1932

Abstract

Cerebral edema, a common and often fatal companion to most forms of acute central nervous system disease, has been recognized since the time of ancient Egypt. Unfortunately, our therapeutic armamentarium remains limited, in part due to historic limitations in our understanding of cerebral edema pathophysiology. Recent advancements have led to a number of clinical trials for novel therapeutics that could fundamentally alter the treatment of cerebral edema. In this review, we discuss these agents, their targets, and the data supporting their use, with a focus on agents that have progressed to clinical trials.

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2020-01-06
2024-04-24
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Literature Cited

  1. 1. 
    Kochanek KD, Xu J, Murphy SL, Minino AM, Kung HC 2011. Deaths: final data for 2009. Natl. Vital Stat. Rep. 60:1–116
    [Google Scholar]
  2. 2. 
    Battey TW, Karki M, Singhal AB, Wu O, Sadaghiani S et al. 2014. Brain edema predicts outcome after nonlacunar ischemic stroke. Stroke 45:3643–48
    [Google Scholar]
  3. 3. 
    Donkin JJ, Vink R. 2010. Mechanisms of cerebral edema in traumatic brain injury: therapeutic developments. Curr. Opin. Neurol. 23:293–99
    [Google Scholar]
  4. 4. 
    Wu CX, Lin GS, Lin ZX, Zhang JD, Liu SY, Zhou CF 2015. Peritumoral edema shown by MRI predicts poor clinical outcome in glioblastoma. World J. Surg. Oncol. 13:97
    [Google Scholar]
  5. 5. 
    Hammoud MA, Sawaya R, Shi W, Thall PF, Leeds NE 1996. Prognostic significance of preoperative MRI scans in glioblastoma multiforme. J. Neurooncol. 27:65–73
    [Google Scholar]
  6. 6. 
    Pope WB, Sayre J, Perlina A, Villablanca JP, Mischel PS, Cloughesy TF 2005. MR imaging correlates of survival in patients with high-grade gliomas. Am. J. Neuroradiol. 26:2466–74
    [Google Scholar]
  7. 7. 
    Arima H, Wang JG, Huang Y, Heeley E, Skulina C et al. 2009. Significance of perihematomal edema in acute intracerebral hemorrhage: the INTERACT trial. Neurology 73:1963–68
    [Google Scholar]
  8. 8. 
    Stokum JA, Gerzanich V, Simard JM 2016. Molecular pathophysiology of cerebral edema. J. Cereb. Blood Flow Metab. 36:513–38
    [Google Scholar]
  9. 9. 
    Norenberg MD. 1994. Astrocyte responses to CNS injury. J. Neuropathol. Exp. Neurol. 53:213–20
    [Google Scholar]
  10. 10. 
    Risher WC, Andrew RD, Kirov SA 2009. Real-time passive volume responses of astrocytes to acute osmotic and ischemic stress in cortical slices and in vivo revealed by two-photon microscopy. Glia 57:207–21
    [Google Scholar]
  11. 11. 
    Chen M, Dong Y, Simard JM 2003. Functional coupling between sulfonylurea receptor type 1 and a nonselective cation channel in reactive astrocytes from adult rat brain. J. Neurosci. 23:8568–77
    [Google Scholar]
  12. 12. 
    Chen M, Simard JM. 2001. Cell swelling and a nonselective cation channel regulated by internal Ca2+ and ATP in native reactive astrocytes from adult rat brain. J. Neurosci. 21:6512–21
    [Google Scholar]
  13. 13. 
    Su G, Kintner DB, Flagella M, Shull GE, Sun D 2002. Astrocytes from Na+-K+-Cl cotransporter-null mice exhibit absence of swelling and decrease in EAA release. Am. J. Physiol. Cell Physiol. 282:C1147–60
    [Google Scholar]
  14. 14. 
    Su G, Kintner DB, Sun D 2002. Contribution of Na+-K+-Cl cotransporter to high-[K+]o- induced swelling and EAA release in astrocytes. Am. J. Physiol. Cell Physiol. 282:C1136–46
    [Google Scholar]
  15. 15. 
    Jakubovicz DE, Klip A. 1989. Lactic acid-induced swelling in C6 glial cells via Na+/H+ exchange. Brain Res 485:215–24
    [Google Scholar]
  16. 16. 
    Hansson E, Muyderman H, Leonova J, Allansson L, Sinclair J et al. 2000. Astroglia and glutamate in physiology and pathology: aspects on glutamate transport, glutamate-induced cell swelling and gap-junction communication. Neurochem. Int. 37:317–29
    [Google Scholar]
  17. 17. 
    Mori K, Miyazaki M, Iwase H, Maeda M 2002. Temporal profile of changes in brain tissue extracellular space and extracellular ion (Na+, K+) concentrations after cerebral ischemia and the effects of mild cerebral hypothermia. J. Neurotrauma 19:1261–70
    [Google Scholar]
  18. 18. 
    Kitayama J, Kitazono T, Yao H, Ooboshi H, Takaba H et al. 2001. Inhibition of Na+/H+ exchanger reduces infarct volume of focal cerebral ischemia in rats. Brain Res 922:223–28
    [Google Scholar]
  19. 19. 
    Yan Y, Dempsey RJ, Flemmer A, Forbush B, Sun D 2003. Inhibition of Na+-K+-Cl cotransporter during focal cerebral ischemia decreases edema and neuronal damage. Brain Res 961:22–31
    [Google Scholar]
  20. 20. 
