neurosurg 89:559–67PubMedGoogle Scholar
  54. 54.
    Sprague AH, Khalil RA (2009) Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol 78:539–52PubMedGoogle Scholar
  55. 55.
    Lu H, Shi JX, Chen HL, Hang CH, Wang HD, Yin HX (2009) Expression of monocyte chemoattractant protein-1 in the cerebral artery after experimental subarachnoid hemorrhage. Brain Res 1262:73–80PubMedGoogle Scholar
  56. 56.
    Vikman P, Ansar S, Edvinsson L (2007) Transcriptional regulation of inflammatory and extracellular matrix-regulating genes in cerebral arteries following experimental subarachnoid hemorrhage in rats. Laboratory investigation. J Neurosurg 107:1015–22PubMedGoogle Scholar
  57. 57.
    Aihara Y, Kasuya H, Onda H, Hori T, Takeda J (2001) Quantitative analysis of gene expressions related to inflammation in canine spastic artery after subarachnoid hemorrhage. Stroke 32:212–7PubMedGoogle Scholar
  58. 58.
    Luster AD (1998) Chemokines–chemotactic cytokines that mediate inflammation. N Engl J Med 338:436–45PubMedGoogle Scholar
  59. 59.
    Ehrenreich H, Anderson RW, Fox CH, Rieckmann P, Hoffman GS, Travis WD et al (1990) Endothelins, peptides with potent vasoactive properties, are produced by human macrophages. J Exp Med 172:1741–8PubMedGoogle Scholar
  60. 60.
    Sessa WC, Kaw S, Hecker M, Vane JR (1991) The biosynthesis of endothelin-1 by human polymorphonuclear leukocytes. Biochem Biophys Res Commun 174:613–8PubMedGoogle Scholar
  61. 61.
    Tierney TS, Clatterbuck RE, Lawson C, Thai QA, Rhines LD, Tamargo RJ (2001) Prevention and reversal of experimental posthemorrhagic vasospasm by the periadventitial administration of nitric oxide from a controlled-release polymer. Neurosurgery 49:945–53PubMedGoogle Scholar
  62. 62.
    Macdonald RL, Weir BK (1991) A review of hemoglobin and the pathogenesis of cerebral vasospasm. Stroke 22:971–82PubMedGoogle Scholar
  63. 63.
    Sehba FA, Schwartz AY, Chereshnev I, Bederson JB (2000) Acute decrease in cerebral nitric oxide levels after subarachnoid hemorrhage. J Cereb Blood Flow Metab 20:604–11PubMedGoogle Scholar
  64. 64.
    Moro MA, Almeida A, Bolanos JP, Lizasoain I (2005) Mitochondrial respiratory chain and free radical generation in stroke. Free Radic Biol Med 39:1291–304PubMedGoogle Scholar
  65. 65.
    Szabó C, Dawson VL (1998) Role of poly(ADP-ribose) synthetase in inflammation and ischaemia-reperfusion. Trends Pharmacol Sci 19:287–98PubMedGoogle Scholar
  66. 66.
    Calvert JW, Zhang JH (2005) Pathophysiology of an hypoxic-ischemic insult during the perinatal period. Neurol Res 27:246–60PubMedGoogle Scholar
  67. 67.
    Weller R (2003) Nitric oxide: a key mediator in cutaneous physiology. Clin Exp Dermatol 28:511–4PubMedGoogle Scholar
  68. 68.
    Huang Z, Huang PL, Panahian N, Dalkara T, Fishman MC, Moskowitz MA (1994) Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase. Science 265:1883–5PubMedGoogle Scholar
  69. 69.
    Huang Z, Huang PL, Ma J, Meng W, Ayata C, Fishman MC et al (1996) Enlarged infarcts in endothelial nitric oxide synthase knockout mice are attenuated by nitro-l-arginine. J Cereb Blood Flow Metab 16:981–7PubMedGoogle Scholar
  70. 70.
    Iadecola C, Zhang F, Casey R, Clark HB, Ross ME (1996) Inducible nitric oxide synthase gene expression in vascular cells after transient focal cerebral ischemia. Stroke 27:1373–80PubMedGoogle Scholar
  71. 71.
    Yatsushige H, Calvert JW, Cahill J, Zhang JH (2006) Limited role of inducible nitric oxide synthase in blood–brain barrier function after experimental subarachnoid hemorrhage. J Neurotrauma 23:1874–82PubMedGoogle Scholar
  72. 72.
    McGirt MJ, Lynch JR, Parra A, Sheng H, Pearlstein RD, Laskowitz DT et al (2002) Simvastatin increases endothelial nitric oxide synthase and ameliorates cerebral vasospasm resulting from subarachnoid hemorrhage. Stroke 33:2950–6PubMedGoogle Scholar
  73. 73.
    Sugawara T, Ayer R, Jadhav V, Chen W, Tsubokawa T, Zhang JH (2008) Simvastatin attenuation of cerebral vasospasm after subarachnoid hemorrhage in rats via increased phosphorylation of Akt and endothelial nitric oxide synthase. J Neurosci Res 86:3635–43PubMedGoogle Scholar
  74. 74.
