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Role of Aquaporin-4 in Cerebral Edema and Stroke

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Book cover Aquaporins

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 190))

Cerebral edema plays a central role in the pathophysiology of many diseases of the central nervous system (CNS) including ischemia, trauma, tumors, inflammation, and metabolic disturbances. The formation of cerebral edema results in an increase in tissue water content and brain swelling which, if unchecked, can lead to elevated intracranial pressure (ICP), reduced cerebral blood flow, and ultimately cerebral herniation and death. Despite the clinical significance of cerebral edema, the mechanism of brain water transport and edema formation remain poorly understood. As a result, current therapeutic tools for managing cerebral edema have changed little in the past 90 years. “Malignant ischemic stroke” is characterized by high mortality (̃80%) and represents a major clinical problem in cerebrovascu-lar disease. Widespread ischemic injury in these patients causes progressive cerebral edema, increased ICP, and rapid clinical decline. In response to these observations, a series of recent studies have begun to target cerebral edema in the management of large ischemic strokes. During cerebral edema formation, the glial water channel aquaporin-4 (AQP4) has been show to facilitate astrocyte swelling (“cytotoxic swelling”). AQP4 has also been seen to be responsible for the reabsorp-tion of extracellular edema fluid (“vasogenic edema”). In the present review, the role of AQP4 in the development of cerebral edema is discussed with emphasis on its contribution to ischemic edema. We also examine the potential of AQP4 as a therapeutic target in edema associated with stroke.

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References

  • Amiry-Moghaddam M, Otsuka T, Hurn PD, et al. (2003a) 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

    Article  CAS  Google Scholar 

  • Amiry-Moghaddam M, Williamson A, Palomba M, et al. (2003b) 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

    Article  CAS  Google Scholar 

  • Amiry-Moghaddam M, Frydenlund DS, Ottersen OP (2004a) Anchoring of aquaporin-4 in brain: molecular mechanisms and implications for the physiology and pathophysiology of water transport. Neuroscience 129:999–1010

    CAS  Google Scholar 

  • Amiry-Moghaddam M, Xue R, Haug FM, et al. (2004b) 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  Google Scholar 

  • Asahi M, Wang X, Mori T, Sumii T, Jung JC, Moskowitz MA, Fini ME, Lo EH. Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood-brain barrier and white matter components after cerebral ischemia. J Neurosci. 2001 Oct 1;21(19):7724–32

    PubMed  CAS  Google Scholar 

  • Bardutzky J, Schwab S (2007) Antiedema therapy in ischemic stroke. Stroke 38:3084–3094

    Article  PubMed  CAS  Google Scholar 

  • Bereczki D, Liu M, Prado GF, Fekete I (2000) Cochrane report: a systematic review of mannitol therapy for acute ischemic stroke and cerebral parenchymal hemorrhage. Stroke 31:2719–2722

    PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  Google Scholar 

  • Brown RC, Davis TP (2002) Calcium modulation of adherens and tight junction function: a potential mechanism for blood—brain barrier disruption after stroke. Stroke 33:1706–1711

    Article  PubMed  CAS  Google Scholar 

  • Castejon OJ (1984) Formation of transendothelial channels in traumatic human brain edema. Pathol Res Pract 179:7–12

    PubMed  CAS  Google Scholar 

  • Connors NC, Kofuji P (2002) Dystrophin Dp71 is critical for the clustered localization of potassium channels in retinal glial cells. J Neurosci 22:4321–4327

    PubMed  CAS  Google Scholar 

  • Figueroa BE, Keep RF, Betz AL, Hoff JT (1998) Plasminogen activators potentiate thrombin-induced brain injury. Stroke 29:1202–1207; discussion 1208

    PubMed  CAS  Google Scholar 

  • Fort PE, Sene A, Pannicke T, et al. (2008) Kir4.1 and AQP4 associate with Dp71- and utrophin-DAPs complexes in specific and defined microdomains of Muller retinal glial cell membrane. Glia 56:597–610

    Article  PubMed  Google Scholar 

  • Goldstein L, Teng ZP, Zeserson E, Patel M, Regan RF (2003) Hemin induces an iron-dependent, oxidative injury to human neuron-like cells. J Neurosci Res 73:113–121

