Skip to main content

Advertisement

SpringerLink
Log in

Mechanisms of Astrocyte-Mediated Cerebral Edema

  • Overview
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Cerebral edema formation stems from disruption of blood brain barrier (BBB) integrity and occurs after injury to the CNS. Due to the restrictive skull, relatively small increases in brain volume can translate into impaired tissue perfusion and brain herniation. In excess, cerebral edema can be gravely harmful. Astrocytes are key participants in cerebral edema by virtue of their relationship with the cerebral vasculature, their unique compliment of solute and water transport proteins, and their general role in brain volume homeostasis. Following the discovery of aquaporins, passive conduits of water flow, aquaporin 4 (AQP4) was identified as the predominant astrocyte water channel. Normally, AQP4 is highly enriched at perivascular endfeet, the outermost layer of the BBB, whereas after injury, AQP4 expression disseminates to the entire astrocytic plasmalemma, a phenomenon termed dysregulation. Arguably, the most important role of AQP4 is to rapidly neutralize osmotic gradients generated by ionic transporters. In pathological conditions, AQP4 is believed to be intimately involved in the formation and clearance of cerebral edema. In this review, we discuss aquaporin function and localization in the BBB during health and injury, and we examine post-injury ionic events that modulate AQP4-dependent edema formation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Daneman R, Zhou L, Kebede AA, Barres BA (2010) Pericytes are required for blood–brain barrier integrity during embryogenesis. Nature 468:562–566

    PubMed Central  CAS  PubMed  Google Scholar 

  2. Brinker T, Stopa E, Morrison J, Klinge P (2014) A new look at cerebrospinal fluid circulation. Fluids Barriers CNS 11:10

    PubMed Central  PubMed  Google Scholar 

  3. Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, Benveniste H, Vates GE, Deane R, Goldman SA, Nagelhus EA, Nedergaard M (2012) A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med 4:147ra111

  4. Zhang ET, Inman CBE, Weller RO (1990) Interrelationships of the pia mater and the perivascular (Virchow-Robin) spaces in the human cerebrum. J Anat 170:111–123

  5. Bushong EA, Martone ME, Jones YZ, Ellisman MH (2002) Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J Neurosci 22:183–192

    CAS  PubMed  Google Scholar 

  6. Preston GM, Carroll TP, Guggino WB, Agre P (1992) Appearance of water channels in Xenopus oocytes expressing red cell CHIP28 protein. Science 256:385–387

    CAS  PubMed  Google Scholar 

  7. Ho JD, Yeh R, Sandstrom A, Chorny I, Harries WE, Robbins RA, Miercke LJ, Stroud RM (2009) Crystal structure of human aquaporin 4 at 1.8 A and its mechanism of conductance. Proc Natl Acad Sci USA 106:7437–7442

    PubMed Central  CAS  PubMed  Google Scholar 

  8. Pohl P (2004) Combined transport of water and ions through membrane channels. Biol Chem 385:921–926

    CAS  PubMed  Google Scholar 

  9. Nielsen S, Nagelhus EA, Amiry-Moghaddam M, Bourque C, Agre P, Ottersen OP (1997) Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci 17:171–180

    CAS  PubMed  Google Scholar 

  10. Tomas-Camardiel M, Venero JL, de Pablos RM, Rite I, Machado A, Cano J (2004) In vivo expression of aquaporin-4 by reactive microglia. J Neurochem 91:891–899

    CAS  PubMed  Google Scholar 

  11. Papadopoulos MC, Verkman AS (2013) Aquaporin water channels in the nervous system. Nat Rev Neurosci 14:265–277

    PubMed Central  CAS  PubMed  Google Scholar 

  12. Badaut J, Petit JM, Brunet JF, Magistretti PJ, Charriaut-Marlangue C, Regli L (2004) Distribution of Aquaporin 9 in the adult rat brain: preferential expression in catecholaminergic neurons and in glial cells. Neuroscience 128:27–38

    CAS  PubMed  Google Scholar 

  13. Sui H, Han BG, Lee JK, Walian P, Jap BK (2001) Structural basis of water-specific transport through the AQP1 water channel. Nature 414:872–878

    CAS  PubMed  Google Scholar 

  14. Tsukaguchi H, Weremowicz S, Morton CC, Hediger MA (1999) Functional and molecular characterization of the human neutral solute channel aquaporin-9. Am J Physiol 277:F685–F696

    CAS  PubMed  Google Scholar 

  15. Viadiu H, Gonen T, Walz T (2007) Projection map of aquaporin-9 at 7 A resolution. J Mol Biol 367:80–88

    PubMed Central  CAS  PubMed  Google Scholar 

  16. Jung JS, Bhat RV, Preston GM, Guggino WB, Baraban JM, Agre P (1994) Molecular characterization of an aquaporin cDNA from brain: candidate osmoreceptor and regulator of water balance. Proc Natl Acad Sci U S A 91:13052–13056

