Disease Influence on BBB Transport in Neurodegenerative Disorders

Chapter
Part of the AAPS Advances in the Pharmaceutical Sciences Series book series (AAPS, volume 10)

Abstract

For the pharmacotherapy of neurodegenerative diseases, drugs have to pass the blood–brain barrier (BBB). Many changes in BBB properties in neurodegeneration have been reported. Furthermore, the BBB seems to play an important role in the disease initiation and or progression. While information on unbound drug concentrations in plasma and brain are needed to decipher BBB transport properties and target site concentrations, and changes thereof in disease conditions, surprisingly, only a very limited number of BBB transport studies in neurodegeneration have been performed on the basis of the unbound drug, and even fewer have taken into account disease conditions and/or measurements of an effect parameter. For better understanding and treatment, a much more integrative and translational pharmacometric research approach is needed, instead of studying neurodegenerative components in isolation. As the human brain is not accessible for sampling, we have to rely on animal models and translational approaches.

Keywords

Dopamine Laminin Phenobarbital Inulin Baclofen 

References

  1. Abbott NJ, Khan EU, Rollinson CM, Reichel A, Janigro D, Dombrowski SM, Dobbie MS, Begley DJ (2002) Drug resistance in epilepsy: the role of the blood–brain barrier. Novartis Found Symp 243:38–47, discussion 47–53, 180–185PubMedGoogle Scholar
  2. Abuznait AH, Cain C, Ingram D, Burk D, Kaddoumi A (2011) Up-regulation of P-glycoprotein reduces intracellular accumulation of beta amyloid: investigation of P-glycoprotein as a novel therapeutic target for Alzheimer's disease. J Pharm Pharmacol 63(8):1111–1118PubMedCentralPubMedGoogle Scholar
  3. Aijaz S, Balda MS, Matter K (2006) Tight junctions: molecular architecture and function. Int Rev Cytol 248:261–298PubMedGoogle Scholar
  4. Al Ahmad A, Gassmann M, Ogunshola OO (2012) Involvement of oxidative stress in hypoxia-induced blood–brain barrier breakdown. Microvasc Res 84(2):222–225PubMedGoogle Scholar
  5. Alexander GE, Chen K, Merkley TL, Reiman EM, Caselli RJ, Aschenbrenner M, Santerre-Lemmon L, Lewis DJ, Pietrini P, Teipel SJ, Hampel H, Rapoport SI, Moeller JR (2006) Regional network of magnetic resonance imaging gray matter volume in healthy aging. Neuroreport 17(10):951–956PubMedGoogle Scholar
  6. Alexander GM, Godwin DW (2006) Metabotropic glutamate receptors as a strategic target for the treatment of epilepsy. Epilepsy Res 71:1–22PubMedGoogle Scholar
  7. Allain H, Bentué-Ferrer D, Akwa Y (2008) Disease-modifying drugs and Parkinson's disease. Prog Neurobiol 84(1):25–39PubMedGoogle Scholar
  8. Allt G, Lawrenson JG (2001) Pericytes: cell biology and pathology. Cells Tissues Organs 169:1–11PubMedGoogle Scholar
  9. Alon R, Feigelson S (2002) From rolling to arrest on blood vessels: leukocyte tap dancing on endothelial integrin ligands and chemokines at sub-second contacts. Semin Immunol 14(2):93–104PubMedGoogle Scholar
  10. Amenta PS, Jallo JI, Tuma RF, Elliott MB (2012) A cannabinoid type 2 receptor agonist attenuates blood–brain barrier damage and neurodegeneration in a murine model of traumatic brain injury. J Neurosci Res 90(12):2293–2305PubMedGoogle Scholar
  11. Andersen PM, Sims KB, Xin WW, Kiely R, O'Neill G, Ravits J, Pioro E, Harati Y, Brower RD, Levine JS, Heinicke HU, Seltzer W, Boss M, Brown RH Jr (2003) Sixteen novel mutations in the Cu/Zn superoxide dismutase gene in amyotrophic lateral sclerosis: a decade of discoveries, defects and disputes. Amyotroph Lateral Scler Other Motor Neuron Disord 4(2):62–73PubMedGoogle Scholar
  12. Anderson GD, Shen DD (2007) Where is the evidence that p-glycoprotein limits brain uptake of antiepileptic drug and contributes to drug resistance in epilepsy? Epilepsia 48(12):2372–2374PubMedGoogle Scholar
  13. Armulik A, Genové G, Betsholtz C (2011a) Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell 21(2):193–215PubMedGoogle Scholar
  14. Armulik A, Mäe M, Betsholtz C (2011b) Pericytes and the blood–brain barrier: recent advances and implications for the delivery of CNS therapy. Ther Deliv 2(4):419–422PubMedGoogle Scholar
  15. Arnold S (2012) The power of life–cytochrome c oxidase takes center stage in metabolic control, cell signalling and survival. Mitochondrion 12(1):46–56PubMedGoogle Scholar
  16. Artal-Sanz M, Tavernarakis N (2005) Proteolytic mechanisms in necrotic cell death and neurodegeneration. FEBS Lett 579(15):3287–3296PubMedGoogle Scholar
  17. Ates N, Esen N, Ilbay G (1999) Absence epilepsy and regional blood–brain barrier permeability: the effects of pentylenetetrazole-induced convulsions. Pharmacol Res 39(4):305–310PubMedGoogle Scholar