    Sabri M, Ai J, Knight B, Tariq A, Jeon H, Shang X et al (2011) Uncoupling of endothelial nitric oxide synthase after experimental subarachnoid hemorrhage. J Cereb Blood Flow Metab 31:190–9PubMedGoogle Scholar
  75. 75.
    Sabri M, Ai J, Marsden PA, Macdonald RL (2011) Simvastatin re-couples dysfunctional endothelial nitric oxide synthase in experimental subarachnoid hemorrhage. PLoS One 6:e17062PubMedGoogle Scholar
  76. 76.
    Misra HP, Fridovich I (1972) The generation of superoxide radical during the autoxidation of hemoglobin. J Biol Chem 247:6960–2PubMedGoogle Scholar
  77. 77.
    Rubbo H, Trostchansky A, O’Donnell VB (2009) Peroxynitrite-mediated lipid oxidation and nitration: mechanisms and consequences. Arch Biochem Biophys 484:167–72PubMedGoogle Scholar
  78. 78.
    Sehba FA, Bederson JB (2006) Mechanisms of acute brain injury after subarachnoid hemorrhage. Neurol Res 28:381–98PubMedGoogle Scholar
  79. 79.
    Giulivi C, Hochstein P, Davies KJA (1994) Hydrogen peroxide production by red blood cells. Free Radic Biol Med 16:123–9PubMedGoogle Scholar
  80. 80.
    Bruce Van Dykea R, Saltama P (1996) Hemoglobin: a mechanism for the generation of hydroxyl radicals. Free Radic Biol Med 20:985–9Google Scholar
  81. 81.
    Gutteridge JM (1986) Iron promoters of the Fenton reaction and lipid peroxidation can be released from haemoglobin by peroxides. FEBS Lett 201:291–5PubMedGoogle Scholar
  82. 82.
    Mori T, Nagata K, Town T, Tan J, Matsui T, Asano T (2001) Intracisternal increase of superoxide anion production in a canine subarachnoid hemorrhage model. Stroke 32:636–42PubMedGoogle Scholar
  83. 83.
    Facchinetti F, Dawson VL, Dawson TM (1998) Free radicals as mediators of neuronal injury. Cell Mol Neurobiol 18:667–82PubMedGoogle Scholar
  84. 84.
    Weiss SJ (1989) Tissue destruction by neutrophils. N Engl J Med 320:365–76PubMedGoogle Scholar
  85. 85.
    Lin CL, Hsu YT, Lin TK, Morrow JD, Hsu JC, Hsu YH et al (2006) Increased levels of F2-isoprostanes following aneurysmal subarachnoid hemorrhage in humans. Free Radic Biol Med 40:1466–73PubMedGoogle Scholar
  86. 86.
    Lewen A, Matz P, Chan PH (2000) Free radical pathways in CNS injury. J Neurotrauma 17:871–90PubMedGoogle Scholar
  87. 87.
    Gaetani P, Lombardi D (1992) Brain damage following subarachnoid hemorrhage: the imbalance between anti-oxidant systems and lipid peroxidative processes. J Neurosurg Sci 36:1–10PubMedGoogle Scholar
  88. 88.
    Matz PG, Fujimura M, Lewen A, Morita-Fujimura Y, Chan PH (2001) Increased cytochrome c-mediated DNA fragmentation and cell death in manganese-superoxide dismutase-deficient mice after exposure to subarachnoid hemolysate. Stroke 32:506–15PubMedGoogle Scholar
  89. 89.
    Weyrich AS, Schwertz H, Kraiss LW, Zimmerman GA (2009) Protein synthesis by platelets: historical and new perspectives. J Thromb Haemost 7:241–6PubMedGoogle Scholar
  90. 90.
    Akopov S, Sercombe R, Seylaz J (1996) Endothelium–plateletleukocyte interactions in the cerebral circulation. Cerebrovasc Brain Metab Rev 8:11–94PubMedGoogle Scholar
  91. 91.
    Sehba FA, Mostafa G, Friedrich V Jr, Bederson JB (2005) Acute microvascular platelet aggregation after subarachnoid hemorrhage. J Neurosurg 102:1094–100PubMedGoogle Scholar
  92. 92.
    Friedrich V, Flores R, Muller A, Sehba FA (2010) Escape of intraluminal platelets into brain parenchyma after subarachnoid hemorrhage. Neuroscience 165:968–75PubMedGoogle Scholar
  93. 93.
    Friedrich V, Flores R, Muller A, Sehba FA (2010) Luminal platelet aggregates in functional deficits inparenchymal vessels after subarachnoid hemorrhage. Brain Res 1354:179–87PubMedGoogle Scholar
  94. 94.
    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 25:202–11PubMedGoogle Scholar
  95. 95.
    Sehba FA, Mostafa G, Knopman J, Friedrich V Jr, Bederson JB (2004) Acute alterations in microvascular basal lamina after subarachnoid hemorrhage. J Neurosurg 101:633–40PubMedGoogle Scholar
  96. 96.
    Sehba FA, Friedrich V Jr, Makonnen G, Bederson JB (2007) Acute cerebral vascular injury after subarachnoid hemorrhage and its prevention by administration of a nitric oxide donor. J Neurosurg 106:321–9PubMedGoogle Scholar
  97. 97.