    PubMed Central  CAS  PubMed  Google Scholar 

  17. Strand L, Moe SE, Solbu TT, Vaadal M, Holen T (2009) Roles of aquaporin-4 isoforms and amino acids in square array assembly. Biochemistry 48:5785–5793

    CAS  PubMed  Google Scholar 

  18. Moe SE, Sorbo JG, Sogaard R, Zeuthen T, Petter OO, Holen T (2008) New isoforms of rat Aquaporin-4. Genomics 91:367–377

    CAS  PubMed  Google Scholar 

  19. Potokar M, Stenovec M, Jorgacevski J, Holen T, Kreft M, Ottersen OP, Zorec R (2013) Regulation of AQP4 surface expression via vesicle mobility in astrocytes. Glia 61:917–928

    PubMed  Google Scholar 

  20. Silberstein C, Bouley R, Huang Y, Fang P, Pastor-Soler N, Brown D, van Hoek AN (2004) Membrane organization and function of M1 and M23 isoforms of aquaporin-4 in epithelial cells. Am J Physiol Renal Physiol 287:F501–F511

    CAS  PubMed  Google Scholar 

  21. Rossi A, Moritz TJ, Ratelade J, Verkman AS (2012) Super-resolution imaging of aquaporin-4 orthogonal arrays of particles in cell membranes. J Cell Sci 125:4405–4412

    PubMed Central  CAS  PubMed  Google Scholar 

  22. Nicchia GP, Cogotzi L, Rossi A, Basco D, Brancaccio A, Svelto M, Frigeri A (2008) Expression of multiple AQP4 pools in the plasma membrane and their association with the dystrophin complex. J Neurochem 105:2156–2165

    CAS  PubMed  Google Scholar 

  23. Hirt L, Ternon B, Price M, Mastour N, Brunet JF, Badaut J (2009) Protective role of early aquaporin 4 induction against postischemic edema formation. J Cereb Blood Flow Metab 29:423–433

    CAS  PubMed  Google Scholar 

  24. Neely JD, Amiry-Moghaddam M, Ottersen OP, Froehner SC, Agre P, Adams ME (2001) Syntrophin-dependent expression and localization of Aquaporin-4 water channel protein. Proc Natl Acad Sci U S A 98:14108–14113

    PubMed Central  CAS  PubMed  Google Scholar 

  25. Nakahama K, Fujioka A, Nagano M, Satoh S, Furukawa K, Sasaki H, Shigeyoshi Y (2002) A role of the C-terminus of aquaporin 4 in its membrane expression in cultured astrocytes. Genes Cells 7:731–741

    CAS  PubMed  Google Scholar 

  26. Wen H, Nagelhus EA, Amiry-Moghaddam M, Agre P, Ottersen OP, Nielsen S (1999) Ontogeny of water transport in rat brain: postnatal expression of the aquaporin-4 water channel. Eur J Neurosci 11:935–945

    CAS  PubMed  Google Scholar 

  27. Hsu MS, Seldin M, Lee DJ, Seifert G, Steinhauser C, Binder DK (2011) Laminar-specific and developmental expression of aquaporin-4 in the mouse hippocampus. Neuroscience 178:21–32

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Badaut J, Nehlig A, Verbavatz J, Stoeckel M, Freund-Mercier MJ, Lasbennes F (2000) Hypervascularization in the magnocellular nuclei of the rat hypothalamus: relationship with the distribution of aquaporin-4 and markers of energy metabolism. J Neuroendocrinol 12:960–969

    CAS  PubMed  Google Scholar 

  29. Bragg AD, Amiry-Moghaddam M, Ottersen OP, Adams ME, Froehner SC (2006) Assembly of a perivascular astrocyte protein scaffold at the mammalian blood–brain barrier is dependent on alpha-syntrophin. Glia 53:879–890

    PubMed  Google Scholar 

  30. Noell S, Wolburg-Buchholz K, Mack AF, Beedle AM, Satz JS, Campbell KP, Wolburg H, Fallier-Becker P (2011) Evidence for a role of dystroglycan regulating the membrane architecture of astroglial endfeet. Eur J Neurosci 33:2179–2186

    PubMed Central  PubMed  Google Scholar 

  31. Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood–brain barrier. Nat Rev Neurosci 7:41–53

    CAS  PubMed  Google Scholar 

  32. Mokgokong R, Wang S, Taylor CJ, Barrand MA, Hladky SB (2013) Ion transporters in brain endothelial cells that contribute to formation of brain interstitial fluid. Pflugers Arch 466:887–901

  33. Rennels ML, Gregory TF, Blaumanis OR, Fujimoto K, Grady PA (1985) Evidence for a ‘paravascular’ fluid circulation in the mammalian central nervous system, provided by the rapid distribution of tracer protein throughout the brain from the subarachnoid space. Brain Res 326:47–63

