Journal of Neural Transmission

, Volume 118, Issue 1, pp 87–114 | Cite as

Cardiac arrest-induced regional blood–brain barrier breakdown, edema formation and brain pathology: a light and electron microscopic study on a new model for neurodegeneration and neuroprotection in porcine brain

  • Hari Shanker Sharma
  • Adriana Miclescu
  • Lars Wiklund
Original Article


Brief cardiac arrest and survival is often associated with marked neurological alterations related to cognitive and sensory motor functions. However, detail studies using selective vulnerability of brain after cardiac arrest in animal models are still lacking. We examined selective vulnerability of five brain regions in our well-established cardiac arrest model in pigs. Using light and electron microscopic techniques in combinations with immunohistochemistry, we observed that 5, 30, 60 and 180 min after cardiac arrest results in progressive neuronal damage that was most marked in the thalamus followed by cortex, hippocampus, hypothalamus and the brain stem. The neuronal damages are largely evident in the areas showing leakage of serum albumin in the neuropil. Furthermore, a tight correlation was seen between neuronal damage and increase in brain water content and Na+ indicating vasogenic edema formation after cardiac arrest. Damage to myelinated fibers and loss of myelin as seen using Luxol fast blue and myelin basic protein (MBP) immunoreactivity is clearly evident in the brain areas exhibiting neuronal damage. Upregulation of GFAP positive astrocytes closely corresponds with neuronal damages in different brain areas after cardiac arrest. At the ultrastructural level, perivascular edema together with neuronal, glial and endothelia cell damages is frequent in the brain areas showing albumin leakage. Damage to both pre- and post-synaptic membrane is also common. Treatment with methylene blue, an antioxidant markedly reduced neuronal damage, leakage of albumin, overexpression of GFAP and damage to myelin following cardiac arrest. Taken together, these observations suggest that (a) cardiac arrest is capable to induce selective neuronal, glial and myelin damage in different parts of the pig brain, and (b) antioxidant methylene blue is capable to induce neuroprotection by reducing BBB disruption. These observations strongly suggest that the model could be used to explore new therapeutic agents to enhance neurorepair following cardiac arrest-induced brain damage for therapeutic purposes.


Cardiac arrest Pig brain Neuronal damage Nissl stain Glial changes Astrocytes GFAP Myelin Luxol fast blue Myelin basic protein Edema Ultrastructure Endothelial cells Perivascular edema 



This research is supported by Laerdal Foundation for Acute Medicine, Stavanger, Norway. Authors are grateful to expert reviewers for their suggestions to enlarge Methods and Results sections by providing details and including correlation data in the manuscript. Extended laboratory support by Ranjana Patnaik and José Vicente Lafuente; technical assistance of Mari-Anne Carlsson and secretarial assistance of Aruna Sharma is highly appreciated.


  1. Aleu FP, Katzman R, Terry RD (1963) Fine structure and electrolyte analyses of cerebral edema induced by alkyl tin intoxication. J Neuropathol Exp Neurol 22(3):403–413PubMedCrossRefGoogle Scholar
  2. Alpers BJ (1940) Personality and emotional disorders associated with hypothalamic lesions. Psychosom Med I(3)Google Scholar
  3. Atamna H, Kumar R (2010) Protective role of methylene blue in Alzheimer’s disease via mitochondria and cytochrome c oxidase. J Alzheimers Dis 20(Suppl 2):S439–S452PubMedGoogle Scholar
