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Drug Delivery in the Context of Stroke and Brain Trauma

  • Richard F. Keep
  • Jianming Xiang
  • Ningna Zhou
  • Anuska V. Andjelkovic
Chapter
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 10)

Abstract

Stroke and traumatic brain injury (TBI) cause marked changes in blood–brain barrier (BBB) function. These changes result in increased barrier permeability, vasogenic edema, and an influx of leukocytes into brain. As such, they are a therapeutic target. In addition, changes at the BBB can affect the entry of therapeutics into the brain. This chapter describes the changes in BBB function that occur after brain injury, the impact on drug delivery for stroke and TBI and potential ways of circumventing the BBB for therapy.

Keywords

Traumatic Brain Injury Cerebral Ischemia Cerebral Endothelium Tight Junction Structure Small Molecular Weight Compound 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Abbreviations

ABC transporters

ATP-binding cassette transporters

BBB

Blood–brain barrier

BDNF

Brain-derived neurotrophic factor

bFGF

Basic fibroblast growth factor

CSF

Cerebrospinal fluid

ICH

Intracerebral hemorrhage

IVH

Intraventricular hemorrhage

KO

Knockout

SAH

Subarachnoid hemorrhage

SVCT2

Na-dependent Vitamin C Transporter 2

TBI

Traumatic brain injury

TJ

Tight junction

tPA

Tissue plasminogen activator

Notes

Acknowledgments

This study was supported by grants NS-034709 (RFK), NS 062853 (AVA), and NS075757 (AVA) from the National Institutes of Health (NIH) and a grant from the Motor City Golf Classic (JX). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