    CAS  PubMed  Google Scholar 

  34. Badaut J, Ashwal S, Adami A, Tone B, Recker R, Spagnoli D, Ternon B, Obenaus A (2011) Brain water mobility decreases after astrocytic aquaporin-4 inhibition using RNA interference. J Cereb Blood Flow Metab 31:819–831

    PubMed Central  CAS  PubMed  Google Scholar 

  35. Iliff JJ, Nedergaard M (2013) Is there a cerebral lymphatic system? Stroke 44:S93–S95

    PubMed Central  PubMed  Google Scholar 

  36. Proescholdt MG, Hutto B, Brady LS, Herkenham M (2000) Studies of cerebrospinal fluid flow and penetration into brain following lateral ventricle and cisterna magna injections of the tracer [14C]inulin in rat. Neuroscience 95:577–592

    CAS  PubMed  Google Scholar 

  37. Solenov E, Watanabe H, Manley GT, Verkman AS (2004) Sevenfold-reduced osmotic water permeability in primary astrocyte cultures from AQP-4-deficient mice, measured by a fluorescence quenching method. Am J Physiol Cell Physiol 286:C426–C432

    CAS  PubMed  Google Scholar 

  38. Macaulay N, Hamann S, Zeuthen T (2004) Water transport in the brain: role of cotransporters. Neuroscience 129:1031–1044

    CAS  PubMed  Google Scholar 

  39. Basco D, Blaauw B, Pisani F, Sparaneo A, Nicchia GP, Mola MG, Reggiani C, Svelto M, Frigeri A (2013) AQP4-dependent water transport plays a functional role in exercise-induced skeletal muscle adaptations. PLoS ONE 8:e58712

    PubMed Central  CAS  PubMed  Google Scholar 

  40. Amiry-Moghaddam M, Williamson A, Palomba M, Eid T, de Lanerolle NC, Nagelhus EA, Adams ME, Froehner SC, Agre P, Ottersen OP (2003) Delayed K+ clearance associated with aquaporin-4 mislocalization: phenotypic defects in brains of alpha-syntrophin-null mice. Proc Natl Acad Sci U S A 100:13615–13620

    PubMed Central  CAS  PubMed  Google Scholar 

  41. Binder DK, Yao X, Zador Z, Sick TJ, Verkman AS, Manley GT (2006) Increased seizure duration and slowed potassium kinetics in mice lacking aquaporin-4 water channels. Glia 53:631–636

    PubMed  Google Scholar 

  42. Binder DK, Papadopoulos MC, Haggie PM, Verkman AS (2004) In vivo measurement of brain extracellular space diffusion by cortical surface photobleaching. J Neurosci 24:8049–8056

    CAS  PubMed  Google Scholar 

  43. Yao X, Hrabetova S, Nicholson C, Manley GT (2008) Aquaporin-4-deficient mice have increased extracellular space without tortuosity change. J Neurosci 28:5460–5464

    PubMed Central  CAS  PubMed  Google Scholar 

  44. Strohschein S, Huttmann K, Gabriel S, Binder DK, Heinemann U, Steinhauser C (2011) Impact of aquaporin-4 channels on K+ buffering and gap junction coupling in the hippocampus. Glia 59:973–980

    PubMed  Google Scholar 

  45. Rose CR, Ransom BR (1996) Intracellular sodium homeostasis in rat hippocampal astrocytes. J Physiol 491(Pt 2):291–305

    PubMed Central  CAS  PubMed  Google Scholar 

  46. Papadopoulos MC, Manley GT, Krishna S, Verkman AS (2004) Aquaporin-4 facilitates reabsorption of excess fluid in vasogenic brain edema. FASEB J 18:1291–1293

    CAS  PubMed  Google Scholar 

  47. Binder DK, Oshio K, Ma T, Verkman AS, Manley GT (2004) Increased seizure threshold in mice lacking aquaporin-4 water channels. NeuroReport 15:259–262

    CAS  PubMed  Google Scholar 

  48. Li J, Verkman AS (2001) Impaired hearing in mice lacking aquaporin-4 water channels. J Biol Chem 276:31233–31237

    CAS  PubMed  Google Scholar 

  49. Saadoun S, Tait MJ, Reza A, Davies DC, Bell BA, Verkman AS, Papadopoulos MC (2009) AQP4 gene deletion in mice does not alter blood–brain barrier integrity or brain morphology. Neuroscience 161:764–772

    CAS  PubMed  Google Scholar 

  50. Eilert-Olsen M, Haj-Yasein NN, Vindedal GF, Enger R, Gundersen GA, Hoddevik EH, Petersen PH, Haug FM, Skare O, Adams ME, Froehner SC, Burkhardt JM, Thoren AE, Nagelhus EA (2012) Deletion of aquaporin-4 changes the perivascular glial protein scaffold without disrupting the brain endothelial barrier. Glia 60:432–440