  4. Burns WA (1978) Thick sections: technique and applications. In: Trump BF, Jones RJ (eds) Diagnostic electron microscopy, Chap 4. Wiley, New YorkGoogle Scholar
  5. Cantor JB, Ashman T, Gordon W, Ginsberg A, Engmann C, Egan M et al (2008) Fatigue after traumatic brain injury and its impact on participation and quality of life. J Head Trauma Rehabil 23:41–51PubMedCrossRefGoogle Scholar
  6. Castejón OJ (1985) Electron microscopic study of central axons degeneration in traumatic human brain edema. J Submicrosc Cytol 17(4):703–718PubMedGoogle Scholar
  7. Castejón OJ (2009) The extracellular space in the edematous human cerebral cortex: an electron microscopic study using cortical biopsies. Ultrastruct Pathol 33(3):102–111PubMedCrossRefGoogle Scholar
  8. Castejón OJ, Castejón HV, Zavala M, Sánchez ME, Díaz M (2002) A light and electron microscopic study of oedematous human cerebral cortex in two patients with post-traumatic seizures. Brain Inj 16(4):331–346PubMedCrossRefGoogle Scholar
  9. Castejòn OJ, Valero C, Dìaz M (1995) Synaptic degenerative changes in human traumatic brain edema. An electron microscopic study of cerebral cortical biopsies. J Neurosurg Sci 39(1):47–65PubMedGoogle Scholar
  10. Cervo′s-Navarro J, Turker T, Worthmann F (1994) Morphology of nonvascular intracerebral fluid spaces. Acta Neurochir Suppl (Wien) 60:147–150Google Scholar
  11. Clark G (1973) Staining procedures, 3rd edn. Williams & Wilkins, BaltimoreGoogle Scholar
  12. Clark G (1981) Staining procedures, 4th edn. Williams & Wilkins, Baltimore, p 412Google Scholar
  13. De Vries HE, Kuiper J, de Boer AG, Van Berkel TJ, Breimer DD (1997) The blood–brain barrier in neuroinflammatory diseases. Pharmacol Rev 49:143–155PubMedGoogle Scholar
  14. Deasy C, Bernard SA, Cameron P, Jaison A, Smith K, Harriss L, Walker T, Masci K, Tibballs J (2010) Epidemiology of paediatric out-of-hospital cardiac arrest in Melbourne, Australia. Resuscitation 81:1095–1100PubMedCrossRefGoogle Scholar
  15. Faas FH, Ommaya AK (1968) Brain tissue electrolytes and water content in experimental concussion in the monkey. J Neurosurg 28(2):137–144PubMedCrossRefGoogle Scholar
  16. Félix B, Léger ME, Albe-Fessard D, Marcilloux JC, Rampin O, Laplace JP (1999) Stereotaxic atlas of the pig brain. Brain Res Bull 49(1–2):1–137PubMedCrossRefGoogle Scholar
  17. Fichet J, Dumas F, Charbonneau H, Giovanetti O, Cariou A (2010) What is the outcome of cardiac arrest survivors? Presse Med 39(6):694–700 (in French)PubMedCrossRefGoogle Scholar
  18. Gallyas F, Gasz B, Sziget A, Mázló M (2006) Pathological circumstances impair the ability of “dark” neurons to undergo spontaneous recovery. Brain Res 1110:211–220PubMedCrossRefGoogle Scholar
  19. Gallyas F, Kiglics V, Baracskay P, Juhász G, Czurkó A (2008) The mode of death of epilepsy-induced “dark” neurons is neither necrosis nor apoptosis: an electron-microscopic study. Brain Res 1239:207–215PubMedCrossRefGoogle Scholar
  20. Go KG, Gazendam J, van der Meulen-Woldendorp DA, Teelken AW (1980) Changes of brain extracellular space as reflected by the composition of brain edema fluid. Adv Neurol 28:9–13PubMedGoogle Scholar
  21. Gordh T, Chu H, Sharma HS (2006) Spinal nerve lesion alters blood–spinal cord barrier function and activates astrocytes in the rat. Pain 124(1–2):211–221PubMedCrossRefGoogle Scholar
  22. Graeber MB, Moran LB (2002) Mechanism of cell death in neurodegenerative diseases: fashion, fiction and facts. Brain Pathol 12:385–390PubMedCrossRefGoogle Scholar
  23. Hirano A, Kawanami T, Llena JF (1994) Electron microscopy of the blood–brain barrier in disease. Microsc Res Tech 27(6):543–556 (review)PubMedCrossRefGoogle Scholar