    Rosenberg GA, Cunningham LA, Wallace J, Alexander S, Estrada EY, Grossetete M et al (2001) Immunohistochemistry of matrix metalloproteinases in reperfusion injury to rat brain: activation of MMP-9 linked to stromelysin-1 and microglia in cell cultures. Brain Res 893:104–12PubMedGoogle Scholar
  98. 98.
    Liu W, Hendren J, Qin XJ, Shen J, Liu KJ (2009) Normobaric hyperoxia attenuates early blood-brain barrier disruption by inhibiting MMP-9-mediated occludin degradation in focal cerebral ischemia. J Neurochem 108:811–20PubMedGoogle Scholar
  99. 99.
    Asano T, Ikegaki I, Suzuki Y, Satoh S, Shibuya M (1989) Endothelin and the production of cerebral vasospasm in dogs. Biochem Biophys Res Commun 159:1345–51PubMedGoogle Scholar
  100. 100.
    Zimmermann M, Seifert V (2004) Endothelin receptor antagonists and cerebral vasospasm. Clin Auton Res 14:143–5PubMedGoogle Scholar
  101. 101.
    Sercombe R, Dinh YR, Gomis P (2002) Cerebrovascular inflammation following subarachnoid hemorrhage. Jpn J Pharmacol 88:227–49PubMedGoogle Scholar
  102. 102.
    Saleh MA, Pollock DM (2011) Endothelin in renal inflammation and hypertension. Contrib Nephrol 172:160–70PubMedGoogle Scholar
  103. 103.
    Narushima I, Kita T, Kubo K, Yonetani Y, Momochi C, Yoshikawa I et al (1999) Contribution of endothelin-1 to disruption of blood-brain barrier permeability in dogs. Naunyn Schmiedebergs Arch Pharmacol 360:639–45PubMedGoogle Scholar
  104. 104.
    Haorah J, Knipe B, Leibhart J, Ghorpade A, Persidsky Y (2005) Alcohol-induced oxidative stress in brain endothelial cells causes blood-brain barrier dysfunction. J Leukoc Biol 78:1223–32PubMedGoogle Scholar
  105. 105.
    Imaizumi S, Kondo T, Deli MA, Gobbel G, Joó F, Epstein CJ et al (1996) The influence of oxygen free radicals on the permeability of the monolayer of cultured brain endothelial cells. Neurochem Int 29:205–11PubMedGoogle Scholar
  106. 106.
    Ballabh P, Braun A, Nedergaard M (2004) The blood–brain barrier: an overview: structure, regulation, and clinical implications. Neurobiol Dis 16:1–13PubMedGoogle Scholar
  107. 107.
    van der Goes A, Wouters D, van Der Pol SM, Huizinga R, Ronken E, Adamson P et al (2001) Reactive oxygen species enhance the migration of monocytes across the blood–brain barrier in vitro. FASEB J 15:1852–4PubMedGoogle Scholar
  108. 108.
    Bavbek M, Polin R, Kwan AL, Arthur AS, Kassell NF, Lee KS (1998) Monoclonal antibodies against ICAM-1 and CD18 attenuate cerebral vasospasm after experimental subarachnoid hemorrhage in rabbits. Stroke 29:1930–6PubMedGoogle Scholar
  109. 109.
    Clatterbuck RE, Gailloud P, Ogata L, Gebremariam A, Dietsch GN, Murphy KJ et al (2003) Prevention of cerebral vasospasm by a humanized anti-CD11/CD18 monoclonal antibody administered after experimental subarachnoid hemorrhage in nonhuman primates. J Neurosurg 99:376–82PubMedGoogle Scholar
  110. 110.
    Lin CL, Dumont AS, Calisaneller T, Kwan AL, Hwong SL, Lee KS (2005) Monoclonal antibody against E selectin attenuates subarachnoid hemorrhage-induced cerebral vasospasm. Surg Neurol 64:201–6PubMedGoogle Scholar
  111. 111.
    Provencio JJ, Altay T, Smithason S, Moore SK, Ransohoff RM (2011) Depletion of Ly6G/C(+) cells ameliorates delayed cerebral vasospasm in subarachnoid hemorrhage. J Neuroimmunol 232:94–100PubMedGoogle Scholar
  112. 112.
    Wang Z, Wang KY, Wu Y, Zhou P, Sun XO, Chen G (2010) Potential role of CD34 in cerebral vasospasm after experimental subarachnoid hemorrhage in rats. Cytokine 52:245–51PubMedGoogle Scholar
  113. 113.
    Wu Y, Tang K, Huang RQ, Zhuang Z, Cheng HL, Yin HX et al (2011) Therapeutic potential of peroxisome proliferator-activated receptor γ agonist rosiglitazone in cerebral vasospasm after a rat experimental subarachnoid hemorrhage model. J Neurol Sci 305:85–91PubMedGoogle Scholar
  114. 114.
    Weber C, Erl W, Weber KS, Weber PC (1997) HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia. J Am Coll Cardiol 30:1212–7PubMedGoogle Scholar
  115. 115.