    Simard JM, Chen M, Tarasov KV, Bhatta S, Ivanova S et al. 2006. Newly expressed SUR1-regulated NCCa-ATP channel mediates cerebral edema after ischemic stroke. Nat. Med. 12:433–40
    [Google Scholar]
  21. 21. 
    Kovacs Z, Ikezaki K, Samoto K, Inamura T, Fukui M 1996. VEGF and flt: expression time kinetics in rat brain infarct. Stroke 27:1865–72
    [Google Scholar]
  22. 22. 
    Mun-Bryce S, Rosenberg GA. 1998. Matrix metalloproteinases in cerebrovascular disease. J. Cereb. Blood Flow Metab. 18:1163–72
    [Google Scholar]
  23. 23. 
    Garcia JG, Siflinger-Birnboim A, Bizios R, Del Vecchio PJ, Fenton JW 2nd, Malik AB 1986. Thrombin-induced increase in albumin permeability across the endothelium. J. Cell Physiol. 128:96–104
    [Google Scholar]
  24. 24. 
    Vajkoczy P, Menger MD. 2000. Vascular microenvironment in gliomas. J. Neurooncol. 50:99–108
    [Google Scholar]
  25. 25. 
    Chang YS, di Tomaso E, McDonald DM, Jones R, Jain RK, Munn LL 2000. Mosaic blood vessels in tumors: frequency of cancer cells in contact with flowing blood. PNAS 97:14608–13
    [Google Scholar]
  26. 26. 
    Mao JM, Liu J, Guo G, Mao XG, Li CX 2015. Glioblastoma vasculogenic mimicry: signaling pathways progression and potential anti-angiogenesis targets. Biomark. Res. 3:8
    [Google Scholar]
  27. 27. 
    Nyström SHM. 1959. Electron microscopical structure of the wall of small blood vessels in human multiform glioblastoma. Nature 184:65
    [Google Scholar]
  28. 28. 
    Cheng L, Huang Z, Zhou W, Wu Q, Donnola S et al. 2013. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell 153:139–52
    [Google Scholar]
  29. 29. 
    Wang R, Chadalavada K, Wilshire J, Kowalik U, Hovinga KE et al. 2010. Glioblastoma stem-like cells give rise to tumour endothelium. Nature 468:829–33
    [Google Scholar]
  30. 30. 
    Liebner S, Fischmann A, Rascher G, Duffner F, Grote EH et al. 2000. Claudin-1 and claudin-5 expression and tight junction morphology are altered in blood vessels of human glioblastoma multiforme. Acta Neuropathol 100:323–31
    [Google Scholar]
  31. 31. 
    Groothuis DR, Pasternak JF, Fischer JM, Blasberg RG, Bigner DD, Vick NA 1983. Regional measurements of blood flow in experimental RG-2 rat gliomas. Cancer Res 43:3362–67
    [Google Scholar]
  32. 32. 
    Bernsen HJ, Rijken PF, Oostendorp T, van der Kogel AJ 1995. Vascularity and perfusion of human gliomas xenografted in the athymic nude mouse. Br. J. Cancer 71:721–26
    [Google Scholar]
  33. 33. 
    Hobbs SK, Monsky WL, Yuan F, Roberts WG, Griffith L et al. 1998. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. PNAS 95:4607–12
    [Google Scholar]
  34. 34. 
    Vajkoczy P, Schilling L, Ullrich A, Schmiedek P, Menger MD 1998. Characterization of angiogenesis and microcirculation of high-grade glioma: an intravital multifluorescence microscopic approach in the athymic nude mouse. J. Cereb. Blood Flow Metab. 18:510–20
    [Google Scholar]
  35. 35. 
    Gerstner ER, Duda DG, di Tomaso E, Ryg PA, Loeffler JS et al. 2009. VEGF inhibitors in the treatment of cerebral edema in patients with brain cancer. Nat. Rev. Clin. Oncol. 6:229–36
    [Google Scholar]
  36. 36. 
    Lee CG, Heijn M, di Tomaso E, Griffon-Etienne G, Ancukiewicz M et al. 2000. Anti-vascular endothelial growth factor treatment augments tumor radiation response under normoxic or hypoxic conditions. Cancer Res 60:5565–70
    [Google Scholar]
  37. 37. 
    Carrillo JA, Lai A, Nghiemphu PL, Kim HJ, Phillips HS et al. 2012. Relationship between tumor enhancement, edema, IDH1 mutational status, MGMT promoter methylation, and survival in glioblastoma. Am. J. Neuroradiol. 33:1349–55
    [Google Scholar]
  38. 38. 
    Narayan RK, Michel ME, Ansell B, Baethmann A, Biegon A et al. 2002. Clinical trials in head injury. J. Neurotrauma 19:503–57
    [Google Scholar]
  39. 39. 
    Marshall LF, Maas AI, Marshall SB, Bricolo A, Fearnside M et al. 1998. A multicenter trial on the efficacy of using tirilazad mesylate in cases of head injury. J. Neurosurg. 89:519–25
    [Google Scholar]
  40. 40. 
    Lee SH, Park HK, Ryu WS, Lee JS, Bae HJ et al. 2013. Effects of celecoxib on hematoma and edema volumes in primary intracerebral hemorrhage: a multicenter randomized controlled trial. Eur. J. Neurol. 20:1161–69
    [Google Scholar]
  41. 41. 