    PubMed  Google Scholar 

  51. Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen AW, Chan P, Verkman AS (2000) Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med 6:159–163

    CAS  PubMed  Google Scholar 

  52. Klatzo I (1987) Pathophysiological aspects of brain edema. Acta Neuropathol 72:236–239

    CAS  PubMed  Google Scholar 

  53. Simard JM, Kent TA, Chen M, Tarasov KV, Gerzanich V (2007) Brain oedema in focal ischaemia: molecular pathophysiology and theoretical implications. Lancet Neurol 6:258–268

    PubMed Central  CAS  PubMed  Google Scholar 

  54. 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 19:1261–1270

    PubMed  Google Scholar 

  55. Haj-Yasein NN, Vindedal GF, Eilert-Olsen M, Gundersen GA, Skare O, Laake P, Klungland A, Thoren AE, Burkhardt JM, Ottersen OP, Nagelhus EA (2011) Glial-conditional deletion of aquaporin-4 (Aqp4) reduces blood–brain water uptake and confers barrier function on perivascular astrocyte endfeet. Proc Natl Acad Sci U S A 108:17815–17820

    PubMed Central  CAS  PubMed  Google Scholar 

  56. Da T, Verkman AS (2004) Aquaporin-4 gene disruption in mice protects against impaired retinal function and cell death after ischemia. Invest Ophthalmol Vis Sci 45:4477–4483

    PubMed  Google Scholar 

  57. Higashida T, Kreipke CW, Rafols JA, Peng C, Schafer S, Schafer P, Ding JY, Dornbos D III, Li X, Guthikonda M, Rossi NF, Ding Y (2011) The role of hypoxia-inducible factor-1alpha, aquaporin-4, and matrix metalloproteinase-9 in blood–brain barrier disruption and brain edema after traumatic brain injury. J Neurosurg 114:92–101

    CAS  PubMed  Google Scholar 

  58. Shenaq M, Kassem H, Peng C, Schafer S, Ding JY, Fredrickson V, Guthikonda M, Kreipke CW, Rafols JA, Ding Y (2012) Neuronal damage and functional deficits are ameliorated by inhibition of aquaporin and HIF1alpha after traumatic brain injury (TBI). J Neurol Sci 323:134–140

    CAS  PubMed  Google Scholar 

  59. Yang B, Zador Z, Verkman AS (2008) Glial cell aquaporin-4 overexpression in transgenic mice accelerates cytotoxic brain swelling. J Biol Chem 283:15280–15286

    PubMed Central  CAS  PubMed  Google Scholar 

  60. Amiry-Moghaddam M, Xue R, Haug FM, Neely JD, Bhardwaj A, Agre P, Adams ME, Froehner SC, Mori S, Ottersen OP (2004) Alpha-syntrophin deletion removes the perivascular but not endothelial pool of aquaporin-4 at the blood–brain barrier and delays the development of brain edema in an experimental model of acute hyponatremia. FASEB J 18:542–544

    CAS  PubMed  Google Scholar 

  61. Vajda Z, Pedersen M, Fuchtbauer EM, Wertz K, Stodkilde-Jorgensen H, Sulyok E, Doczi T, Neely JD, Agre P, Frokiaer J, Nielsen S (2002) Delayed onset of brain edema and mislocalization of aquaporin-4 in dystrophin-null transgenic mice. Proc Natl Acad Sci U S A 99:13131–13136

    PubMed Central  CAS  PubMed  Google Scholar 

  62. Marmarou A, Hochwald G, Nakamura T, Tanaka K, Weaver J, Dunbar J (1994) Brain edema resolution by CSF pathways and brain vasculature in cats. Am J Physiol 267:H514–H520

    CAS  PubMed  Google Scholar 

  63. Steiner E, Enzmann GU, Lin S, Ghavampour S, Hannocks MJ, Zuber B, Ruegg MA, Sorokin L, Engelhardt B (2012) Loss of astrocyte polarization upon transient focal brain ischemia as a possible mechanism to counteract early edema formation. Glia 60:1646–1659

    PubMed  Google Scholar 

  64. Fukuda AM, Pop V, Spagnoli D, Ashwal S, Obenaus A, Badaut J (2012) Delayed increase of astrocytic aquaporin 4 after juvenile traumatic brain injury: possible role in edema resolution? Neuroscience 222:366–378

    PubMed Central  CAS  PubMed  Google Scholar 

  65. Ren Z, Iliff JJ, Yang L, Yang J, Chen X, Chen MJ, Giese RN, Wang B, Shi X, Nedergaard M (2013) ‘Hit & Run’ model of closed-skull traumatic brain injury (TBI) reveals complex patterns of post-traumatic AQP4 dysregulation. J Cereb Blood Flow Metab 33:834–845