    Kallen J, Welzenbach K, Ramage P, Geyl D, Kriwacki R, Legge G et al (1999) Structural basis for LFA-1 inhibition upon lovastatin binding to the CD11a I-domain. J Mol Biol 292:1–9PubMedGoogle Scholar
  116. 116.
    McGirt MJ, Pradilla G, Legnani FG, Thai QA, Recinos PF, Tamargo RJ et al (2006) Systemic administration of simvastatin after the onset of experimental subarachnoid hemorrhage attenuates cerebral vasospasm. Neurosurgery 58:945–51PubMedGoogle Scholar
  117. 117.
    Thai QA, Oshiro EM, Tamargo RJ (1999) Inhibition of experimental vasospasm in rats with the periadventitial administration of ibuprofen using controlled-release polymers. Stroke 30:140–7PubMedGoogle Scholar
  118. 118.
    Hino A, Weir BK, Macdonald RL, Thisted RA, Kim CJ, Johns LM (1995) Prospective, randomized, double-blind trial of BQ-123 and bosentan for prevention of vasospasm following subarachnoid hemorrhage in monkeys. J Neurosurg 83:503–9PubMedGoogle Scholar
  119. 119.
    Itoh S, Sasaki T, Ide K, Ishikawa K, Nishikibe M, Yano M (1993) A novel endothelin ETA receptor antagonist, BQ-485, and its preventive effect on experimental cerebral vasospasm in dogs. Biochem Biophys Res Commun 195:969–75PubMedGoogle Scholar
  120. 120.
    Itoh S, Sasaki T, Asai A, Kuchino Y (1994) Prevention of delayed vasospasm by an endothelin ETA receptor antagonist, BQ-123: change of ETA receptor mRNA expression in a canine subarachnoid hemorrhage model. J Neurosurg 81:759–64PubMedGoogle Scholar
  121. 121.
    Kita T, Kubo K, Hiramatsu K, Sakaki T, Yonetani Y, Sato S et al (1998) Profiles of an intravenously available endothelin A-receptor antagonist, S-0139, for preventing cerebral vasospasm in a canine two-hemorrhage model. Life Sci 63:305–15PubMedGoogle Scholar
  122. 122.
    Macdonald RL, Bassiouny M, Johns L, Sajdak M, Marton LS, Weir BK et al (1998) U74389G prevents vasospasm after subarachnoid hemorrhage in dogs. Neurosurgery 42:1339–46PubMedGoogle Scholar
  123. 123.
    Macdonald RL, Johns L, Lin G, Marton LS, Hallak H, Marcoux F et al (1998) Prevention of vasospasm after subarachnoid hemorrhage in dogs by continuous intravenous infusion of PD156707. Neurol Med Chir (Tokyo) 38(Suppl):138–45Google Scholar
  124. 124.
    Nirei H, Hamada K, Shoubo M, Sogabe K, Notsu Y, Ono T (1993) An endothelin ETA receptor antagonist, FR139317, ameliorates cerebral vasospasm in dogs. Life Sci 52:1869–74PubMedGoogle Scholar
  125. 125.
    Roux S, Breu V, Giller T, Neidhart W, Ramuz H, Coassolo P et al (1997) Ro 61-1790, a new hydrosoluble endothelin antagonist: general pharmacology and effects on experimental cerebral vasospasm. J Pharmacol Exp Ther 283:1110–8PubMedGoogle Scholar
  126. 126.
    Shigeno T, Clozel M, Sakai S, Saito A, Goto K (1995) The effect of bosentan, a new potent endothelin receptor antagonist, on the pathogenesis of cerebral vasospasm. Neurosurgery 37:87–91PubMedGoogle Scholar
  127. 127.
    Wanebo JE, Louis HG, Arthur AS, Zhou J, Kassell NF, Lee KS, et al (1997) Attenuation of cerebral vasospasm by systemic administration of an endothelin-A receptor antagonist, TBC 11251, in a rabbit model of subarachnoid hemorrhage. Neurosurg Focus 3:articleGoogle Scholar
  128. 128.
    Wanebo JE, Arthur AS, Louis HG, West K, Kassell NF, Lee KS et al (1998) Systemic administration of the endothelin-A receptor antagonist TBC 11251 attenuates cerebral vasospasm after experimental subarachnoid hemorrhage: dose study and review of endothelin-based therapies in the literature on cerebral vasospasm. Neurosurgery 43:1409–18PubMedGoogle Scholar
  129. 129.
    Willette RN, Zhang H, Mitchell MP, Sauermelch CF, Ohlstein EH, Sulpizio AC (1994) Nonpeptide endothelin antagonist. Cerebrovascular characterization and effects on delayed cerebral vasospasm. Stroke 25:2450–6PubMedGoogle Scholar
  130. 130.
    Zimmermann M, Seifert V, Löffler BM, Stolke D, Stenzel W (1996) Prevention of cerebral vasospasm after experimental subarachnoid hemorrhage by RO 47-0203, a newly developed orally active endothelin receptor antagonist. Neurosurgery 38:115–20PubMedGoogle Scholar
  131. 131.