  24. Hochstenbach JB, Anderson PG, van Limbeek J, Mulder TT (2001) Is there a relation between neuropsychologic variables and quality of life after stroke? Arch Phys Med Rehabil 82:1360–1366PubMedCrossRefGoogle Scholar
  25. Hof PR, Cox K, Young WG, Celio MR, Rogers J, Morrison JH (1991) Parvalbumin-immunoreactive neurons in the neocortex are resistant to degeneration in Alzheimer’s disease. J Neuropathol Exp Neurol 50(4):451–462PubMedCrossRefGoogle Scholar
  26. Jones EG (2007) The thalamus. Cambridge University Press, CambridgeGoogle Scholar
  27. Jones EG (2009) Synchrony in the interconnected circuitry of the thalamus and cerebral cortex. Ann N Y Acad Sci 1157:10–23 (review)PubMedCrossRefGoogle Scholar
  28. Joó F, Klatzo I (1989) Role of cerebral endothelium in brain oedema. Neurol Res 11(2):67–75 ReviewPubMedGoogle Scholar
  29. Kitamura T, Iwami T, Kawamura T, Nagao K, Tanaka H, Hiraide A (2010) Implementation Working Group for All-Japan Utstein Registry of the Fire and Disaster Management Agency Bystander-initiated rescue breathing for out-of-hospital cardiac arrests of noncardiac origin. Circulation 122(3):293–299PubMedCrossRefGoogle Scholar
  30. Kiyatkin EA, Sharma HS (2009) Permeability of the blood–brain barrier depends on brain temperature. Neuroscience 161(3):926–939PubMedCrossRefGoogle Scholar
  31. Kiyatkin EA, Brown PL, Sharma HS (2007) Brain edema and breakdown of the blood–brain barrier during methamphetamine intoxication: critical role of brain hyperthermia. Eur J Neurosci 26(5):1242–1253PubMedCrossRefGoogle Scholar
  32. Klatzo I (1967) Presidental address. Neuropathological aspects of brain edema. J Neuropathol Exp Neurol 26(1):1–14 ReviewPubMedCrossRefGoogle Scholar
  33. Kluver H, Barrera E (1953) A method for the combined staining of cells and fibers in the Nervous system. J Neuropathol Exp Neurol 12:400–403Google Scholar
  34. Kuroiwa T, Shibutani M, Okeda R (1988) Blood–brain barrier disruption and exacerbation of ischemic brain edema after restoration of blood flow in experimental focal cerebral ischemia. Acta Neuropathol 76(1):62–70PubMedCrossRefGoogle Scholar
  35. Lennon VA, Wilks AV, Carnegie PR (1971) Immunologic properties of the main encephalitogenic peptide from the basic protein of human myelin. J Immunol 105(5):1223–1230Google Scholar
  36. Liu DZ, Ander BP, Xu H, Shen Y, Kaur P, Deng W, Sharp FR (2010) Blood–brain barrier breakdown and repair by Src after thrombin-induced injury. Ann Neurol 67(4):526–533PubMedCrossRefGoogle Scholar
  37. Løberg EM, Torvik A (1991) Uptake of plasma proteins into damaged neurons. An experimental study on cryogenic lesions in rats. Acta Neuropathol 81(5):479–485PubMedCrossRefGoogle Scholar
  38. Løberg EM, Torvik A (1992) Neuronal uptake of plasma proteins in brain contusions. An immunohistochemical study. Acta Neuropathol 84(3):234–237PubMedCrossRefGoogle Scholar
  39. Löffler S, Wurm A, Kutzera F, Pannicke T, Krügel K, Linnertz R, Wiedemann P, Reichenbach A, Bringmann A (2010) Serum albumin induces osmotic swelling of rat retinal glial cells. Brain Res 1317:268–276PubMedCrossRefGoogle Scholar
  40. Long DM, Hartmann JF, French LA (1966) The ultrastructure of human cerebral edema. J Neuropathol Exp Neurol 25(3):373–395PubMedCrossRefGoogle Scholar
  41. Majno G (1955) Ultrastructure of thc vascular mcmbrane. In: Hamilton WF (ed) Handbook of physiology, vol 3, Sect 2. American Physiological Society, Washington, DC, pp 2293–2375Google Scholar
  42. Miclescu A, Sharma HS, Martijn C, Wiklund L (2010) Methylene blue protects the cortical blood–brain barrier against ischemia/reperfusion-induced disruptions. Crit Care Med [Epub ahead of print]Google Scholar