    Fu Y, Hao J, Zhang N, Ren L, Sun N et al. 2014. Fingolimod for the treatment of intracerebral hemorrhage: a 2-arm proof-of-concept study. JAMA Neurol 71:1092–101
    [Google Scholar]
  42. 42. 
    Yoo AJ, Sheth KN, Kimberly WT, Chaudhry ZA, Elm JJ et al. 2013. Validating imaging biomarkers of cerebral edema in patients with severe ischemic stroke. J. Stroke Cerebrovasc. Dis. 22:742–49
    [Google Scholar]
  43. 43. 
    Sheth KN, Elm JJ, Molyneaux BJ, Hinson H, Beslow LA et al. 2016. Safety and efficacy of intravenous glyburide on brain swelling after large hemispheric infarction (GAMES-RP): a randomised, double-blind, placebo-controlled phase 2 trial. Lancet Neurol 15:1160–69
    [Google Scholar]
  44. 44. 
    Kimberly WT, Bevers MB, von Kummer R, Demchuk AM, Romero JM et al. 2018. Effect of IV glyburide on adjudicated edema endpoints in the GAMES-RP trial. Neurology 91:e2163–69
    [Google Scholar]
  45. 45. 
    Dogterom J, Van Wimersma Greidanus TB, Swabb DF 1977. Evidence for the release of vasopressin and oxytocin into cerebrospinal fluid: measurements in plasma and CSF of intact and hypophysectomized rats. Neuroendocrinology 24:108–18
    [Google Scholar]
  46. 46. 
    Dogterom J, van Wimersma Greidanus TB, De Wied D 1978. Vasopressin in cerebrospinal fluid and plasma of man, dog, and rat. Am. J. Physiol. 234:E463–67
    [Google Scholar]
  47. 47. 
    Vakili A, Kataoka H, Plesnila N 2005. Role of arginine vasopressin V1 and V2 receptors for brain damage after transient focal cerebral ischemia. J. Cereb. Blood Flow Metab. 25:1012–19
    [Google Scholar]
  48. 48. 
    Liu X, Nakayama S, Amiry-Moghaddam M, Ottersen OP, Bhardwaj A 2010. Arginine-vasopressin V1 but not V2 receptor antagonism modulates infarct volume, brain water content, and aquaporin-4 expression following experimental stroke. Neurocrit. Care 12:124–31
    [Google Scholar]
  49. 49. 
    Corbani M, Marir R, Trueba M, Chafai M, Vincent A et al. 2018. Neuroanatomical distribution and function of the vasopressin V1B receptor in the rat brain deciphered using specific fluorescent ligands. Gen. Comp. Endocrinol. 258:15–32
    [Google Scholar]
  50. 50. 
    Szot P, Bale TL, Dorsa DM 1994. Distribution of messenger RNA for the vasopressin V1a receptor in the CNS of male and female rats. Mol. Brain Res. 24:1–10
    [Google Scholar]
  51. 51. 
    Zlokovic BV, Hyman S, McComb JG, Lipovac MN, Tang G, Davson H 1990. Kinetics of arginine-vasopressin uptake at the blood-brain barrier. Biochim. Biophys. Acta 1025:191–98
    [Google Scholar]
  52. 52. 
    Chodobski A, Loh YP, Corsetti S, Szmydynger-Chodobska J, Johanson CE et al. 1997. The presence of arginine vasopressin and its mRNA in rat choroid plexus epithelium. Brain Res. Mol. Brain Res. 48:67–72
    [Google Scholar]
  53. 53. 
    Szmydynger-Chodobska J, Zink BJ, Chodobski A 2011. Multiple sites of vasopressin synthesis in the injured brain. J. Cereb. Blood Flow Metab. 31:47–51
    [Google Scholar]
  54. 54. 
    Buijs RM, Swaab DF, Dogterom J, van Leeuwen FW 1978. Intra- and extrahypothalamic vasopressin and oxytocin pathways in the rat. Cell Tissue Res 186:423–33
    [Google Scholar]
  55. 55. 
    Doczi T, Szerdahelyi P, Gulya K, Kiss J 1982. Brain water accumulation after the central administration of vasopressin. Neurosurgery 11:402–7
    [Google Scholar]
  56. 56. 
    Raichle ME, Grubb RL Jr 1978. Regulation of brain water permeability by centrally-released vasopressin. Brain Res 143:191–94
    [Google Scholar]
  57. 57. 
    Sarfaraz D, Fraser CL. 1999. Effects of arginine vasopressin on cell volume regulation in brain astrocyte in culture. Am. J. Physiol. 276:E596–601
    [Google Scholar]
  58. 58. 
    Latzkovits L, Cserr HF, Park JT, Patlak CS, Pettigrew KD, Rimanoczy A 1993. Effects of arginine vasopressin and atriopeptin on glial cell volume measured as 3-MG space. Am. J. Physiol. 264:C603–8
    [Google Scholar]
  59. 59. 
    Faraci FM, Mayhan WG, Heistad DD 1990. Effect of vasopressin on production of cerebrospinal fluid: possible role of vasopressin (V1)-receptors. Am. J. Physiol. 258:R94–98
    [Google Scholar]
  60. 60. 