    Zuccarello M, Soattin GB, Lewis AI, Breu V, Hallak H, Rapoport RM (1996) Prevention of subarachnoid hemorrhage-induced cerebral vasospasm by oral administration of endothelin receptor antagonists. J Neurosurg 84:503–7PubMedGoogle Scholar
  132. 132.
    Zuccarello M, Boccaletti R, Romano A, Rapoport RM (1998) Endothelin B receptor antagonists attenuate subarachnoid hemorrhage-induced cerebral vasospasm. Stroke 29:1924–9PubMedGoogle Scholar
  133. 133.
    Caner HH, Kwan AL, Arthur A, Jeng AY, Lappe RW, Kassell NF et al (1996) Systemic administration of an inhibitor of endothelin-converting enzyme for attenuation of cerebral vasospasm following experimental subarachnoid hemorrhage. J Neurosurg 85:917–22PubMedGoogle Scholar
  134. 134.
    Kwan AL, Bavbek M, Jeng AY, Maniara W, Toyoda T, Lappe RW et al (1997) Prevention and reversal of cerebral vasospasm by an endothelin-converting enzyme inhibitor, CGS 26303, in an experimental model of subarachnoid hemorrhage. J Neurosurg 87:281–6PubMedGoogle Scholar
  135. 135.
    Kwan AL, Lin CL, Chang CZ, Wu HJ, Hwong SL, Jeng AY et al (2001) Continuous intravenous infusion of CGS 26303, an endothelin-converting enzyme inhibitor, prevents and reverses cerebral vasospasm after experimental subarachnoid hemorrhage. Neurosurgery 49:422–9PubMedGoogle Scholar
  136. 136.
    Kwan AL, Lin CL, Yen CP, Winardi W, Su YF, Winardi D, Dai ZK, Jeng AY, Kassell NF, Howng SL, Wang CJ (2006) Prevention and reversal of vasospasm and ultrastructural changes in basilar artery by continuous infusion of CGS 35066 following subarachnoid hemorrhage. Exp Biol Med (Maywood) 231:1069–74Google Scholar
  137. 137.
    Lin CL, Kwan AL, Dumont AS, Su YF, Kassell NF, Wang CJ et al (2007) Attenuation of experimental subarachnoid hemorrhage-induced increases in circulating intercellular adhesion molecule-1 and cerebral vasospasm by the endothelin-converting enzyme inhibitor CGS 26303. J Neurosurg 106:442–8PubMedGoogle Scholar
  138. 138.
    Macdonald RL, Higashida RT, Keller E, Mayer SA, Molyneux A, Raabe A et al (2011) Clazosentan, an endothelin receptor antagonist, in patients with aneurysmal subarachnoid haemorrhage undergoing surgical clipping: a randomised, double-blind, placebo-controlled phase 3 trial (CONSCIOUS-2). Lancet Neurol 10:618–25PubMedGoogle Scholar
  139. 139.
    Macdonald RL, Weir BK, Runzer TD, Grace MG, Poznansky MJ (1992) Effect of intrathecal superoxide dismutase and catalase on oxyhemoglobin-induced vasospasm in monkeys. Neurosurgery 30:529–39PubMedGoogle Scholar
  140. 140.
    Shishido T, Suzuki R, Qian L, Hirakawa K (1994) The role of superoxide anions in the pathogenesis of cerebral vasospasm. Stroke 25:864–8PubMedGoogle Scholar
  141. 141.
    Mori T, Nagata K, Matsui T, Ishida T, Ohami H, Asano T (1995) Superoxide anions in the pathogenesis of talc-induced cerebral vasocontraction. Neuropathol Appl Neurobiol 21:378–85PubMedGoogle Scholar
  142. 142.
    Kamii H, Kato I, Kinouchi H, Chan PH, Epstein CJ, Akabane A et al (1999) Amelioration of vasospasm after subarachnoid hemorrhage in transgenic mice overexpressing CuZn-superoxide dismutase. Stroke 30:867–72PubMedGoogle Scholar
  143. 143.
    Güney O, Erdi F, Esen H, Kiyici A, Kocaogullar Y (2010) N-acetylcysteine prevents vasospasm after subarachnoid hemorrhage. World Neurosurg 73(42–9):e3Google Scholar
  144. 144.
    Kuo CP, Lu CH, Wen LL, Cherng CH, Wong CS, Borel CO et al (2011) Neuroprotective effect of curcumin in an experimental rat model of subarachnoid hemorrhage. Anesthesiology 115:1229–38PubMedGoogle Scholar
  145. 145.
    Germano A, Imperatore C, d’Avella D, Costa G, Tomasello F (1998) Antivasospastic and brain-protective effects of a hydroxyl radical scavenger (AVS) after experimental subarachnoid hemorrhage. J Neurosurg 88:1075–81PubMedGoogle Scholar
  146. 146.
    Imperatore C, Germano A, d’Avella D, Tomasello F, Costa G (2000) Effects of the radical scavenger AVS on behavioral and BBB changes after experimental subarachnoid hemorrhage. Life Sci 66:779–90PubMedGoogle Scholar
  147. 147.