References

  1. Abbott NJ, Patabendige AAK, Dolman DEM, Yusof SR, Begley DJ (2010) Structure and function of the blood–brain barrier. Neurobiol Dis 37:13–25PubMedGoogle Scholar
  2. Adeoye O, Broderick JP (2010) Advances in the management of intracerebral hemorrhage. Nat Rev Neurol 6:593–601PubMedGoogle Scholar
  3. Akpan N, Serrano-Saiz E, Zacharia BE, Otten ML, Ducruet AF, Snipas SJ, Liu W, Velloza J, Cohen G, Sosunov SA, Frey WH 2nd, Salvesen GS, Connolly ES Jr, Troy CM (2011) Intranasal delivery of caspase-9 inhibitor reduces caspase-6-dependent axon/neuron loss and improves neurological function after stroke. J Neurosci 31:8894–8904PubMedCentralPubMedGoogle Scholar
  4. Alexandrov AV (2010) Current and future recanalization strategies for acute ischemic stroke. J Intern Med 267:209–219PubMedGoogle Scholar
  5. Anonymous (1995) Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med 333:1581–1587Google Scholar
  6. Bauer B, Hartz AMS, Fricker G, Miller DS (2004) Pregnane X receptor up-regulation of P-glycoprotein expression and transport function at the blood–brain barrier. Mol Pharmacol 66:413–419PubMedGoogle Scholar
  7. Bederson JB, Connolly ES Jr, Batjer HH, Dacey RG, Dion JE, Diringer MN, Duldner JE Jr, Harbaugh RE, Patel AB, Rosenwasser RH (2009) Guidelines for the management of aneurysmal subarachnoid hemorrhage: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke 40:994–1025PubMedGoogle Scholar
  8. Bobo RH, Laske DW, Akbasak A, Morrison PF, Dedrick RL, Oldfield EH (1994) Convection-enhanced delivery of macromolecules in the brain. Proc Natl Acad Sci U S A 91:2076–2080PubMedCentralPubMedGoogle Scholar
  9. Bor-Seng-Shu E, Nogueira RDC, Figueiredo EG, Evaristo EF, Conforto AB, Teixeira MJ (2012) Sonothrombolysis for acute ischemic stroke: a systematic review of randomized controlled trials. Neurosurg Focus 32:E5PubMedGoogle Scholar
  10. Borlongan CV, Glover LE, Tajiri N, Kaneko Y, Freeman TB (2011) The great migration of bone marrow-derived stem cells toward the ischemic brain: therapeutic implications for stroke and other neurological disorders. Prog Neurobiol 95:213–228PubMedCentralPubMedGoogle Scholar
  11. Bradford ST, Stamatovic SM, Dondeti RS, Keep RF, Andjelkovic AV (2011) Nicotine aggravates the brain postischemic inflammatory response. Am J Physiol - Heart Circ Physiol 300:H1518–H1529PubMedGoogle Scholar
  12. Burns TC, Verfaillie CM, Low WC (2009) Stem cells for ischemic brain injury: a critical review. J Comp Neurol 515:125–144PubMedGoogle Scholar
  13. Cordonnier C, van der Flier WM (2011) Brain microbleeds and Alzheimer's disease: innocent observation or key player? Brain 134:335–344PubMedGoogle Scholar
  14. del Zoppo GJ (2010) Acute anti-inflammatory approaches to ischemic stroke. Ann N Y Acad Sci 1207:143–148PubMedGoogle Scholar
  15. Denes A, Ferenczi S, Kovacs KJ (2011) Systemic inflammatory challenges compromise survival after experimental stroke via augmenting brain inflammation, blood- brain barrier damage and brain oedema independently of infarct size. J Neuroinflam 8:164Google Scholar
  16. Dietrich WD, Prado R, Watson BD, Nakayama H (1988) Middle cerebral artery thrombosis: acute blood–brain barrier consequences. J Neuropathol Experimental Neurol 47:443–451Google Scholar
  17. Dimitrijevic OB, Stamatovic SM, Keep RF, Andjelkovic AV (2006) Effects of the chemokine CCL2 on blood–brain barrier permeability during ischemia-reperfusion injury. J Cereb Blood Flow Metab 26:797–810PubMedGoogle Scholar
  18. el-Bacha RS, Minn A (1999) Drug metabolizing enzymes in cerebrovascular endothelial cells afford a metabolic protection to the brain. Cell Mol Biol 45:15–23PubMedGoogle Scholar
  19. Ennis SR, Keep RF (2006) The effects of cerebral ischemia on the rat choroid plexus. J Cereb Blood Flow Metab 26:675–683PubMedGoogle Scholar