  43. Middelkamp W, Moulaert VR, Verbunt JA, van Heugten CM, Bakx WG, Wade DT (2007) Life after survival: long-term daily life functioning and quality of life of patients with hypoxic brain injury as a result of a cardiac arrest. Clin Rehabil 21(5):425–431PubMedCrossRefGoogle Scholar
  44. Moulaert VR, Verbunt JA, van Heugten CM, Wade DT (2009) Cognitive impairments in survivors of out-of-hospital cardiac arrest: a systematic review. Resuscitation 80(3):297–305PubMedCrossRefGoogle Scholar
  45. Moulaert VR, Wachelder EM, Verbunt JA, Wade DT, van Heugten CM (2010) Determinants of quality of life in survivors of cardiac arrest. J Rehabil Med 42(6):553–558PubMedCrossRefGoogle Scholar
  46. Muresanu DF, Sharma A, Sharma HS (2010) Diabetes aggravates heat stress-induced blood–brain barrier breakdown, reduction in cerebral blood flow, edema formation, and brain pathology: possible neuroprotection with growth hormone. Ann N Y Acad Sci 1199:15–26PubMedCrossRefGoogle Scholar
  47. Myerburg RJ, Kessler KM, Castellanos A (1993) Sudden cardiac death: epidemiology, transient risk, and intervention assessment. Ann Intern Med 119:1187–1197PubMedGoogle Scholar
  48. Nissl F (1894) Ueber eine neue Untersuchungsmethode des Centralorgans zur Feststellung der Localisation der Nervenzellen. Neurologisches Centralblatt Leipzig 13:507–508Google Scholar
  49. Ooigawa H, Nawashiro H, Fukui S, Otani N, Osumi A, Toyooka T, Shima K (2006) The fate of Nissl-stained dark neurons following traumatic brain injury in rats: difference between neocortex and hippocampus regarding survival rate. Acta Neuropathol 112(4):471–481 [Epub 21 Jul 2006]PubMedCrossRefGoogle Scholar
  50. Percheron G (1982) The arterial supply of the thalamus. In: Schaltenbrand G, Walker AE (eds) Stereotaxy of the human brain. Thieme, Stuttgart, pp 218–232Google Scholar
  51. Percheron G (2003) Thalamus. In: Paxinos G, May J (eds) The human nervous system, 2nd edn. Elsevier, Amsterdam, pp 592–675Google Scholar
  52. Prohl J, Bodenburg S, Rustenbach SJ (2009) Early prediction of long-term cognitive impairment after cardiac arrest. J Int Neuropsychol Soc 15(3):344–353PubMedCrossRefGoogle Scholar
  53. Rapoport SI (1976) Blood–brain barrier in physiology and medicine. Raven Press, New York, pp 1–316Google Scholar
  54. Rea TD, Eisenberg MS, Sinibaldi G, White RD (2004) Incidence of EMS-treated out-of-hospital cardiac arrest in the United States. Resuscitation 63:17–24PubMedCrossRefGoogle Scholar
  55. Reed DJ, Woodbury DM, Holtzer RL (1964) Brain edema, electrolytes, and extracellular space. Effect of triethyl tin on brain and skeletal muscle. Arch Neurol 10(6):604–616PubMedGoogle Scholar
  56. Rojas JC, Simola N, Kermath BA, Kane JR, Schallert T, Gonzalez-Lima F (2009) Striatal neuroprotection with methylene blue. Neuroscience 163(3):877–889PubMedCrossRefGoogle Scholar
  57. Salahuddin TS, Kalimo H, Johansson BB, Olsson Y (1988a) Observations on exsudation of fibronectin, fibrinogen and albumin in the brain after carotid infusion of hyperosmolar solutions. An immunohistochemical study in the rat indicating longlasting changes in the brain microenvironment and multifocal nerve cell injuries. Acta Neuropathol 76(1):1–10 (review)PubMedCrossRefGoogle Scholar
  58. Salahuddin TS, Johansson BB, Kalimo H, Olsson Y (1988b) Structural changes in the rat brain after carotid infusions of hyperosmolar solutions: a light microscopic and immunohistochemical study. Neuropathol Appl Neurobio 14(6):467–482Google Scholar
  59. Schmahmann JD (2003) Vascular syndromes of the thalamus. Stroke 34:2264–2278PubMedCrossRefGoogle Scholar