    Turner CP, Panter SS, Sharp FR (1999) Anti-oxidants prevent focal rat brain injury as assessed by induction of heat shock proteins (HSP70, HO-1/HSP32, HSP47) following subarachnoid injections of lysed blood. Brain Res Mol Brain Res 65:87–102PubMedGoogle Scholar
  148. 148.
    Kanamaru K, Weir BK, Simpson I, Witbeck T, Grace M (1991) Effect of 21-aminosteroid U-74006F on lipid peroxidation in subarachnoid clot. J Neurosurg 74:454–9PubMedGoogle Scholar
  149. 149.
    Matsui T, Asano T (1994) Effects of new 21-aminosteroid tirilazad mesylate (U74006F) on chronic cerebral vasospasm in a “two-hemorrhage” model of beagle dogs. Neurosurgery 34:1035–9PubMedGoogle Scholar
  150. 150.
    Vollmer DG, Kassell NF, Hongo K, Ogawa H, Tsukahara T (1989) Effect of the nonglucocorticoid 21-aminosteroid U74006F experimental cerebral vasospasm. Surg Neurol 31:190–4PubMedGoogle Scholar
  151. 151.
    Zuccarello M, Marsch JT, Schmitt G, Woodward J, Anderson DK (1989) Effect of the 21-aminosteroid U-74006F on cerebral vasospasm following subarachnoid hemorrhage. J Neurosurg 71:98–104PubMedGoogle Scholar
  152. 152.
    Suzuki H, Kanamaru K, Kuroki M, Sun H, Waga S, Miyazawa T (1999) Effects of tirilazad mesylate on vasospasm and phospholipid hydroperoxides in a primate model of subarachnoid hemorrhage. Stroke 30:450–6PubMedGoogle Scholar
  153. 153.
    Hall ED (1992) The neuroprotective pharmacology of methylprednisolone. J Neurosurg 76:13–22PubMedGoogle Scholar
  154. 154.
    Gaetani P, Marzatico F, Renault B, Fulle I, Lombardi D, Ferlenga P et al (1990) High-dose methylprednisolone and ‘ex vivo’ release of eicosanoids after experimental subarachnoid haemorrhage. Neurol Res 12:111–6PubMedGoogle Scholar
  155. 155.
    Tang WH, Chen Z, Liu Z, Zhang JH, Xi G, Feng H (2008) The effect of ecdysterone on cerebral vasospasm following experimental subarachnoid hemorrhage in vitro and in vivo. Neurol Res 30:571–80PubMedGoogle Scholar
  156. 156.
    Handa Y, Kaneko M, Takeuchi H, Tsuchida A, Kobayashi H, Kubota T (2000) Effect of an antioxidant, ebselen, on development of chronic cerebral vasospasm after subarachnoid hemorrhage in primates. Surg Neurol 53:323–9PubMedGoogle Scholar
  157. 157.
    Watanabe T, Nishiyama M, Hori T, Asano T, Shimizu T, Masayasu H (1997) Ebselen (DR3305) ameliorates delayed cerebral vasospasm in a canine two-hemorrhage model. Neurol Res 19:563–5PubMedGoogle Scholar
  158. 158.
    Nakagomi T, Yamakawa K, Sasaki T, Saito I, Takakura K (2003) Effect of edaravone on cerebral vasospasm following experimental subarachnoid hemorrhage. J Stroke Cerebrovasc Dis 12:17–21PubMedGoogle Scholar
  159. 159.
    Shimada Y, Tsunoda H, Zang L, Hirano M, Oka T, Tanaka T (2009) Synergistic induction of heme oxygenase-1 by nicaraven after subarachnoid hemorrhage to prevent delayed cerebral vasospasm. Eur J Pharmacol 620:16–20PubMedGoogle Scholar
  160. 160.
    Aladag MA, Turkoz Y, Ozcan C, Sahna E, Parlakpinar H, Akpolat N et al (2006) Caffeic acid phenethyl ester (CAPE) attenuates cerebral vasospasm after experimental subarachnoidal haemorrhage by increasing brain nitric oxide levels. Int J Dev Neurosci 24:9–14PubMedGoogle Scholar
  161. 161.
    Saito I, Asano T, Sano K, Takakura K, Abe H, Yoshimoto T et al (1998) Neuroprotective effect of an antioxidant, ebselen, in patients with delayed neurological deficits after aneurysmal subarachnoid hemorrhage. Neurosurgery 42:269–78PubMedGoogle Scholar
  162. 162.
    Munakata A, Ohkuma H, Nakano T, Shimamura N, Asano K, Naraoka M (2009) Effect of a free radical scavenger, edaravone, in the treatment of patients with aneurysmal subarachnoid hemorrhage. Neurosurgery 64:423–9PubMedGoogle Scholar
  163. 163.
    Kassell NF, Haley EC Jr, Apperson-Hansen C, Alves WM (1996) Randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in Europe, Australia, and New Zealand. J Neurosurg 84:221–8PubMedGoogle Scholar
  164. 164.