  20. Ennis SR, Keep RF (2007) Effect of sustained-mild and transient-severe hyperglycemia on ischemia-induced blood–brain barrier opening. J Cereb Blood Flow Metab 27:1573–1582PubMedGoogle Scholar
  21. Etminan N, Vergouwen MDI, Ilodigwe D, Macdonald RL (2011) Effect of pharmaceutical treatment on vasospasm, delayed cerebral ischemia, and clinical outcome in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis. J Cereb Blood Flow Metab 31:1443–1451PubMedGoogle Scholar
  22. Fernandez-Lopez D, Faustino J, Daneman R, Zhou L, Lee SY, Derugin N, Wendland MF, Vexler ZS (2012) Blood–brain barrier permeability is increased after acute adult stroke but not neonatal stroke in the rat. J Neurosci 32:9588–9600PubMedGoogle Scholar
  23. Finkelstein RA, Alam HB (2010) Induced hypothermia for trauma: current research and practice. J Intensive Care Med 25:205–226PubMedGoogle Scholar
  24. Fisher M, Meadows ME, Do T, Weise J, Trubetskoy V, Charette M, Finklestein SP (1995) Delayed treatment with intravenous basic fibroblast growth factor reduces infarct size following permanent focal cerebral ischemia in rats. J Cereb Blood Flow Metab 15:953–959PubMedGoogle Scholar
  25. Gess B, Sevimli S, Strecker J-K, Young P, Schabitz W-R (2011) Sodium-dependent vitamin C transporter 2 (SVCT2) expression and activity in brain capillary endothelial cells after transient ischemia in mice. PLoS ONE [Electronic Resource] 6:e17139Google Scholar
  26. Ghersi-Egea J-F, Strazielle N, Murat A, Jouvet A, Buenerd A, Belin M-F (2006) Brain protection at the blood-cerebrospinal fluid interface involves a glutathione-dependent metabolic barrier mechanism. J Cereb Blood Flow Metab 26:1165–1175PubMedGoogle Scholar
  27. Gomes JA, Stevens RD, Lewin JJ 3rd, Mirski MA, Bhardwaj A (2005) Glucocorticoid therapy in neurologic critical care. Crit Care Med 33:1214–1224PubMedGoogle Scholar
  28. Haar PJ, Broaddus WC, Chen Z-J, Fatouros PP, Gillies GT, Corwin FD (2010) Quantification of convection-enhanced delivery to the ischemic brain. Physiol Meas 31:1075–1089PubMedGoogle Scholar
  29. Hanson LR, Frey WH 2nd (2008) Intranasal delivery bypasses the blood–brain barrier to target therapeutic agents to the central nervous system and treat neurodegenerative disease. BMC Neurosci 9 Suppl 3:S5PubMedGoogle Scholar
  30. Hawkins BT, Davis TP (2005) The blood–brain barrier/neurovascular unit in health and disease. Pharmacol Rev 57:173–185PubMedGoogle Scholar
  31. Heile A, Brinker T (2011) Clinical translation of stem cell therapy in traumatic brain injury: the potential of encapsulated mesenchymal cell biodelivery of glucagon-like peptide-1. Dialogues Clin Neurosci 13:279–286PubMedCentralPubMedGoogle Scholar
  32. Herve F, Ghinea N, Scherrmann J-M (2008) CNS delivery via adsorptive transcytosis. AAPS J 10:455–472PubMedGoogle Scholar
  33. Higashida T, Kreipke CW, Rafols JA, Peng C, Schafer S, Schafer P, Ding JY, Dornbos D 3rd, 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 114:92–101PubMedGoogle Scholar
  34. Hollt V, Kouba M, Dietel M, Vogt G (1992) Stereoisomers of calcium antagonists which differ markedly in their potencies as calcium blockers are equally effective in modulating drug transport by P-glycoprotein. Biochem Pharmacol 43:2601–2608PubMedGoogle Scholar
  35. Hrabetova S, Hrabe J, Nicholson C (2003) Dead-space microdomains hinder extracellular diffusion in rat neocortex during ischemia. J Neurosci 23:8351–8359PubMedGoogle Scholar
  36. Iadecola C, Anrather J (2011) The immunology of stroke: from mechanisms to translation. Nat Med 17:796–808PubMedCentralPubMedGoogle Scholar
  37. Jenny B, Kanemitsu M, Tsupykov O, Potter G, Salmon P, Zgraggen E, Gascon E, Skibo G, Dayer AG, Kiss JZ (2009) Fibroblast growth factor-2 overexpression in transplanted neural progenitors promotes perivascular cluster formation with a neurogenic potential. Stem Cells 27:1309–1317PubMedGoogle Scholar