  60. Schmidt-Kastner R, Heim C, Sontag KH (1991) Damage of substantia nigra pars reticulata during pilocarpine-induced status epilepticus in the rat: immunohistochemical study of neurons, astrocytes and serum-protein extravasation. Exp Brain Res 86(1):125–140PubMedCrossRefGoogle Scholar
  61. Schuier FJ, Hossmann KA (1980) Experimental brain infarcts in cats II Ischemic brain edema. Stroke 11(6):593–601PubMedGoogle Scholar
  62. Sharma HS (2006) Hyperthermia influences excitatory and inhibitory amino acid neurotransmitters in the central nervous system. An experimental study in the rat using behavioural, biochemical, pharmacological, and morphological approaches. J. Neural Transm 113(4):497–519PubMedCrossRefGoogle Scholar
  63. Sharma HS (2009) Blood–central nervous system barriers: the gateway to neurodegeneration, neuroprotection and neuroregeneration. Handbook of neurochemistry and molecular neurobiology, pp 363–457. doi: 10.1007/978-0-387-30375-8_17
  64. Sharma HS, Ali SF (2006) Alterations in blood–brain barrier function by morphine and methamphetamine. Ann N Y Acad Sci 1074:198–224PubMedCrossRefGoogle Scholar
  65. Sharma HS, Ali SF (2008) Acute administration of 3, 4-methylenedioxymethamphetamine induces profound hyperthermia, blood–brain barrier disruption, brain edema formation, and cell injury. Ann N Y Acad Sci 1139:242–258PubMedCrossRefGoogle Scholar
  66. Sharma HS, Cervós-Navarro J (1990) Brain oedema and cellular changes induced by acute heat stress in young rats. Acta Neurochir Suppl (Wien) 51:383–386Google Scholar
  67. Sharma HS, Johanson CE (2007) Blood–cerebrospinal fluid barrier in hyperthermia. Prog Brain Res 162:459–478 (review)PubMedCrossRefGoogle Scholar
  68. Sharma HS, Kiyatkin EA (2009) Rapid morphological brain abnormalities during acute methamphetamine intoxication in the rat: an experimental study using light and electron microscopy. J Chem Neuroanat 37(1):18–32PubMedCrossRefGoogle Scholar
  69. Sharma HS, Olsson Y (1990) Edema formation and cellular alterations following spinal cord injury in the rat and their modification with p-chlorophenylalanine. Acta Neuropathol 79(6):604–610PubMedCrossRefGoogle Scholar
  70. Sharma HS, Sharma A (2010) Breakdown of the blood–brain barrier in stress alters cognitive dysfunction and induces brain pathology. New perspective for neuroprotective strategies. In: Ritsner M (ed) Brain protection in schizophrenia, mood and cognitive disorders. Springer-Verlag, Berlin, pp 243–304Google Scholar
  71. Sharma HS, Olsson Y, Dey PK (1990) Changes in blood–brain barrier and cerebral blood flow following elevation of circulating serotonin level in anesthetized rats. Brain Res 517(1–2):215–223Google Scholar
  72. Sharma HS, Wiklund L (2010a) Cardiac arrest induces selective myelin degradation in the brain. An experimental study using light and electron microscopy in the piglet. J Chem Neuronan (to be published)Google Scholar
  73. Sharma HS, Wiklund (2010b) Selective vulnerability of astrocytes in the brain following acute cardiac arrest in piglets. An experimental study using biochemical and morphological approaches (to be published)Google Scholar
  74. Sharma HS, Cervós-Navarro J, Dey PK (1991) Acute heat exposure causes cellular alteration in cerebral cortex of young rats. Neuroreport 2(3):155–158PubMedCrossRefGoogle Scholar
  75. Sharma HS, Zimmer C, Westman J, Cervós-Navarro J (1992a) Acute systemic heat stress increases glial fibrillary acidic protein immunoreactivity in brain: experimental observations in conscious normotensive young rats. Neuroscience 48(4):889–901PubMedCrossRefGoogle Scholar
  76. Sharma HS, Kretzschmar R, Cervós-Navarro J, Ermisch A, Rühle HJ, Dey PK (1992b) Age-related pathophysiology of the blood–brain barrier in heat stress. Prog Brain Res 91:189–196PubMedCrossRefGoogle Scholar