    PubMed Central  CAS  PubMed  Google Scholar 

  66. Nico B, Tamma R, Annese T, Mangieri D, De LA, Corsi P, Benagiano V, Longo V, Crivellato E, Salmaggi A, Ribatti D (2010) Glial dystrophin-associated proteins, laminin and agrin, are downregulated in the brain of mdx mouse. Lab Invest 90:1645–1660

    CAS  PubMed  Google Scholar 

  67. Frigeri A, Nicchia GP, Nico B, Quondamatteo F, Herken R, Roncali L, Svelto M (2001) Aquaporin-4 deficiency in skeletal muscle and brain of dystrophic mdx mice. FASEB J 15:90–98

    CAS  PubMed  Google Scholar 

  68. Noell S, Fallier-Becker P, Deutsch U, Mack AF, Wolburg H (2009) Agrin defines polarized distribution of orthogonal arrays of particles in astrocytes. Cell Tissue Res 337:185–195

    CAS  PubMed  Google Scholar 

  69. Amiry-Moghaddam M, Otsuka T, Hurn PD, Traystman RJ, Haug FM, Froehner SC, Adams ME, Neely JD, Agre P, Ottersen OP, Bhardwaj A (2003) An alpha-syntrophin-dependent pool of AQP4 in astroglial end-feet confers bidirectional water flow between blood and brain. Proc Natl Acad Sci U S A 100:2106–2111

    PubMed Central  CAS  PubMed  Google Scholar 

  70. Saadoun S, Papadopoulos MC, Watanabe H, Yan D, Manley GT, Verkman AS (2005) Involvement of aquaporin-4 in astroglial cell migration and glial scar formation. J Cell Sci 118:5691–5698

    CAS  PubMed  Google Scholar 

  71. Li L, Zhang H, Varrin-Doyer M, Zamvil SS, Verkman AS (2011) Proinflammatory role of aquaporin-4 in autoimmune neuroinflammation. FASEB J 25:1556–1566

    PubMed Central  CAS  PubMed  Google Scholar 

  72. Auguste KI, Jin S, Uchida K, Yan D, Manley GT, Papadopoulos MC, Verkman AS (2007) Greatly impaired migration of implanted aquaporin-4-deficient astroglial cells in mouse brain toward a site of injury. FASEB J 21:108–116

    CAS  PubMed  Google Scholar 

  73. Kong H, Fan Y, Xie J, Ding J, Sha L, Shi X, Sun X, Hu G (2008) AQP4 knockout impairs proliferation, migration and neuronal differentiation of adult neural stem cells. J Cell Sci 121:4029–4036

    CAS  PubMed  Google Scholar 

  74. Roemer SF, Parisi JE, Lennon VA, Benarroch EE, Lassmann H, Bruck W, Mandler RN, Weinshenker BG, Pittock SJ, Wingerchuk DM, Lucchinetti CF (2007) Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. Brain 130:1194–1205

    PubMed  Google Scholar 

  75. Hoshi A, Yamamoto T, Shimizu K, Ugawa Y, Nishizawa M, Takahashi H, Kakita A (2012) Characteristics of aquaporin expression surrounding senile plaques and cerebral amyloid angiopathy in Alzheimer disease. J Neuropathol Exp Neurol 71:750–759

    CAS  PubMed  Google Scholar 

  76. Somjen GG (2002) Ion regulation in the brain: implications for pathophysiology. Neuroscientist 8:254–267

    CAS  PubMed  Google Scholar 

  77. Djukic B, Casper KB, Philpot BD, Chin LS, McCarthy KD (2007) Conditional knock-out of Kir4.1 leads to glial membrane depolarization, inhibition of potassium and glutamate uptake, and enhanced short-term synaptic potentiation. J Neurosci 27:11354–11365

    CAS  PubMed  Google Scholar 

  78. Orkand RK, Nicholls JG, Kuffler SW (1966) Effect of nerve impulses on the membrane potential of glial cells in the central nervous system of amphibia. J Neurophysiol 29:788–806

    CAS  PubMed  Google Scholar 

  79. Holthoff K, Witte OW (2000) Directed spatial potassium redistribution in rat neocortex. Glia 29:288–292

    CAS  PubMed  Google Scholar 

  80. Larsen BR, Assentoft M, Cotrina ML, Hua SZ, Nedergaard M, Kaila K, Voipio J, Macaulay N (2014) Contributions of the Na(+)/K(+) -ATPase, NKCC1, and Kir4.1 to hippocampal K(+) clearance and volume responses. Glia 62:608–622

    PubMed  Google Scholar 

  81. Florence CM, Baillie LD, Mulligan SJ (2012) Dynamic volume changes in astrocytes are an intrinsic phenomenon mediated by bicarbonate ion flux. PLoS ONE 7:e51124

    PubMed Central  CAS  PubMed  Google Scholar 

  82. Ransom BR, Yamate CL, Connors BW (1985) Activity-dependent shrinkage of extracellular space in rat optic nerve: a developmental study. J Neurosci 5:532–535