  38. Jiao H, Wang Z, Liu Y, Wang P, Xue Y (2011) Specific role of tight junction proteins claudin-5, occludin, and ZO-1 of the blood–brain barrier in a focal cerebral ischemic insult. J Mol Neurosci 44:130–139PubMedGoogle Scholar
  39. Johanson CE, Palm DE, Primiano MJ, McMillan PN, Chan P, Knuckey NW, Stopa EG (2000) Choroid plexus recovery after transient forebrain ischemia: role of growth factors and other repair mechanisms. Cell Mol Neurobiol 20:197–216PubMedGoogle Scholar
  40. Jones AR, Shusta EV (2007) Blood–brain barrier transport of therapeutics via receptor-mediation. Pharm Res 24:1759–1771PubMedCentralPubMedGoogle Scholar
  41. Jones TH, Morawetz RB, Crowell RM, Marcoux FW, FitzGibbon SJ, DeGirolami U, Ojemann RG (1981) Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurg 54:773–782PubMedGoogle Scholar
  42. Kageyama T, Nakamura M, Matsuo A, Yamasaki Y, Takakura Y, Hashida M, Kanai Y, Naito M, Tsuruo T, Minato N, Shimohama S (2000) The 4F2hc/LAT1 complex transports L-DOPA across the blood–brain barrier. Brain Res 879:115–121PubMedGoogle Scholar
  43. Kago T, Takagi N, Date I, Takenaga Y, Takagi K, Takeo S (2006) Cerebral ischemia enhances tyrosine phosphorylation of occludin in brain capillaries. Biochem Biophys Res Commun 339:1197–1203PubMedGoogle Scholar
  44. Kamouchi M, Ago T, Kuroda J, Kitazono T (2012) The possible roles of brain pericytes in brain ischemia and stroke. Cell Mol Neurobiol 32:159–165PubMedGoogle Scholar
  45. Kawai N, Keep RF, Betz AL (1997) Hyperglycemia and the vascular effects of cerebral ischemia. Stroke 28:149–154PubMedGoogle Scholar
  46. Kawai N, Stummer W, Ennis SR, Betz AL, Keep RF (1999) Blood–brain barrier glutamine transport during normoglycemic and hyperglycemic focal cerebral ischemia. J Cereb Blood Flow Metab 19:79–86PubMedGoogle Scholar
  47. Keep RF, Xiang J, Ennis SR, Andjelkovic A, Hua Y, Xi G, Hoff JT (2008) Blood–brain barrier function in intracerebral hemorrhage. Acta Neurochirurgica - Supplement 105:73–77PubMedGoogle Scholar
  48. Kernie SG, Parent JM (2010) Forebrain neurogenesis after focal Ischemic and traumatic brain injury. Neurobiol Dis 37:267–274PubMedCentralPubMedGoogle Scholar
  49. Kleinschnitz C, Blecharz K, Kahles T, Schwarz T, Kraft P, Gobel K, Meuth SG, Burek M, Thum T, Stoll G, Forster C (2011) Glucocorticoid insensitivity at the hypoxic blood–brain barrier can be reversed by inhibition of the proteasome. Stroke 42:1081–1089PubMedGoogle Scholar
  50. Kwon I, Kim EH, del Zoppo GJ, Heo JH (2009) Ultrastructural and temporal changes of the microvascular basement membrane and astrocyte interface following focal cerebral ischemia. J Neurosci Res 87:668–676PubMedCentralPubMedGoogle Scholar
  51. Leary MC, Saver JL (2003) Annual incidence of first silent stroke in the United States: a preliminary estimate. Cerebrovasc Dis 16:280–285PubMedGoogle Scholar
  52. Li Y, Chopp M (2009) Marrow stromal cell transplantation in stroke and traumatic brain injury. Neurosci Lett 456:120–123PubMedCentralPubMedGoogle Scholar
  53. Lippmann ES, Azarin SM, Kay JE, Nessler RA, Wilson HK, Al-Ahmad A, Palecek SP, Shusta EV (2012) Derivation of blood–brain barrier endothelial cells from human pluripotent stem cells. Nat Biotechnol 30:783–791PubMedCentralPubMedGoogle Scholar
  54. Liu XD, Zhang L, Xie L (2003) Effect of P-glycoprotein inhibitors erythromycin and cyclosporin A on brain pharmacokinetics of nimodipine in rats. Eur J Drug Metab Pharmacokinet 28:309–313PubMedGoogle Scholar
  55. Liu XF, Fawcett JR, Thorne RG, DeFor TA, Frey WH 2nd (2001) Intranasal administration of insulin-like growth factor-I bypasses the blood–brain barrier and protects against focal cerebral ischemic damage. J Neurol Sci 187:91–97PubMedGoogle Scholar
  56. Liu Y, Lu J-B, Ye Z-R (2006) Permeability of injured blood brain barrier for exogenous bFGF and protection mechanism of bFGF in rat brain ischemia. Neuropathology 26:257–266PubMedGoogle Scholar
  57. Maas AI, Stocchetti N, Bullock R (2008) Moderate and severe traumatic brain injury in adults. Lancet Neurol 7:728–741PubMedGoogle Scholar