    Seckl JR, Lightman SL. 1991. Intracerebroventricular vasopressin reduces CSF absorption rate in the conscious goat. Exp. Brain Res. 84:173–76
    [Google Scholar]
  61. 61. 
    Fernandez N, Martinez MA, Garcia-Villalon AL, Monge L, Dieguez G 2001. Cerebral vasoconstriction produced by vasopressin in conscious goats: role of vasopressin V1 and V2 receptors and nitric oxide. Br. J. Pharmacol. 132:1837–44
    [Google Scholar]
  62. 62. 
    Liu X, Jin Y, Zheng H, Chen G, Tan B, Wu B 2000. Arginine vasopressin gene expression in supraoptic nucleus and paraventricular nucleus of hypothalamus following cerebral ischemia and reperfusion. Chin. Med. Sci. J. 15:157–61
    [Google Scholar]
  63. 63. 
    Szmydynger-Chodobska J, Chung I, Kozniewska E, Tran B, Harrington FJ et al. 2004. Increased expression of vasopressin V1a receptors after traumatic brain injury. J. Neurotrauma 21:1090–102
    [Google Scholar]
  64. 64. 
    Zeynalov E, Jones SM, Seo JW, Snell LD, Elliott JP 2015. Arginine-vasopressin receptor blocker conivaptan reduces brain edema and blood-brain barrier disruption after experimental stroke in mice. PLOS ONE 10:e0136121
    [Google Scholar]
  65. 65. 
    Reeder RF, Nattie EE, North WG 1986. Effect of vasopressin on cold-induced brain edema in cats. J. Neurosurg. 64:941–50
    [Google Scholar]
  66. 66. 
    Krieg SM, Trabold R, Plesnila N 2017. Time-dependent effects of arginine-vasopressin V1 receptor inhibition on secondary brain damage after traumatic brain injury. J. Neurotrauma 34:1329–36
    [Google Scholar]
  67. 67. 
    Arieff AI, Llach F, Massry SG 1976. Neurological manifestations and morbidity of hyponatremia: correlation with brain water and electrolytes. Medicine 55:121–29
    [Google Scholar]
  68. 68. 
    Gill G, Huda B, Boyd A, Skagen K, Wile D et al. 2006. Characteristics and mortality of severe hyponatraemia—a hospital-based study. Clin. Endocrinol. 65:246–49
    [Google Scholar]
  69. 69. 
    Sherlock M, O'Sullivan E, Agha A, Behan LA, Owens D et al. 2009. Incidence and pathophysiology of severe hyponatraemia in neurosurgical patients. Postgrad Med. J. 85:171–75
    [Google Scholar]
  70. 70. 
    Knepper MA. 1997. Molecular physiology of urinary concentrating mechanism: regulation of aquaporin water channels by vasopressin. Am. J. Physiol. 272:F3–12
    [Google Scholar]
  71. 71. 
    Kleindienst A, Hannon MJ, Buchfelder M, Verbalis JG 2016. Hyponatremia in neurotrauma: the role of vasopressin. J. Neurotrauma 33:615–24
    [Google Scholar]
  72. 72. 
    Nakayama S, Amiry-Moghaddam M, Ottersen OP, Bhardwaj A 2016. Conivaptan, a selective arginine vasopressin V1a and V2 receptor antagonist attenuates global cerebral edema following experimental cardiac arrest via perivascular pool of aquaporin-4. Neurocrit. Care 24:273–82
    [Google Scholar]
  73. 73. 
    Hockel K, Scholler K, Trabold R, Nussberger J, Plesnila N 2012. Vasopressin V1a receptors mediate posthemorrhagic systemic hypertension thereby determining rebleeding rate and outcome after experimental subarachnoid hemorrhage. Stroke 43:227–32
    [Google Scholar]
  74. 74. 
    Marmarou CR, Liang X, Abidi NH, Parveen S, Taya K et al. 2014. Selective vasopressin-1a receptor antagonist prevents brain edema, reduces astrocytic cell swelling and GFAP, V1aR and AQP4 expression after focal traumatic brain injury. Brain Res 1581:89–102
    [Google Scholar]
  75. 75. 
    Krieg SM, Sonanini S, Plesnila N, Trabold R 2015. Effect of small molecule vasopressin V1a and V2 receptor antagonists on brain edema formation and secondary brain damage following traumatic brain injury in mice. J. Neurotrauma 32:221–27
    [Google Scholar]
  76. 76. 
    Dhar R, Murphy-Human T. 2011. A bolus of conivaptan lowers intracranial pressure in a patient with hyponatremia after traumatic brain injury. Neurocrit. Care 14:97–102
    [Google Scholar]
  77. 77. 
    Hedna VS, Bidari S, Gubernick D, Ansari S, Satriotomo I et al. 2014. Treatment of stroke related refractory brain edema using mixed vasopressin antagonism: a case report and review of the literature. BMC Neurol 14:213
    [Google Scholar]
  78. 78. 
    Groves A, Kihara Y, Chun J 2013. Fingolimod: direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy. J. Neurol. Sci. 328:9–18
    [Google Scholar]
  79. 79. 
    Yatomi Y, Yamamura S, Ruan F, Igarashi Y 1997. Sphingosine 1-phosphate induces platelet activation through an extracellular action and shares a platelet surface receptor with lysophosphatidic acid. J. Biol. Chem. 272:5291–97
    [Google Scholar]
  80. 80. 