    Haley EC Jr, Kassell NF, Apperson-Hansen C, Maile MH, Alves WM (1997) A randomized, double-blind, vehicle-controlled trial of tirilazad mesylate in patients with aneurysmal subarachnoid hemorrhage: a cooperative study in North America. J Neurosurg 86:467–74PubMedGoogle Scholar
  165. 165.
    Asano T, Takakura K, Sano K, Kikuchi H, Nagai H, Saito I et al (1996) Effects of a hydroxyl radical scavenger on delayed ischemic neurological deficits following aneurysmal subarachnoid hemorrhage: results of a multicenter, placebo-controlled double-blind trial. J Neurosurg 84:792–803PubMedGoogle Scholar
  166. 166.
    Hashi K, Takakura K, Sano K, Ohta T, Saito I, Okada K (1988) Intravenous hydrocortisone in large doses in the treatment of delayed ischemic neurological deficits following subarachnoid hemorrhage—results of a multi-center controlled double-blind clinical study. No to Shinkei—Brain & Nerve 40:373–82 [Japanese]Google Scholar
  167. 167.
    Chyatte D, Fode NC, Nichols DA, Sundt TM Jr (1987) Preliminary report: effects of high dose methylprednisolone on delayed cerebral ischemia in patients at high risk for vasospasm after aneurysmal subarachnoid hemorrhage. Neurosurgery 21:157–160PubMedGoogle Scholar
  168. 168.
    Gomis P, Graftieaux JP, Sercombe R, Hettler D, Scherpereel B, Rousseaux P (2010) Randomized, double-blind, placebo-controlled, pilot trial of high-dose methylprednisolone in aneurysmal subarachnoid hemorrhage. J Neurosurg 112:681–8PubMedGoogle Scholar
  169. 169.
    Sehba FA, Ding WH, Chereshnev I, Bederson JB (1999) Effects of S-nitrosoglutathione on acute vasoconstriction and glutamate release after subarachnoid hemorrhage. Stroke 30:1955–61PubMedGoogle Scholar
  170. 170.
    Pluta RM, Afshar JK, Thompson BG, Boock RJ, Harvey-White J, Oldfield EH (2000) Increased cerebral blood flow but no reversal or prevention of vasospasm in response to l-arginine infusion after subarachnoid hemorrhage. J Neurosurg 92:121–6PubMedGoogle Scholar
  171. 171.
    Marbacher S, Neuschmelting V, Graupner T, Jakob SM, Fandino J (2008) Prevention of delayed cerebral vasospasm by continuous intrathecal infusion of glyceroltrinitrate and nimodipine in the rabbit model in vivo. Intensive Care Med 34:932–8PubMedGoogle Scholar
  172. 172.
    Zheng B, Zheng T, Wang L, Chen X, Shi C, Zhao S (2010) Aminoguanidine inhibition of iNOS activity ameliorates cerebral vasospasm after subarachnoid hemorrhage in rabbits via restoration of dysfunctional endothelial cells. J Neurol Sci 295:97–103PubMedGoogle Scholar
  173. 173.
    Stoodley M, Weihl CC, Zhang ZD, Lin G, Johns LM, Kowalczuk A et al (2000) Effect of adenovirus-mediated nitric oxide synthase gene transfer on vasospasm after experimental subarachnoid hemorrhage. Neurosurgery 46:1193–1203PubMedGoogle Scholar
  174. 174.
    Chou SH, Smith EE, Badjatia N, Nogueira RG, Sims JR 2nd, Ogilvy CS et al (2008) A randomized, double-blind, placebo-controlled pilot study of simvastatin in aneurysmal subarachnoid hemorrhage. Stroke 39:2891–3PubMedGoogle Scholar
  175. 175.
    Lynch JR, Wang H, McGirt MJ, Floyd J, Friedman AH, Coon AL et al (2005) Simvastatin reduces vasospasm after aneurysmal subarachnoid hemorrhage: results of a pilot randomized clinical trial. Stroke 36:2024–6PubMedGoogle Scholar
  176. 176.
    Tseng MY, Czosnyka M, Richards H, Pickard JD, Kirkpatrick PJ (2005) Effects of acute treatment with pravastatin on cerebral vasospasm, autoregulation, and delayed ischemic deficits after aneurysmal subarachnoid hemorrhage: a phase II randomized placebo-controlled trial. Stroke 36:1627–32PubMedGoogle Scholar
  177. 177.
    Vergouwen MD, Meijers JC, Geskus RB, Coert BA, Horn J, Stroes ES et al (2009) Biologic effects of simvastatin in patients with aneurysmal subarachnoid hemorrhage: a double-blind, placebo-controlled randomized trial. J Cereb Blood Flow Metab 29:1444–53PubMedGoogle Scholar
  178. 178.
    Linder M, Alksne JF (1978) Prevention of persistent cerebral smooth muscle contraction in response to whole blood. Stroke 9:472–7PubMedGoogle Scholar
  179. 179.
    Juvela S (1995) Aspirin and delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. J Neurosurg 82:945–52PubMedGoogle Scholar
  180. 180.
    Bilginer B, Onal MB, Narin F, Soylemezoglu F, Ziyal IM, Ozgen T (2009) The effects of intravenous cilostazol and nimodipine on cerebral vasospasm after subarachnoid hemorrhage in an experimental rabbit model. Turk Neurosurg 19:374–9PubMedGoogle Scholar
  181. 181.