    CAS  PubMed  Google Scholar 

  83. Kitaura H, Tsujita M, Huber VJ, Kakita A, Shibuki K, Sakimura K, Kwee IL, Nakada T (2009) Activity-dependent glial swelling is impaired in aquaporin-4 knockout mice. Neurosci Res 64:208–212

    CAS  PubMed  Google Scholar 

  84. Haj-Yasein NN, Bugge CE, Jensen V, Ostby I, Ottersen OP, Hvalby O, Nagelhus EA (2014) Deletion of aquaporin-4 increases extracellular K concentration during synaptic stimulation in mouse hippocampus. Brain Struct Funct. doi:10.1007/s00429-014-0767-z

  85. Illarionova NB, Gunnarson E, Li Y, Brismar H, Bondar A, Zelenin S, Aperia A (2010) Functional and molecular interactions between aquaporins and Na, K-ATPase. Neuroscience 168:915–925

    CAS  PubMed  Google Scholar 

  86. Haj-Yasein NN, Jensen V, Ostby I, Omholt SW, Voipio J, Kaila K, Ottersen OP, Hvalby O, Nagelhus EA (2012) Aquaporin-4 regulates extracellular space volume dynamics during high-frequency synaptic stimulation: a gene deletion study in mouse hippocampus. Glia 60:867–874

    PubMed  Google Scholar 

  87. Scharfman HE, Binder DK (2013) Aquaporin-4 water channels and synaptic plasticity in the hippocampus. Neurochem Int 63:702–711

    CAS  PubMed  Google Scholar 

  88. Bondarenko A, Svichar N, Chesler M (2005) Role of Na+-H+ and Na+-Ca2+ exchange in hypoxia-related acute astrocyte death. Glia 49:143–152

    PubMed  Google Scholar 

  89. Katayama Y, Becker DP, Tamura T, Hovda DA (1990) Massive increases in extracellular potassium and the indiscriminate release of glutamate following concussive brain injury. J Neurosurg 73:889–900

    CAS  PubMed  Google Scholar 

  90. Gido G, Kristian T, Siesjo BK (1997) Extracellular potassium in a neocortical core area after transient focal ischemia. Stroke 28:206–210

    CAS  PubMed  Google Scholar 

  91. Gamba G (2005) Molecular physiology and pathophysiology of electroneutral cation-chloride cotransporters. Physiol Rev 85:423–493

    CAS  PubMed  Google Scholar 

  92. Su G, Haworth RA, Dempsey RJ, Sun D (2000) Regulation of Na(+)-K(+)-Cl(-) cotransporter in primary astrocytes by dibutyryl cAMP and high [K(+)](o). Am J Physiol Cell Physiol 279:C1710–C1721

    CAS  PubMed  Google Scholar 

  93. Hamann S, Herrera-Perez JJ, Zeuthen T, Alvarez-Leefmans FJ (2010) Cotransport of water by the Na+-K+ -2Cl(-) cotransporter NKCC1 in mammalian epithelial cells. J Physiol 588:4089–4101

    PubMed Central  CAS  PubMed  Google Scholar 

  94. 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–C1146

    CAS  PubMed  Google Scholar 

  95. 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–C1160

    CAS  PubMed  Google Scholar 

  96. Zeuthen T (1994) Cotransport of K+, Cl- and H2O by membrane proteins from choroid plexus epithelium of Necturus maculosus. J Physiol 478(Pt 2):203–219

    PubMed Central  CAS  PubMed  Google Scholar 

  97. Jayakumar AR, Panickar KS, Curtis KM, Tong XY, Moriyama M, Norenberg MD (2011) Na-K-Cl cotransporter-1 in the mechanism of cell swelling in cultured astrocytes after fluid percussion injury. J Neurochem 117:437–448

    CAS  PubMed  Google Scholar 

  98. Lu KT, Cheng NC, Wu CY, Yang YL (2008) NKCC1-mediated traumatic brain injury-induced brain edema and neuron death via Raf/MEK/MAPK cascade. Crit Care Med 36:917–922

    CAS  PubMed  Google Scholar 

  99. 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

    CAS  PubMed  Google Scholar 

  100. O’Donnell ME, Tran L, Lam TI, Liu XB, Anderson SE (2004) Bumetanide inhibition of the blood–brain barrier Na-K-Cl cotransporter reduces edema formation in the rat middle cerebral artery occlusion model of stroke. J Cereb Blood Flow Metab 24:1046–1056

    PubMed  Google Scholar 

  101. O’Donnell ME, Lam TI, Tran L, Anderson SE (2004) The role of the blood–brain barrier Na-K-2Cl cotransporter in stroke. Adv Exp Med Biol 559:67–75

    PubMed  Google Scholar 

  102. Benveniste H, Drejer J, Schousboe A, Diemer NH (1984) Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral microdialysis. J Neurochem 43:1369–1374