  58. Mabuchi T, Lucero J, Feng A, Koziol JA, del Zoppo GJ (2005) Focal cerebral ischemia preferentially affects neurons distant from their neighboring microvessels. J Cereb Blood Flow Metab 25:257–266PubMedGoogle Scholar
  59. MacLellan CL, Clark DL, Silasi G, Colbourne F (2009) Use of prolonged hypothermia to treat ischemic and hemorrhagic stroke. J Neurotrauma 26:313–323PubMedGoogle Scholar
  60. McDannold N, Vykhodtseva N, Raymond S, Jolesz FA, Hynynen K (2005) MRI-guided targeted blood–brain barrier disruption with focused ultrasound: histological findings in rabbits. Ultrasound Med Biol 31:1527–1537PubMedGoogle Scholar
  61. Meijer OC, de Lange EC, Breimer DD, de Boer AG, Workel JO, de Kloet ER (1998) Penetration of dexamethasone into brain glucocorticoid targets is enhanced in mdr1A P-glycoprotein knockout mice. Endocrinology 139:1789–1793PubMedGoogle Scholar
  62. Menzies SA, Betz AL, Hoff JT (1993) Contributions of ions and albumin to the formation and resolution of ischemic brain edema. J Neurosurg 78:257–266PubMedGoogle Scholar
  63. Milhorat TH, Hammock MK, Fenstermacher JD, Levin VA (1971) Cerebrospinal fluid production by the choroid plexus and brain. Science 173:330–332PubMedGoogle Scholar
  64. Nagaraja TN, Keenan KA, Brown SL, Fenstermacher JD, Knight RA (2007) Relative distribution of plasma flow markers and red blood cells across BBB openings in acute cerebral ischemia. Neurol Res 29:78–80PubMedGoogle Scholar
  65. Noor R, Wang CX, Shuaib A (2005) Hyperthermia masks the neuroprotective effects of tissue plaminogen activator. Stroke 36:665–669PubMedGoogle Scholar
  66. Patak P, Hermann DM (2011) ATP-binding cassette transporters at the blood–brain barrier in ischaemic stroke. Curr Pharm Des 17:2787–2792PubMedGoogle Scholar
  67. Piriyawat P, Labiche LA, Burgin WS, Aronowski JA, Grotta JC (2003) Pilot dose-escalation study of caffeine plus ethanol (caffeinol) in acute ischemic stroke. Stroke 34:1242–1245PubMedGoogle Scholar
  68. Preston E, Foster DO (1997) Evidence for pore-like opening of the blood–brain barrier following forebrain ischemia in rats. Brain Res 761:4–10PubMedGoogle Scholar
  69. Preston E, Webster J (2002) Differential passage of [14C]sucrose and [3H]inulin across rat blood–brain barrier after cerebral ischemia. Acta Neuropathol 103:237–242PubMedGoogle Scholar
  70. Pun PBL, Lu J, Moochhala S (2009) Involvement of ROS in BBB dysfunction. Free Radic Res 43:348–364PubMedGoogle Scholar
  71. Reinhard M, Hetzel A, Kruger S, Kretzer S, Talazko J, Ziyeh S, Weber J, Els T (2006) Blood–brain barrier disruption by low-frequency ultrasound. Stroke 37:1546–1548PubMedGoogle Scholar
  72. Rhodes J (2011) Peripheral immune cells in the pathology of traumatic brain injury? Curr Opin Crit Care 17:122–130PubMedGoogle Scholar
  73. Richardson RM, Singh A, Sun D, Fillmore HL, Dietrich DW 3rd, Bullock MR (2010) Stem cell biology in traumatic brain injury: effects of injury and strategies for repair. J Neurosurg 112:1125–1138PubMedGoogle Scholar
  74. Roger VL, Go AS, Lloyd-Jones DM, Benjamin EJ, Berry JD, Borden WB, Bravata DM, Dai S, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Hailpern SM, Heit JA, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Soliman EZ, Sorlie PD, Sotoodehnia N, Turan TN, Virani SS, Wong ND, Woo D, Turner MB (2012) Heart disease and stroke statistics–2012 update: a report from the American Heart Association. Circulation 125:e2–e220PubMedGoogle Scholar
  75. Rosenberg GA, Yang Y (2007) Vasogenic edema due to tight junction disruption by matrix metalloproteinases in cerebral ischemia. Neurosurg Focus 22:E4PubMedGoogle Scholar
  76. Schinkel AH, Wagenaar E, van Deemter L, Mol CA, Borst P (1995) Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and cyclosporin A. J Clin Investigation 96:1698–1705Google Scholar