    Nishino A, Umegaki M, Fujinaka T, Yoshimine T (2010) Cilostazol attenuates cerebral vasospasm after experimental subarachnoid hemorrhage. Neurol Res 32:873–8PubMedGoogle Scholar
  182. 182.
    Hirashima Y, Endo S, Kato R, Takaku A (1996) Prevention of cerebrovasospasm following subarachnoid hemorrhage in rabbits by the platelet-activating factor antagonist, E5880. J Neurosurg 84:826–30PubMedGoogle Scholar
  183. 183.
    Dorhout Mees SM, van den Bergh WM, Algra A, Rinkel GJ (2007) Antiplatelet therapy for aneurysmal subarachnoid haemorrhage. Cochrane Database Syst Rev 17, CD006184Google Scholar
  184. 184.
    Fujii M, Yan J, Rolland WB, Soejima Y, Caner B, Zhang JH (2013) Early brain injury, an evolving frontier in subarachnoid hemorrhage research. Transl Stroke Res 4:432–46Google Scholar
  185. 185.
    Bederson JB, Germano IM, Guarino L (1995) Cortical blood flow and cerebral perfusion pressure in a new noncraniotomy model of subarachnoid hemorrhage in the rat. Stroke 26:1086–92PubMedGoogle Scholar
  186. 186.
    Veelken JA, Laing RJ, Jakubowski J (1995) The Sheffield model of subarachnoid hemorrhage in rats. Stroke 26:1279–84PubMedGoogle Scholar
  187. 187.
    Sozen T, Tsuchiyama R, Hasegawa Y, Suzuki H, Jadhav V, Nishizawa S et al (2009) Role of interleukin-1beta in early brain injury after subarachnoid hemorrhage in mice. Stroke 40:2519–25PubMedGoogle Scholar
  188. 188.
    Sugawara T, Jadhav V, Ayer R, Chen W, Suzuki H, Zhang JH (2009) Thrombin inhibition by argatroban ameliorates early brain injury and improves neurological outcomes after experimental subarachnoid hemorrhage in rats. Stroke 40:1530–2PubMedGoogle Scholar
  189. 189.
    Suzuki H, Ayer R, Sugawara T, Chen W, Sozen T, Hasegawa Y et al (2010) Protective effects of recombinant osteopontin on early brain injury after subarachnoid hemorrhage in rats. Crit Care Med 38:612–8PubMedGoogle Scholar
  190. 190.
    Endo H, Nito C, Kamada H, Yu F, Chan PH (2007) Reduction in oxidative stress by superoxide dismutase overexpression attenuates acute brain injury after subarachnoid hemorrhage via activation of Akt/glycogensynthase kinase-3beta survival signaling. J Cereb Blood Flow Metab 27:975–982PubMedGoogle Scholar
  191. 191.
    Gao Y, Ding XS, Xu S, Wang W, Zuo QL, Kuai F (2009) Neuroprotective effects of edaravone on early brain injury in rats after subarachnoid hemorrhage. Chin Med J (Engl) 122:1935–40Google Scholar
  192. 192.
    Erşahin M, Toklu HZ, Erzik C, Cetinel S, Akakin D, Velioğlu-Oğünç A et al (2010) The anti-inflammatory and neuroprotective effects of ghrelin in subarachnoid hemorrhage-induced oxidative brain damage in rats. J Neurotrauma 27:1143–55PubMedGoogle Scholar
  193. 193.
    Kassell NF, Sasaki T, Colohan AR, Nazar G (1985) Cerebral vasospasm following aneurysmal subarachnoid hemorrhage. Stroke 16:562–72PubMedGoogle Scholar
  194. 194.
    Megyesi JF, Vollrath B, Cook DA, Findlay JM (2000) In vivo animal models of cerebral vasospasm: a review. Neurosurgery 46:448–61PubMedGoogle Scholar
  195. 195.
    Alaraj A, Charbel FT, Amin-Hanjani S (2009) Peri-operative measures for treatment and prevention of cerebral vasospasm following subarachnoid hemorrhage. Neurol Res 31:651–9PubMedGoogle Scholar
  196. 196.
    Caner B, Hou J, Altay O, Fujii M, Zhang JH (2012) Transition of research focus from vasospasm to early brain injury after subarachnoid hemorrhage. J Neurochem 123(Suppl 2):12–21PubMedGoogle Scholar
  197. 197.
    Lee JY, Sagher O, Keep R, Hua Y, Xi G (2009) Comparison of experimental rat models of early brain injury after subarachnoid hemorrhage. Neurosurgery 65:331–43PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Mutsumi Fujii
    • 1
  • Sheng Chen
    • 1
  • Damon Klebe
    • 1
  • Yoshiteru Soejima
    • 1
  • Alexander Vakhmyanin
    • 1
  • John H. Zhang
    • 2
  1. 1.Department of PhysiologyLoma Linda UniversityLoma LindaUSA
  2. 2.Department of Physiology, Pharmacology, and NeurosurgeryLoma Linda UniversityLoma LindaUSA

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