    Pappu R, Schwab SR, Cornelissen I, Pereira JP, Regard JB et al. 2007. Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 316:295–98
    [Google Scholar]
  81. 81. 
    Venkataraman K, Lee YM, Michaud J, Thangada S, Ai Y et al. 2008. Vascular endothelium as a contributor of plasma sphingosine 1-phosphate. Circ. Res. 102:669–76
    [Google Scholar]
  82. 82. 
    Prager B, Spampinato SF, Ransohoff RM 2015. Sphingosine 1-phosphate signaling at the blood-brain barrier. Trends Mol. Med. 21:354–63
    [Google Scholar]
  83. 83. 
    Fischer I, Alliod C, Martinier N, Newcombe J, Brana C, Pouly S 2011. Sphingosine kinase 1 and sphingosine 1-phosphate receptor 3 are functionally upregulated on astrocytes under pro-inflammatory conditions. PLOS ONE 6:e23905
    [Google Scholar]
  84. 84. 
    Kimura A, Ohmori T, Ohkawa R, Madoiwa S, Mimuro J et al. 2007. Essential roles of sphingosine 1-phosphate/S1P1 receptor axis in the migration of neural stem cells toward a site of spinal cord injury. Stem Cells 25:115–24
    [Google Scholar]
  85. 85. 
    Pham THM, Okada T, Matloubian M, Lo CG, Cyster JG 2008. S1P1 receptor signaling overrides retention mediated by Gαi-coupled receptors to promote T cell egress. Immunity 28:122–33
    [Google Scholar]
  86. 86. 
    Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y et al. 2004. Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427:355–60
    [Google Scholar]
  87. 87. 
    Du J, Zeng C, Li Q, Chen B, Liu H et al. 2012. LPS and TNF-α induce expression of sphingosine-1-phosphate receptor-2 in human microvascular endothelial cells. Pathol. Res. Pract. 208:82–88
    [Google Scholar]
  88. 88. 
    Garcia JG, Liu F, Verin AD, Birukova A, Dechert MA et al. 2001. Sphingosine 1-phosphate promotes endothelial cell barrier integrity by Edg-dependent cytoskeletal rearrangement. J. Clin. Investig. 108:689–701
    [Google Scholar]
  89. 89. 
    Liu Y, Wada R, Yamashita T, Mi Y, Deng CX et al. 2000. Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J. Clin. Investig. 106:951–61
    [Google Scholar]
  90. 90. 
    Camerer E, Regard JB, Cornelissen I, Srinivasan Y, Duong DN et al. 2009. Sphingosine-1-phosphate in the plasma compartment regulates basal and inflammation-induced vascular leak in mice. J. Clin. Investig. 119:1871–79
    [Google Scholar]
  91. 91. 
    Sanchez T, Skoura A, Wu MT, Casserly B, Harrington EO, Hla T 2007. Induction of vascular permeability by the sphingosine-1-phosphate receptor-2 (S1P2R) and its downstream effectors ROCK and PTEN. Arterioscler. Thromb. Vasc. Biol. 27:1312–18
    [Google Scholar]
  92. 92. 
    Nofer JR, van der Giet M, Tolle M, Wolinska I, von Wnuck Lipinski K et al. 2004. HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3. J. Clin. Investig. 113:569–81
    [Google Scholar]
  93. 93. 
    Salomone S, Potts EM, Tyndall S, Ip PC, Chun J et al. 2008. Analysis of sphingosine 1-phosphate receptors involved in constriction of isolated cerebral arteries with receptor null mice and pharmacological tools. Br. J. Pharmacol. 153:140–47
    [Google Scholar]
  94. 94. 
    Cohen JA, Chun J. 2011. Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis. Ann. Neurol. 69:759–77
    [Google Scholar]
  95. 95. 
    Kappos L, Radue E-W, O'Connor P, Polman C, Hohlfeld R et al. 2010. A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis. N. Engl. J. Med. 362:387–401
    [Google Scholar]
  96. 96. 
    Kappos L, O'Connor P, Radue E-W, Polman C, Hohlfeld R et al. 2015. Long-term effects of fingolimod in multiple sclerosis: the randomized FREEDOMS extension trial. Neurology 84:1582–91
    [Google Scholar]
  97. 97. 
    Cohen JA, Barkhof F, Comi G, Hartung H-P, Khatri BO et al. 2010. Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis. N. Engl. J. Med. 362:402–15
    [Google Scholar]
  98. 98. 
    Cohen JA, Khatri B, Barkhof F, Comi G, Hartung H-P et al. 2016. Long-term (up to 4.5 years) treatment with fingolimod in multiple sclerosis: results from the extension of the randomised TRANSFORMS study. J. Neurol. Neurosurg. Psychiatry 87:468–75
    [Google Scholar]
  99. 99. 
    Chun J, Hartung HP. 2010. Mechanism of action of oral fingolimod (FTY720) in multiple sclerosis. Clin. Neuropharmacol. 33:91–101
    [Google Scholar]
  100. 100. 
    Rolland WB, Lekic T, Krafft PR, Hasegawa Y, Altay O et al. 2013. Fingolimod reduces cerebral lymphocyte infiltration in experimental models of rodent intracerebral hemorrhage. Exp. Neurol. 241:45–55
    [Google Scholar]
  101. 101. 