    CAS  PubMed  Google Scholar 

  103. Faden AI, Demediuk P, Panter SS, Vink R (1989) The role of excitatory amino acids and NMDA receptors in traumatic brain injury. Science 244:798–800

    CAS  PubMed  Google Scholar 

  104. Kimelberg HK, Goderie SK, Higman S, Pang S, Waniewski RA (1990) Swelling-induced release of glutamate, aspartate, and taurine from astrocyte cultures. J Neurosci 10:1583–1591

    CAS  PubMed  Google Scholar 

  105. Longuemare MC, Swanson RA (1995) Excitatory amino acid release from astrocytes during energy failure by reversal of sodium-dependent uptake. J Neurosci Res 40:379–386

    CAS  PubMed  Google Scholar 

  106. Bender AS, Schousboe A, Reichelt W, Norenberg MD (1998) Ionic mechanisms in glutamate-induced astrocyte swelling: role of K+ influx. J Neurosci Res 52:307–321

    CAS  PubMed  Google Scholar 

  107. Yuan F, Wang T (1996) Glutamate-induced swelling of cultured astrocytes is mediated by metabotropic glutamate receptor. Sci China C Life Sci 39:517–522

    CAS  PubMed  Google Scholar 

  108. Porter JT, McCarthy KD (1996) Hippocampal astrocytes in situ respond to glutamate released from synaptic terminals. J Neurosci 16:5073–5081

    CAS  PubMed  Google Scholar 

  109. Staub F, Baethmann A, Peters J, Weigt H, Kempski O (1990) Effects of lactacidosis on glial cell volume and viability. J Cereb Blood Flow Metab 10:866–876

    CAS  PubMed  Google Scholar 

  110. Kempski O, Staub F, Jansen M, Schodel F, Baethmann A (1988) Glial swelling during extracellular acidosis in vitro. Stroke 19:385–392

    CAS  PubMed  Google Scholar 

  111. Morishima T, Aoyama M, Iida Y, Yamamoto N, Hirate H, Arima H, Fujita Y, Sasano H, Tsuda T, Katsuya H, Asai K, Sobue K (2008) Lactic acid increases aquaporin 4 expression on the cell membrane of cultured rat astrocytes. Neurosci Res 61:18–26

    CAS  PubMed  Google Scholar 

  112. Bevensee MO, Weed RA, Boron WF (1997) Intracellular pH regulation in cultured astrocytes from rat hippocampus. I. Role Of HCO3-. J Gen Physiol 110:453–465

    PubMed Central  CAS  PubMed  Google Scholar 

  113. Brune T, Fetzer S, Backus KH, Deitmer JW (1994) Evidence for electrogenic sodium-bicarbonate cotransport in cultured rat cerebellar astrocytes. Pflugers Arch 429:64–71

    CAS  PubMed  Google Scholar 

  114. Bevensee MO, Apkon M, Boron WF (1997) Intracellular pH regulation in cultured astrocytes from rat hippocampus. II. Electrogenic Na/HCO3 cotransport. J Gen Physiol 110:467–483

    PubMed Central  CAS  PubMed  Google Scholar 

  115. Sohn Y, Yoo KY, Park OK, Kwon SH, Lee CH, Choi JH, Hwang IK, Seo JY, Cho JH, Won MH (2011) Na+/HCO3- cotransporter immunoreactivity changes in neurons and expresses in astrocytes in the gerbil hippocampal CA1 region after ischemia/reperfusion. Neurochem Res 36:2459–2469

    CAS  PubMed  Google Scholar 

  116. Xue J, Haddad GG (2010) The Na+/H+ exchanger: a target for therapeutic intervention in cerebral ischemia. In: Annunziato L (ed) New strategies in stroke intervention: ionic transporters, pumps, and new channels. Humana Press, New York, pp 113–128

    Google Scholar 

  117. Pizzonia JH, Ransom BR, Pappas CA (1996) Characterization of Na+/H+ exchange activity in cultured rat hippocampal astrocytes. J Neurosci Res 44:191–198

    CAS  PubMed  Google Scholar 

  118. Lin CW, Kalaria RN, Kroon SN, Bae JY, Sayre LM, LaManna JC (1996) The amiloride-sensitive Na+/H+ exchange antiporter and control of intracellular pH in hippocampal brain slices. Brain Res 731:108–113

    CAS  PubMed  Google Scholar 

  119. Kintner DB, Su G, Lenart B, Ballard AJ, Meyer JW, Ng LL, Shull GE, Sun D (2004) Increased tolerance to oxygen and glucose deprivation in astrocytes from Na(+)/H(+) exchanger isoform 1 null mice. Am J Physiol Cell Physiol 287:C12–C21

    CAS  PubMed  Google Scholar 

  120. Jakubovicz DE, Klip A (1989) Lactic acid-induced swelling in C6 glial cells via Na+/H+ exchange. Brain Res 485:215–224