  77. Schubert GA, Thome C (2008) Cerebral blood flow changes in acute subarachnoid hemorrhage. Front Biosci 13:1594–1603PubMedGoogle Scholar
  78. Shlosberg D, Benifla M, Kaufer D, Friedman A (2010) Blood–brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat Rev Neurosci 6:393–403Google Scholar
  79. Smith DE, Hu Y, Shen H, Nagaraja TN, Fenstermacher JD, Keep RF (2011) Distribution of glycylsarcosine and cefadroxil among cerebrospinal fluid, choroid plexus, and brain parenchyma after intracerebroventricular injection is markedly different between wild-type and Pept2 null mice. J Cereb Blood Flow Metab 31:250–261PubMedGoogle Scholar
  80. Smith SL, Hall ED (1996) Mild pre- and posttraumatic hypothermia attenuates blood–brain barrier damage following controlled cortical impact injury in the rat. J Neurotrauma 13:1–9PubMedGoogle Scholar
  81. Song B-W, Vinters HV, Wu D, Pardridge WM (2002) Enhanced neuroprotective effects of basic fibroblast growth factor in regional brain ischemia after conjugation to a blood–brain barrier delivery vector. J Pharmacol Exp Therap 301:605–610Google Scholar
  82. Spudich A, Kilic E, Xing H, Kilic U, Rentsch KM, Wunderli-Allenspach H, Bassetti CL, Hermann DM (2006) Inhibition of multidrug resistance transporter-1 facilitates neuroprotective therapies after focal cerebral ischemia. Nat Neurosci 9:487–488PubMedGoogle Scholar
  83. Stamatovic SM, Keep RF, Andjelkovic AV (2008) Brain endothelial cell-cell junctions: how to "open" the blood brain barrier. Curr Neuropharmacol 6:179–192PubMedGoogle Scholar
  84. Stamatovic SM, Keep RF, Wang MM, Jankovic I, Andjelkovic AV (2009) Caveolae-mediated internalization of occludin and claudin-5 during CCL2-induced tight junction remodeling in brain endothelial cells. J Biol Chem 284:19053–19066PubMedGoogle Scholar
  85. Stummer W, Betz AL, Shakui P, Keep RF (1995) Blood–brain barrier taurine transport during osmotic stress and in focal cerebral ischemia. J Cereb Blood Flow Metab 15:852–859PubMedGoogle Scholar
  86. Sykova E (1997) Extracellular space volume and geometry of the rat brain after ischemia and central injury. Adv Neurol 73:121–135PubMedGoogle Scholar
  87. Szmydynger-Chodobska J, Strazielle N, Zink BJ, Ghersi-Egea J-F, Chodobski A (2009) The role of the choroid plexus in neutrophil invasion after traumatic brain injury. J Cereb Blood Flow Metab 29:1503–1516PubMedCentralPubMedGoogle Scholar
  88. Szmydynger-Chodobska J, Strazielle N, Gandy JR, Keefe TH, Zink BJ, Ghersi-Egea J-F, Chodobski A (2012) Posttraumatic invasion of monocytes across the blood-cerebrospinal fluid barrier. J Cereb Blood Flow Metab 32:93–104PubMedGoogle Scholar
  89. Tanaka H, Mizojiri K (1999) Drug-protein binding and blood–brain barrier permeability. J Pharmacol Exp Therap 288:912–918Google Scholar
  90. Topakian R, Barrick TR, Howe FA, Markus HS (2010) Blood–brain barrier permeability is increased in normal-appearing white matter in patients with lacunar stroke and leucoaraiosis. J Neurol Neurosurg Psychiatry 81:192–197PubMedGoogle Scholar
  91. Uchida Y, Ohtsuki S, Kamiie J, Terasaki T (2011) Blood–brain barrier (BBB) pharmacoproteomics: reconstruction of in vivo brain distribution of 11 P-glycoprotein substrates based on the BBB transporter protein concentration, in vitro intrinsic transport activity, and unbound fraction in plasma and brain in mice. J Pharmacol Exp Therap 339:579–588Google Scholar
  92. van Velthoven CTJ, Kavelaars A, van Bel F, Heijnen CJ (2009) Regeneration of the ischemic brain by engineered stem cells: fuelling endogenous repair processes. Brain Res Rev 61:1–13PubMedGoogle Scholar
  93. Vemula S, Roder KE, Yang T, Bhat GJ, Thekkumkara TJ, Abbruscato TJ (2009) A functional role for sodium-dependent glucose transport across the blood–brain barrier during oxygen glucose deprivation. J Pharmacol Exp Therap 328:487–495Google Scholar