    Wei Y, Yemisci M, Kim HH, Yung LM, Shin HK et al. 2011. Fingolimod provides long-term protection in rodent models of cerebral ischemia. Ann. Neurol. 69:119–29
    [Google Scholar]
  102. 102. 
    Lu L, Barfejani AH, Qin T, Dong Q, Ayata C, Waeber C 2014. Fingolimod exerts neuroprotective effects in a mouse model of intracerebral hemorrhage. Brain Res 1555:89–96
    [Google Scholar]
  103. 103. 
    Li YJ, Chang GQ, Liu Y, Gong Y, Yang C et al. 2015. Fingolimod alters inflammatory mediators and vascular permeability in intracerebral hemorrhage. Neurosci. Bull. 31:755–62
    [Google Scholar]
  104. 104. 
    Fu Y, Zhang N, Ren L, Yan Y, Sun N et al. 2014. Impact of an immune modulator fingolimod on acute ischemic stroke. PNAS 111:18315–20
    [Google Scholar]
  105. 105. 
    Wang J, Dore S. 2007. Inflammation after intracerebral hemorrhage. J. Cereb. Blood Flow Metab. 27:894–908
    [Google Scholar]
  106. 106. 
    Gong C, Ennis SR, Hoff JT, Keep RF 2001. Inducible cyclooxygenase-2 expression after experimental intracerebral hemorrhage. Brain Res 901:38–46
    [Google Scholar]
  107. 107. 
    Nagayama M, Niwa K, Nagayama T, Ross ME, Iadecola C 1999. The cyclooxygenase-2 inhibitor NS-398 ameliorates ischemic brain injury in wild-type mice but not in mice with deletion of the inducible nitric oxide synthase gene. J. Cereb. Blood Flow Metab. 19:1213–19
    [Google Scholar]
  108. 108. 
    Chu K, Jeong SW, Jung KH, Han SY, Lee ST et al. 2004. Celecoxib induces functional recovery after intracerebral hemorrhage with reduction of brain edema and perihematomal cell death. J. Cereb. Blood Flow Metab. 24:926–33
    [Google Scholar]
  109. 109. 
    Park HK, Lee SH, Chu K, Roh JK 2009. Effects of celecoxib on volumes of hematoma and edema in patients with primary intracerebral hemorrhage. J. Neurol. Sci. 279:43–46
    [Google Scholar]
  110. 110. 
    Woo SK, Kwon MS, Ivanov A, Gerzanich V, Simard JM 2013. The sulfonylurea receptor 1 (Sur1)-transient receptor potential melastatin 4 (Trpm4) channel. J. Biol. Chem. 288:3655–67
    [Google Scholar]
  111. 111. 
    Nilius B, Prenen J, Tang J, Wang C, Owsianik G et al. 2005. Regulation of the Ca2+ sensitivity of the nonselective cation channel TRPM4. J. Biol. Chem. 280:6423–33
    [Google Scholar]
  112. 112. 
    Mehta RI, Ivanova S, Tosun C, Castellani RJ, Gerzanich V, Simard JM 2013. Sulfonylurea receptor 1 expression in human cerebral infarcts. J. Neuropathol. Exp. Neurol. 72:871–83
    [Google Scholar]
  113. 113. 
    Stokum JA, Kwon MS, Woo SK, Tsymbalyuk O, Vennekens R et al. 2018. SUR1-TRPM4 and AQP4 form a heteromultimeric complex that amplifies ion/water osmotic coupling and drives astrocyte swelling. Glia 66:108–25
    [Google Scholar]
  114. 114. 
    Gerzanich V, Woo SK, Vennekens R, Tsymbalyuk O, Ivanova S et al. 2009. De novo expression of Trpm4 initiates secondary hemorrhage in spinal cord injury. Nat. Med. 15:185–91
    [Google Scholar]
  115. 115. 
    Simard JM, Yurovsky V, Tsymbalyuk N, Melnichenko L, Ivanova S, Gerzanich V 2009. Protective effect of delayed treatment with low-dose glibenclamide in three models of ischemic stroke. Stroke 40:604–9
    [Google Scholar]
  116. 116. 
    Zweckberger K, Hackenberg K, Jung CS, Hertle DN, Kiening KL et al. 2014. Glibenclamide reduces secondary brain damage after experimental traumatic brain injury. Neuroscience 272:199–206
    [Google Scholar]
  117. 117. 
    Simard JM, Geng Z, Woo SK, Ivanova S, Tosun C et al. 2009. Glibenclamide reduces inflammation, vasogenic edema, and caspase-3 activation after subarachnoid hemorrhage. J. Cereb. Blood Flow Metab. 29:317–30
    [Google Scholar]
  118. 118. 
    Thompson EM, Pishko GL, Muldoon LL, Neuwelt EA 2013. Inhibition of SUR1 decreases the vascular permeability of cerebral metastases. Neoplasia 15:535–43
    [Google Scholar]
  119. 119. 
    Sheth KN, Kimberly WT, Elm JJ, Kent TA, Mandava P et al. 2014. Pilot study of intravenous glyburide in patients with a large ischemic stroke. Stroke 45:281–83
    [Google Scholar]
  120. 120. 
    Kimberly WT, Battey TW, Pham L, Wu O, Yoo AJ et al. 2014. Glyburide is associated with attenuated vasogenic edema in stroke patients. Neurocrit. Care 20:193–201
    [Google Scholar]
  121. 121. 