    Article  PubMed  CAS  Google Scholar 

  • Hacke W, Schwab S, Horn M, Spranger M, De Georgia M, von Kummer R (1996) ‘Malignant’ middle cerebral artery territory infarction: clinical course and prognostic signs. Arch Neurol 53:309–315

    PubMed  CAS  Google Scholar 

  • Hara-Chikuma M, Verkman AS (2006) Physiological roles of glycerol-transporting aquaporins: the aquaglyceroporins. Cell Mol Life Sci 63:1386–1392

    Article  PubMed  CAS  Google Scholar 

  • Hua Y, Xi G, Keep RF, Hoff JT (2000) Complement activation in the brain after experimental intracerebral hemorrhage. J Neurosurg 92:1016–1022

    Article  PubMed  CAS  Google Scholar 

  • Klatzo I (1967) Presidental address. Neuropathological aspects of brain edema. J Neuropathol Exp Neurol 26:1–14

    Article  PubMed  CAS  Google Scholar 

  • Lee KR, Betz AL, Keep RF, Chenevert TL, Kim S, Hoff JT (1995) Intracerebral infusion of throm-bin as a cause of brain edema. J Neurosurg 83:1045–1050

    PubMed  CAS  Google Scholar 

  • Manley GT, Fujimura M, Ma T, et al. (2000) Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med 6:159–163

    Article  PubMed  CAS  Google Scholar 

  • Manley GT, Binder DK, Papadopoulos MC, Verkman AS (2004) New insights into water transport and edema in the central nervous system from phenotype analysis of aquaporin-4 null mice. Neuroscience 129:983–991

    Article  PubMed  CAS  Google Scholar 

  • Matsuoka H, Hamada R (2002) Role of thrombin in CNS damage associated with intracerebral haemorrhage: opportunity for pharmacological intervention? CNS Drugs 16:509–516

    Article  PubMed  CAS  Google Scholar 

  • Nagelhus EA, Mathiisen TM, Ottersen OP (2004) Aquaporin-4 in the central nervous system: cellular and subcellular distribution and coexpression with KIR4.1. Neuroscience 129:905–913

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • 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

    PubMed  CAS  Google Scholar 

  • Oshio K, Watanabe H, Song Y, Verkman AS, Manley GT (2005) Reduced cerebrospinal fluid production and intracranial pressure in mice lacking choroid plexus water channel Aquaporin-1. FASEB J 19:76–78

    PubMed  CAS  Google Scholar 

  • Oshio K, Watanabe H, Yan D, Verkman AS, Manley GT (2006) Impaired pain sensation in mice lacking aquaporin-1 water channels. Biochem Biophys Res Commun 341:1022–1028

    Article  PubMed  CAS  Google Scholar 

  • Padmawar P, Yao X, Bloch O, Manley GT, Verkman AS (2005) K+ waves in brain cortex visualized using a long-wavelength K+-sensing fluorescent indicator. Nat Methods 2:825–827

    Article  PubMed  CAS  Google Scholar 

  • Papadopoulos MC, Verkman AS (2005) Aquaporin-4 gene disruption in mice reduces brain swelling and mortality in pneumococcal meningitis. J Biol Chem 280:13906–13912

    Article  PubMed  CAS  Google Scholar 

  • Papadopoulos M, Saadoun S, Krishna S, Bell B, Davies D (2002) The aquaporin-1 water channel protein is abnormally expressed in oedematous human brain tumours. J Anat 200:531–532

    Article  PubMed  Google Scholar 

  • Papadopoulos MC, Manley GT, Krishna S, Verkman AS (2004) Aquaporin-4 facilitates reabsorp-tion of excess fluid in vasogenic brain edema. FASEB J 18:1291–3

    PubMed  CAS  Google Scholar 

  • Peters MF, O'Brien KF, Sadoulet-Puccio HM, Kunkel LM, Adams ME, Froehner SC (1997) beta-dystrobrevin, a new member of the dystrophin family. Identification, cloning, and protein associations. J Biol Chem 272:31561–31569

    Article  PubMed  CAS  Google Scholar 

  • Rash JE, Yasumura T, Hudson CS, Agre P, Nielsen S (1998) Direct immunogold labeling of aquaporin-4 in square arrays of astrocyte and ependymocyte plasma membranes in rat brain and spinal cord. Proc Natl Acad Sci U S A 95:11981–11986