  77. Sharma HS, Olsson Y, Cervós-Navarro J (1993a) p-Chlorophenylalanine, a serotonin synthesis inhibitor, reduces the response of glial fibrillary acidic protein induced by trauma to the spinal cord. An immunohistochemical investigation in the rat. Acta Neuropathol 86(5):422–427PubMedCrossRefGoogle Scholar
  78. Sharma HS, Olsson Y, Cervós-Navarro J (1993b) Early perifocal cell changes and edema in traumatic injury of the spinal cord are reduced by indomethacin, an inhibitor of prostaglandin synthesis. Experimental study in the rat. Acta Neuropathol 85(2):145–153PubMedCrossRefGoogle Scholar
  79. Sharma HS, Westman J, Nyberg F (1998) Pathophysiology of brain edema and cell changes following hyperthermic brain injury. Prog Brain Res 115:351–412 (review)PubMedCrossRefGoogle Scholar
  80. Sharma HS, Muresanu D, Sharma A, Patnaik R (2009a) Cocaine-induced breakdown of the blood–brain barrier and neurotoxicity. Int Rev Neurobiol 88:297–334 (review)PubMedCrossRefGoogle Scholar
  81. Sharma HS, Ali SF, Hussain SM, Schlager JJ, Sharma A (2009b) Influence of engineered nanoparticles from metals on the blood–brain barrier permeability, cerebral blood flow, brain edema and neurotoxicity. An experimental study in the rat and mice using biochemical and morphological approaches. J Nanosci Nanotechnol 9(8):5055–5072PubMedCrossRefGoogle Scholar
  82. Sharma HS, Ali SF, Tian ZR, Hussain SM, Schlager JJ, Sjöquist PO, Sharma A, Muresanu DF (2009c) Chronic treatment with nanoparticles exacerbate hyperthermia induced blood–brain barrier breakdown, cognitive dysfunction and brain pathology in the rat. Neuroprotective effects of nanowired-antioxidant compound H-290/51. J. Nanosci Nanotechnol 9(8):5073–5090PubMedCrossRefGoogle Scholar
  83. Sharma HS, Patnaik R, Sharma A, Sjöquist PO, Lafuente JV (2009d) Silicon dioxide nanoparticles (SiO2, 40–50 nm) exacerbate pathophysiology of traumatic spinal cord injury and deteriorate functional outcome in the rat. An experimental study using pharmacological and morphological approaches. J. Nanosci Nanotechnol 9(8):4970–4980PubMedCrossRefGoogle Scholar
  84. Sharma HS, Zimmermann-Meinzingen S, Johanson CE (2010) Cerebrolysin reduces blood–cerebrospinal fluid barrier permeability change, brain pathology, and functional deficits following traumatic brain injury in the rat. Ann N Y Acad Sci 1199:125–137PubMedCrossRefGoogle Scholar
  85. Shlosberg D, Benifla M, Kaufer D, Friedman A (2010) Medscape. Blood–brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat Rev Neurol 6(7):393–403PubMedCrossRefGoogle Scholar
  86. Sokrab TE, Johansson BB, Kalimo H, Olsson Y (1988) A transient hypertensive opening of the blood–brain barrier can lead to brain damage. Extravasation of serum proteins and cellular changes in rats subjected to aortic compression. Acta Neuropathol 75(6):557–565PubMedCrossRefGoogle Scholar
  87. Stalnacke BM (2007) Community integration, social support and life satisfaction in relation to symptoms 3 years after mild traumatic brain injury. Brain Inj 21:933–942PubMedCrossRefGoogle Scholar
  88. Steriade M, Llinas R (1988) The functional states of the thalamus and the associated neuronal interplay. Physiol Rev 68:699–742Google Scholar
  89. Tanaka J, Garcia JH, Max SR, Viloria JE, Kamijyo Y, McLaren NK, Cornblath M, Brady RO (1975) Cerebral sponginess and GM3 gangliosidosis; ultrastructure and probable pathogenesis. J Neuropathol Exp Neurol 34(3):249–262PubMedCrossRefGoogle Scholar
  90. Teschendorf P, Albertsmeier M, Vogel P, Padosch SA, Spöhr F, Kirschfink M, Schwaninger M, Böttiger BW, Popp E (2008) Neurological outcome and inflammation after cardiac arrest–effects of protein C in rats. Resuscitation 79(2):316–324 [Epub 2008 Jul 14]PubMedCrossRefGoogle Scholar