    Sheth KN, Petersen NH, Cheung K, Elm JJ, Hinson HE et al. 2018. Long-term outcomes in patients aged ≤70 years with intravenous glyburide from the phase II GAMES-RP study of large hemispheric infarction: an exploratory analysis. Stroke 49:1457–63
    [Google Scholar]
  122. 122. 
    Kofman S, Garvin JS, Nagamani D, Taylor SG 3rd 1957. Treatment of cerebral metastases from breast carcinoma with prednisolone. J. Am. Med. Assoc. 163:1473–76
    [Google Scholar]
  123. 123. 
    McClelland S 3rd, Long DM 2008. Genesis of the use of corticosteroids in the treatment and prevention of brain edema. Neurosurgery 62:965–67
    [Google Scholar]
  124. 124. 
    Galicich JH, French LA. 1961. Use of dexamethasone in the treatment of cerebral edema resulting from brain tumors and brain surgery. Am. Pract. Dig. Treat. 12:169–74
    [Google Scholar]
  125. 125. 
    Horton J, Baxter DH, Olson KB 1971. The management of metastases to the brain by irradiation and corticosteroids. Am. J. Roentgenol. Radium. Ther. Nucl. Med. 111:334–36
    [Google Scholar]
  126. 126. 
    Vecht CJ, Hovestadt A, Verbiest HB, van Vliet JJ, van Putten WL 1994. Dose-effect relationship of dexamethasone on Karnofsky performance in metastatic brain tumors: a randomized study of doses of 4, 8, and 16 mg per day. Neurology 44:675–80
    [Google Scholar]
  127. 127. 
    Wolfson AH, Snodgrass SM, Schwade JG, Markoe AM, Landy H et al. 1994. The role of steroids in the management of metastatic carcinoma to the brain. A pilot prospective trial. Am. J. Clin. Oncol. 17:234–38
    [Google Scholar]
  128. 128. 
    Piette C, Munaut C, Foidart JM, Deprez M 2006. Treating gliomas with glucocorticoids: from bedside to bench. Acta Neuropathol 112:651–64
    [Google Scholar]
  129. 129. 
    Stellato C. 2004. Post-transcriptional and nongenomic effects of glucocorticoids. Proc. Am. Thorac. Soc. 1:255–63
    [Google Scholar]
  130. 130. 
    Nauck M, Karakiulakis G, Perruchoud AP, Papakonstantinou E, Roth M 1998. Corticosteroids inhibit the expression of the vascular endothelial growth factor gene in human vascular smooth muscle cells. Eur. J. Pharmacol. 341:309–15
    [Google Scholar]
  131. 131. 
    Guerin C, Wolff JE, Laterra J, Drewes LR, Brem H, Goldstein GW 1992. Vascular differentiation and glucose transporter expression in rat gliomas: effects of steroids. Ann. Neurol. 31:481–87
    [Google Scholar]
  132. 132. 
    Gu YT, Qin LJ, Qin X, Xu F 2009. The molecular mechanism of dexamethasone-mediated effect on the blood-brain tumor barrier permeability in a rat brain tumor model. Neurosci. Lett. 452:114–18
    [Google Scholar]
  133. 133. 
    Siegal T, Soti F, Biegon A, Pop E, Brewster ME 1997. Effect of a chemical delivery system for dexamethasone (Dex-CDS) on peritumoral edema in an experimental brain tumor model. Pharm. Res. 14:672–75
    [Google Scholar]
  134. 134. 
    Hempen C, Weiss E, Hess CF 2002. Dexamethasone treatment in patients with brain metastases and primary brain tumors: do the benefits outweigh the side-effects?. Support. Care Cancer 10:322–28
    [Google Scholar]
  135. 135. 
    Wei ET, Gao GC. 1991. Corticotropin-releasing factor: an inhibitor of vascular leakage in rat skeletal muscle and brain cortex after injury. Regul. Pept. 33:93–104
    [Google Scholar]
  136. 136. 
    Tjuvajev J, Uehara H, Desai R, Beattie B, Matei C et al. 1996. Corticotropin-releasing factor decreases vasogenic brain edema. Cancer Res 56:1352–60
    [Google Scholar]
  137. 137. 
    Villalona-Calero MA, Eckardt J, Burris H, Kraynak M, Fields-Jones S et al. 1998. A phase I trial of human corticotropin-releasing factor (hCRF) in patients with peritumoral brain edema. Ann. Oncol. 9:71–77
    [Google Scholar]
  138. 138. 
    Recht L, Mechtler LL, Wong ET, O'Connor PC, Rodda BE 2013. Steroid-sparing effect of corticorelin acetate in peritumoral cerebral edema is associated with improvement in steroid-induced myopathy. J. Clin. Oncol. 31:1182–87
    [Google Scholar]
  139. 139. 
    Jain RK, di Tomaso E, Duda DG, Loeffler JS, Sorensen AG, Batchelor TT 2007. Angiogenesis in brain tumours. Nat. Rev. Neurosci. 8:610–22
    [Google Scholar]
  140. 140. 
    Simons M, Gordon E, Claesson-Welsh L 2016. Mechanisms and regulation of endothelial VEGF receptor signalling. Nat. Rev. Mol. Cell Biol. 17:611–25
    [Google Scholar]
  141. 141. 