  94. Vestweber D (2007) Adhesion and signaling molecules controlling the transmigration of leukocytes through endothelium. Immunol Rev 218:178–196PubMedGoogle Scholar
  95. Vogelbaum MA, Iannotti CA (2012) Convection-enhanced delivery of therapeutic agents into the brain. Handb Clin Neurol 104:355–362PubMedGoogle Scholar
  96. von Wedel-Parlow M, Schrot S, Lemmen J, Treeratanapiboon L, Wegener J, Galla H-J (2011) Neutrophils cross the BBB primarily on transcellular pathways: an in vitro study. Brain Res 1367:62–76Google Scholar
  97. Walker PA, Shah SK, Jimenez F, Gerber MH, Xue H, Cutrone R, Hamilton JA, Mays RW, Deans R, Pati S, Dash PK, Cox CS Jr (2010) Intravenous multipotent adult progenitor cell therapy for traumatic brain injury: preserving the blood brain barrier via an interaction with splenocytes. Exp Neurol 225:341–352PubMedCentralPubMedGoogle Scholar
  98. Wallace BK, Foroutan S, O'Donnell ME (2011) Ischemia-induced stimulation of Na-K-Cl cotransport in cerebral microvascular endothelial cells involves AMP kinase. Am J Physiol - Cell Physiol 301:C316–C326PubMedGoogle Scholar
  99. Wang J (2010) Preclinical and clinical research on inflammation after intracerebral hemorrhage. Prog Neurobiol 92:463–477PubMedCentralPubMedGoogle Scholar
  100. Webb AJ, Ullman NL, Mann S, Muschelli J, Awad IA, Hanley DF (2012) Resolution of intraventricular hemorrhage varies by ventricular region and dose of intraventricular thrombolytic: The clot lysis: Evaluating Accelerated Resolution of IVH (CLEAR IVH) Program. Stroke 43:1666–1668Google Scholar
  101. Westergaard E, Go G, Klatzo I, Spatz M (1976) Increased permeability of cerebral vessels to horseradish peroxidase induced by ischemia in Mongolian Gerbils. Acta Neuropathol 35:307–325PubMedGoogle Scholar
  102. Xi G, Keep RF, Hoff JT (2006) Mechanisms of brain injury after intracerebral haemorrhage. Lancet Neurol 5:53–63PubMedGoogle Scholar
  103. Yamashita T, Kamiya T, Deguchi K, Inaba T, Zhang H, Shang J, Miyazaki K, Ohtsuka A, Katayama Y, Abe K (2009) Dissociation and protection of the neurovascular unit after thrombolysis and reperfusion in ischemic rat brain. J Cereb Blood Flow Metab 29:715–725PubMedGoogle Scholar
  104. Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA (2007) Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 27:697–709PubMedGoogle Scholar
  105. Yenari MA, Han HS (2012) Neuroprotective mechanisms of hypothermia in brain ischaemia. Nat Rev Neurosci 13:267–278PubMedGoogle Scholar
  106. Zhang Y, Pardridge WM (2001) Neuroprotection in transient focal brain ischemia after delayed intravenous administration of brain-derived neurotrophic factor conjugated to a blood–brain barrier drug targeting system. Stroke 32:1378–1384PubMedGoogle Scholar
  107. Zhang Z, Zhang L, Yepes M, Jiang Q, Li Q, Arniego P, Coleman TA, Lawrence DA, Chopp M (2002) Adjuvant treatment with neuroserpin increases the therapeutic window for tissue-type plasminogen activator administration in a rat model of embolic stroke. Circulation 106:740–745PubMedGoogle Scholar
  108. Zhang ZG, Chopp M (2009) Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic. Lancet Neurol 8:491–500PubMedCentralPubMedGoogle Scholar
  109. Zlokovic BV, McComb JG, Lipovac MN, Chen TC, Mackic JB, Schneider J, Gianotta SL, Weiss MH (1993) Differential brain penetration of cerebroprotective drugs. Adv Exp Med Biol 331:117–120PubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  • Richard F. Keep
    • 1
    • 2
  • Jianming Xiang
    • 2
  • Ningna Zhou
    • 2
  • Anuska V. Andjelkovic
    • 2
    • 3
  1. 1.Department of Molecular and Integrative Physiology, R5018 Biomedical Science Research BuildingUniversity of MichiganAnn ArborUSA
  2. 2.Department of Neurosurgery, R5018 Biomedical Science Research BuildingUniversity of MichiganAnn ArborUSA
  3. 3.Department of Pathology, R5018 Biomedical Science Research BuildingUniversity of MichiganAnn ArborUSA

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