    CAS  PubMed  Google Scholar 

  121. Jean T, Frelin C, Vigne P, Lazdunski M (1986) The Na+/H+ exchange system in glial cell lines. Properties and activation by an hyperosmotic shock. Eur J Biochem 160:211–219

    CAS  PubMed  Google Scholar 

  122. Kitayama J, Kitazono T, Yao H, Ooboshi H, Takaba H, Ago T, Fujishima M, Ibayashi S (2001) Inhibition of Na+/H+ exchanger reduces infarct volume of focal cerebral ischemia in rats. Brain Res 922:223–228

    CAS  PubMed  Google Scholar 

  123. Kuribayashi Y, Itoh N, Kitano M, Ohashi N (1999) Cerebroprotective properties of SM-20220, a potent Na(+)/H(+) exchange inhibitor, in transient cerebral ischemia in rats. Eur J Pharmacol 383:163–168

    CAS  PubMed  Google Scholar 

  124. Park HS, Lee BK, Park S, Kim SU, Lee SH, Baik EJ, Lee S, Yi KY, Yoo SE, Moon CH, Jung YS (2005) Effects of sabiporide, a specific Na+/H+ exchanger inhibitor, on neuronal cell death and brain ischemia. Brain Res 1061:67–71

    CAS  PubMed  Google Scholar 

  125. Wang Y, Luo J, Chen X, Chen H, Cramer SW, Sun D (2008) Gene inactivation of Na+/H+ exchanger isoform 1 attenuates apoptosis and mitochondrial damage following transient focal cerebral ischemia. Eur J Neurosci 28:51–61

    PubMed Central  PubMed  Google Scholar 

  126. Ferrazzano P, Shi Y, Manhas N, Wang Y, Hutchinson B, Chen X, Chanana V, Gerdts J, Meyerand ME, Sun D (2011) Inhibiting the Na+/H+ exchanger reduces reperfusion injury: a small animal MRI study. Front Biosci (Elite Ed) 3:81–88

    Google Scholar 

  127. 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 288:3655–3667

    PubMed Central  CAS  PubMed  Google Scholar 

  128. 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 23:8568–8577

    CAS  PubMed  Google Scholar 

  129. Nilius B, Prenen J, Tang J, Wang C, Owsianik G, Janssens A, Voets T, Zhu MX (2005) Regulation of the Ca2+ sensitivity of the nonselective cation channel TRPM4. J Biol Chem 280:6423–6433

    CAS  PubMed  Google Scholar 

  130. Simard JM, Chen M, Tarasov KV, Bhatta S, Ivanova S, Melnitchenko L, Tsymbalyuk N, West GA, Gerzanich V (2006) Newly expressed SUR1-regulated NC(Ca-ATP) channel mediates cerebral edema after ischemic stroke. Nat Med 12:433–440

    PubMed Central  CAS  PubMed  Google Scholar 

  131. Vennekens R, Nilius B (2007) Insights into TRPM4 function, regulation and physiological role. In: Flockerzi V, Nilius B (eds) Handb Exp Pharmacol. Springer, Berlin, pp 269–285

  132. 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 21:6512–6521

    CAS  PubMed  Google Scholar 

  133. 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 40:604–609

    PubMed Central  CAS  PubMed  Google Scholar 

  134. Pasantes-Morales H, Vazquez-Juarez E (2012) Transporters and channels in cytotoxic astrocyte swelling. Neurochem Res 37:2379–2387

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We would like to thank the anonymous reviewers who made invaluable suggestions to improve our manuscript. This work was supported by grants to JMS from the Department of Veterans Affairs (Baltimore) (BX001629), the National Institute of Neurological Disorders and Stroke (NINDS) (NS060801; NS061808), the National Heart, Lung and Blood Institute (HL082517), and the Department of the Army (W81XWH 1010898); and to VG from NINDS (NS061934; NS072501).

Ethical statement

All studies of human tissues were approved by the appropriate ethics committee and have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Conflict of interest

All authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Neurosurgery, University of Maryland School of Medicine, 22 S. Greene St., Suite S12D, Baltimore, MD, 21201-1595, USA

    Jesse A. Stokum, David B. Kurland, Volodymyr Gerzanich & J. Marc Simard

  2. Department of Pathology, University of Maryland School of Medicine, Baltimore, MD, 21201-1595, USA

    J. Marc Simard

  3. Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, 21201-1595, USA

    J. Marc Simard

Authors
  1. Jesse A. Stokum
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. David B. Kurland
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Volodymyr Gerzanich
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J. Marc Simard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Marc Simard.

Additional information

Special Issue: In honor of Michael Norenberg.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Stokum, J.A., Kurland, D.B., Gerzanich, V. et al. Mechanisms of Astrocyte-Mediated Cerebral Edema. Neurochem Res 40, 317–328 (2015). https://doi.org/10.1007/s11064-014-1374-3

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-014-1374-3

Keywords

Search

Navigation