    Dobrogowska DH, Lossinsky AS, Tarnawski M, Vorbrodt AW 1998. Increased blood-brain barrier permeability and endothelial abnormalities induced by vascular endothelial growth factor. J. Neurocytol. 27:163–73
    [Google Scholar]
  142. 142. 
    Schmidt NO, Westphal M, Hagel C, Ergun S, Stavrou D et al. 1999. Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis. Int. J. Cancer 84:10–18
    [Google Scholar]
  143. 143. 
    Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D et al. 2009. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J. Clin. Oncol. 27:4733–40
    [Google Scholar]
  144. 144. 
    Kreisl TN, Kim L, Moore K, Duic P, Royce C et al. 2009. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J. Clin. Oncol. 27:740–45
    [Google Scholar]
  145. 145. 
    van den Bent M, Gorlia T, Bendszus M, Sahm F, Domont J et al. 2016. EH1.3 EORTC 26101 phase III trial exploring the combination of bevacizumab and lomustine versus lomustine in patients with first progression of a glioblastoma. Neuro-Oncology 18:Suppl. 4iv1–2
    [Google Scholar]
  146. 146. 
    Chinot OL, Wick W, Mason W, Henriksson R, Saran F et al. 2014. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N. Engl. J. Med. 370:709–22
    [Google Scholar]
  147. 147. 
    Gilbert MR, Dignam J, Won M, Blumenthal DT, Vogelbaum MA et al. 2013. RTOG 0825: phase III double-blind placebo-controlled trial evaluating bevacizumab (Bev) in patients (Pts) with newly diagnosed glioblastoma (GBM). J. Clin. Oncol. 31:Suppl. 181
    [Google Scholar]
  148. 148. 
    Batchelor TT, Mulholland P, Neyns B, Nabors LB, Campone M et al. 2013. Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J. Clin. Oncol. 31:3212–18
    [Google Scholar]
  149. 149. 
    Wick W, Puduvalli VK, Chamberlain MC, van den Bent MJ, Carpentier AF et al. 2010. Phase III study of enzastaurin compared with lomustine in the treatment of recurrent intracranial glioblastoma. J. Clin. Oncol. 28:1168–74
    [Google Scholar]
  150. 150. 
    Lombardi G, Pambuku A, Bellu L, Farina M, Della Puppa A et al. 2017. Effectiveness of antiangiogenic drugs in glioblastoma patients: a systematic review and meta-analysis of randomized clinical trials. Crit. Rev. Oncol. Hematol. 111:94–102
    [Google Scholar]
  151. 151. 
    Batchelor TT, Duda DG, di Tomaso E, Ancukiewicz M, Plotkin SR et al. 2010. Phase II study of cediranib, an oral pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J. Clin. Oncol. 28:2817–23
    [Google Scholar]
  152. 152. 
    Batchelor TT, Sorensen AG, di Tomaso E, Zhang WT, Duda DG et al. 2007. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, normalizes tumor vasculature and alleviates edema in glioblastoma patients. Cancer Cell 11:83–95
    [Google Scholar]
  153. 153. 
    Vredenburgh JJ, Desjardins A, Herndon JE 2nd, Dowell JM, Reardon DA et al. 2007. Phase II trial of bevacizumab and irinotecan in recurrent malignant glioma. Clin. Cancer Res. 13:1253–59
    [Google Scholar]
  154. 154. 
    Jain RK. 2001. Normalizing tumor vasculature with anti-angiogenic therapy: a new paradigm for combination therapy. Nat. Med. 7:987–89
    [Google Scholar]
  155. 155. 
    Tamura R, Tanaka T, Miyake K, Tabei Y, Ohara K et al. 2016. Histopathological investigation of glioblastomas resected under bevacizumab treatment. Oncotarget 7:52423–35
    [Google Scholar]
  156. 156. 
    Peterson TE, Kirkpatrick ND, Huang Y, Farrar CT, Marijt KA et al. 2016. Dual inhibition of Ang-2 and VEGF receptors normalizes tumor vasculature and prolongs survival in glioblastoma by altering macrophages. PNAS 113:4470–75
    [Google Scholar]
  157. 157. 
    Batchelor TT, Gerstner ER, Emblem KE, Duda DG, Kalpathy-Cramer J et al. 2013. Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation. PNAS 110:19059–64
    [Google Scholar]
  158. 158. 
    Paez-Ribes M, Allen E, Hudock J, Takeda T, Okuyama H et al. 2009. Antiangiogenic therapy elicits malignant progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15:220–31
    [Google Scholar]
  159. 159. 
    Rubenstein JL, Kim J, Ozawa T, Zhang M, Westphal M et al. 2000. Anti-VEGF antibody treatment of glioblastoma prolongs survival but results in increased vascular cooption. Neoplasia 2:306–14
    [Google Scholar]
  160. 160. 
    Zhu Z, Fu Y, Tian D, Sun N, Han W et al. 2015. Combination of the immune modulator fingolimod with alteplase in acute ischemic stroke: a pilot trial. Circulation 132:1104–12
    [Google Scholar]
  161. 161. 
    Sheth KN, Kimberly WT, Elm JJ, Kent TA, Yoo AJ et al. 2014. Exploratory analysis of glyburide as a novel therapy for preventing brain swelling. Neurocrit. Care 21:43–51
    [Google Scholar]
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