  91. Tomaselli GF, Barth AS (2010) Sudden cardio arrest: oxidative stress irritates the heart. Nat Med 16(6):648–649PubMedCrossRefGoogle Scholar
  92. Vaillancourt C, Stiell IG (2004) Canadian Cardiovascular Outcomes Research Team Cardiac arrest care and emergency medical services in Canada. Can J Cardiol 20:1081–1090PubMedGoogle Scholar
  93. van de Port IG, Kwakkel G, Schepers VP, Heinemans CT, Lindeman E (2007) Is fatigue an independent factor associated with activities of daily living, instrumental activities of daily living and health-related quality of life in chronic stroke? Cerebrovasc Dis 23:40–45PubMedCrossRefGoogle Scholar
  94. Visser-Meily JM, Rhebergen ML, Rinkel GJ, van Zandvoort MJ, Post MW (2009) Long-term health-related quality of life after aneurismal subarachnoid hemorrhage. Relationship with psychological symptoms and personality characteristics. Stroke 40:1526–1529PubMedCrossRefGoogle Scholar
  95. Wachelder EM, Moulaert VR, van Heugten C, Verbunt JA, Bekkers SC, Wade DT (2009) Life after survival: long-term daily functioning and quality of life after an out-of-hospital cardiac arrest. Resuscitation 80(5):517–522PubMedCrossRefGoogle Scholar
  96. Wagner KR, Dean C, Beiler S, Bryan DW, Packard BA, Smulian AG, Linke MJ, de Courten-Myers GM (2005) Plasma infusions into porcine cerebral white matter induce early edema, oxidative stress, pro-inflammatory cytokine gene expression and DNA fragmentation: implications for white matter injury with increased blood–brain-barrier permeability. Curr Neurovasc Res 2(2):149–155PubMedCrossRefGoogle Scholar
  97. Ward JD, Hadfield MG, Becker DP, Lovings ET (1974) Endothelial fenestrations and other vascular alterations in primary melanoma of the central nervous system. Cancer 34:1982–1991PubMedCrossRefGoogle Scholar
  98. Wiklund L, Sharma HS, Basu S (2005) Circulatory arrest as a model for studies of global ischemic injury and neuroprotection. Ann N Y Acad Sci 1053:205–219PubMedCrossRefGoogle Scholar
  99. Wiklund L, Basu S, Miclescu A, Wiklund P, Ronquist G, Sharma HS (2007) Neuro- and cardioprotective effects of blockade of nitric oxide action by administration of methylene blue. Ann N Y Acad Sci 1122:231–244 (review)PubMedCrossRefGoogle Scholar
  100. Wiltgen BJ, Zhou M, Cai Y, Balaji J, Karlsson MG, Parivash SN, Li W, Silva AJ (2010) The hippocampus plays a selective role in the retrieval of detailed contextual memories. Curr Biol 20(15):1336–1344PubMedCrossRefGoogle Scholar
  101. Wiśniewski HM, Maślińska D (1996) Beta-protein immunoreactivity in the human brain after cardiac arrest. Folia Neuropathol 34(2):65–71PubMedGoogle Scholar
  102. Xiao D, Zikopoulos B, Barbas H (2009) Laminar and modular organization of prefrontal projections to multiple thalamic nuclei. Neuroscience. 161(4):1067–1081PubMedCrossRefGoogle Scholar
  103. Zador Z, Stiver S, Wang V, Manley GT (2009) Role of aquaporin-4 in cerebral edema and stroke. Handb Exp Pharmacol 190:159–170 (review)PubMedCrossRefGoogle Scholar
  104. Zhang X, Rojas JC, Gonzalez-Lima F (2006) Methylene blue prevents neurodegeneration caused by rotenone in the retina. Neurotox Res 9(1):47–57PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Hari Shanker Sharma
    • 1
    • 2
  • Adriana Miclescu
    • 1
  • Lars Wiklund
    • 1
  1. 1.Laboratory of Cerebrovascular Research, Department of Surgical Sciences, Anesthesiology and Intensive Care MedicineUniversity HospitalUppsalaSweden
  2. 2.Docent in NeuroanatomyUppsala UniversityUppsalaSweden

Personalised recommendations