    Article  PubMed  CAS  Google Scholar 

  • Ribeiro Mde C, Hirt L, Bogousslavsky J, Regli L, Badaut J (2006) Time course of aquaporin expression after transient focal cerebral ischemia in mice. J Neurosci Res 83:1231–1240

    Article  PubMed  CAS  Google Scholar 

  • Rincon F, Mayer SA (2004) Novel therapies for intracerebral hemorrhage. Curr Opin Crit Care 10:94–100

    Article  PubMed  Google Scholar 

  • Saadoun S, Papadopoulos MC, Davies DC, Krishna S, Bell BA (2002) Aquaporin-4 expression is increased in oedematous human brain tumours. J Neurol Neurosurg Psychiatry 72:262–265

    Article  PubMed  CAS  Google Scholar 

  • Saadoun S, Papadopoulos MC, Hara-Chikuma M, Verkman AS (2005a) Impairment of angiogen-esis and cell migration by targeted aquaporin-1 gene disruption. Nature 434:786–792

    Article  CAS  Google Scholar 

  • Saadoun S, Papadopoulos MC, Watanabe H, Yan D, Manley GT, Verkman AS (2005b) Involvement of aquaporin-4 in astroglial cell migration and glial scar formation. J Cell Sci 118:591–598

    Article  CAS  Google Scholar 

  • Satpathy M, Gallagher P, Lizotte-Waniewski M, Srinivas SP (2004) Thrombin-induced phospho-rylation of the regulatory light chain of myosin II in cultured bovine corneal endothelial cells. Exp Eye Res 79:477–486

    Article  PubMed  CAS  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Vajda Z, Pedersen M, Fuchtbauer EM, et al. (2002) Delayed onset of brain edema and mislocaliza-tion of aquaporin-4 in dystrophin-null transgenic mice. Proc Natl Acad Sci U S A 99:13131– 13136

    Article  PubMed  CAS  Google Scholar 

  • Verkman AS (2005) More than just water channels: unexpected cellular roles of aquaporins. J Cell Sci 118:3225–3232

    Article  PubMed  CAS  Google Scholar 

  • Wang X, Mori T, Sumii T, Lo EH (2002) Hemoglobin-induced cytotoxicity in rat cerebral cortical neurons: caspase activation and oxidative stress. Stroke 33:1882–1888

    Article  PubMed  CAS  Google Scholar 

  • Weis SM, Cheresh DA (2005) Pathophysiological consequences of VEGF-induced vascular permeability. Nature 437:497–504

    Article  PubMed  CAS  Google Scholar 

  • Worton R (1995) Muscular dystrophies: diseases of the dystrophin-glycoprotein complex. Science (New York, NY) 270:755–756

    CAS  Google Scholar 

  • Xi G, Keep RF, Hoff JT (2006) Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol 5:53–63

    Article  PubMed  Google Scholar 

  • 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

    Article  PubMed  CAS  Google Scholar 

  • Zador Z, Bloch O, Yao X, Manley GT (2007) Aquaporins: role in cerebral edema and brain water balance. Prog Brain Res 161:185–194

    Article  PubMed  CAS  Google Scholar 

  • Zsolt Zador MD, Xiaoming Yao MD, Ph.D., and Geoffrey T Manley MD, Ph.D. Role of Aqua-porins in Non-synaptic Mechanisms of EpilepsyEncyclopedia of Basic Epilepsy ResearchEd. Schwartzkroin, P., Elsevier, Amsterdam (In Press)

    Google Scholar 

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Authors and Affiliations

  1. Department of Neurological Surgery, University of California, San Francisco, 1001 Potrero Avenue, Room 101, San Francisco, CA 94110, USA

    Zsolt Zador, Shirley Stiver, Vincent Wang & Geoffrey T. Manley

Authors
  1. Zsolt Zador
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  2. Shirley Stiver
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  3. Vincent Wang
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  4. Geoffrey T. Manley
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Corresponding author

Correspondence to Geoffrey T. Manley .

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Editors and Affiliations

  1. Pharmazeutisches Inst., Universität Kiel, Gutenbergstr. 76, Kiel, 24118, Germany

    Eric Beitz

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Zador, Z., Stiver, S., Wang, V., Manley, G.T. (2009). Role of Aquaporin-4 in Cerebral Edema and Stroke. In: Beitz, E. (eds) Aquaporins. Handbook of Experimental Pharmacology, vol 190. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-540-79885-9_7

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