  18. Baeten KM, Akassoglou K (2011) Extracellular matrix and matrix receptors in blood–brain barrier formation and stroke. Periodicals, inc. Dev Neurobiol 71:1018–1039PubMedCentralPubMedGoogle Scholar
  19. Bailey TL, Rivara CB, Rocher AB, Hof PR (2004) The nature and effects of cortical microvascular pathology in aging and Alzheimer’s disease. Neurol Res 26:573–578PubMedGoogle Scholar
  20. Balabanov R, Dore-Duffy P (1998) Role of the CNS microvascular pericyte in the blood–brain barrier. J Neurosci Res 53(6):637–644PubMedGoogle Scholar
  21. Baltes S, Fedrowitz M, Tortós CL, Potschka H, Löscher W (2007a) Valproic acid is not a substrate for P-glycoprotein or multidrug resistance proteins 1 and 2 in a number of in vitro and in vivo transport assays. J Pharmacol Exp Ther 320(1):331–343PubMedGoogle Scholar
  22. Baltes S, Gastens AM, Fedrowitz M, Potschka H, Kaever V, Löscher W (2007b) Differences in the transport of the antiepileptic drugs phenytoin, levetiracetam and carbamazepine by human and mouse P-glycoprotein. Neuropharmacology 52(2):333–346PubMedGoogle Scholar
  23. Banerjee S, Bhat MA (2007) Neuron-glial interactions in blood–brain barrier formation. Annu Rev Neurosci 30:235–258PubMedCentralPubMedGoogle Scholar
  24. Bankstahl JP, Hoffmann K, Bethmann K, Löscher W (2008) Glutamate is critically involved in seizure-induced overexpression of P-glycoprotein in the brain. Neuropharmacology 54(6):1006–1016PubMedGoogle Scholar
  25. Bankstahl JP, Bankstahl M, Kuntner C, Stanek J, Wanek T, Meier M, Ding XQ, Müller M, Langer O, Löscher W (2011) A novel positron emission tomography imaging protocol identifies seizure-induced regional overactivity of P-glycoprotein at the blood–brain barrier. J Neurosci 31(24):8803–8811PubMedCentralPubMedGoogle Scholar
  26. Bano D, Zanetti F, Mende Y, Nicotera P (2011) Neurodegenerative processes in Huntington's disease. Cell Death Dis 2(11):e228PubMedCentralPubMedGoogle Scholar
  27. Baranczyk-Kuzma A, Audus KL, Borchardt RT (1989) Catecholamine-metabolizing enzymes of bovine brain microvessel endothelial cell monolayers. J Neurochem 46(6):1956–1960Google Scholar
  28. Bartels AL (2011) Blood–brain barrier P-glycoprotein function in neurodegenerative disease. Curr Pharm Des 17(26):2771–2777PubMedGoogle Scholar
  29. Bell RD, Zlokovic BV (2009) Neurovascular mechanisms and blood–brain barrier disorder in Alzheimer's disease. Acta Neuropathol 118(1):103–113PubMedCentralPubMedGoogle Scholar
  30. Bell RD, Winkler EA, Sagare AP, Singh I, LaRue B, Deane R, Zlokovic BV (2010) Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron 68(3):409–427PubMedCentralPubMedGoogle Scholar
  31. Bell RD, Winkler EA, Singh I, Sagare AP, Deane R, Wu Z, Holtzman DM, Betsholtz C, Armulik A, Sallstrom J, Berk BC, Zlokovic BV (2012) Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485(7399):512–516PubMedGoogle Scholar
  32. Bendayan R, Ronaldson PT, Gingras D, Bendayan M (2006) In situ localization of P-glycoprotein (ABCB1) in human and rat brain. J Histochem Cytochem 54:1159–1167PubMedGoogle Scholar
  33. Benkovic SA, O'Callaghan JP, Miller DB (2004) Sensitive indicators of injury reveal hippocampal damage in C57BL/6J mice treated with kainic acid in the absence of tonic-clonic seizures. Brain Res 1024(1–2):59–76PubMedGoogle Scholar
  34. Berg D, Youdim MB (2006) Role of iron in neurodegenerative disorders. Top Magn Reson Imaging 17(1):5–17PubMedGoogle Scholar
  35. Bertram L, Tanzi RE (2005) The genetic epidemiology of neurodegenerative disease. J Clin Invest 115(6):1449–1457PubMedCentralPubMedGoogle Scholar
  36. Bethmann K, Fritschy JM, Brandt C, Löscher W (2008) Antiepileptic drug resistant rats differ from drug responsive rats in GABA A receptor subunit expression in a model of temporal lobe epilepsy. Neurobiol Dis 31(2):169–187PubMedGoogle Scholar
  37. Betti M, Minelli A, Ambrogini P, Ciuffoli S, Viola V, Galli F, Canonico B, Lattanzi D, Colombo E, Sestili P, Cuppini R (2011) Dietary supplementation with α-tocopherol reduces neuroinflammation and neuronal degeneration in the rat brain after kainic acid-induced status epilepticus. Free Radic Res 45(10):1136–1142PubMedGoogle Scholar
  38. Bittigau P, Sifringer M, Genz K, Reith E, Pospischil D, Govindarajalu S, Dzietko M, Pesditschek S, Mai I, Dikranian K, Olney JW, Ikonomidou C (2002) Antiepileptic drugs and apoptotic neurodegeneration in the developing brain. Proc Natl Acad Sci U S A 99(23):15089–15094PubMedCentralPubMedGoogle Scholar
  39. Bové J, Perier C (2012) Neurotoxin-based models of Parkinson's disease. Neuroscience 211:51–76PubMedGoogle Scholar
  40. Brandt C, Bethmann K, Gastens AM, Löscher W (2006) The multidrug transporter hypothesis of drug resistance in epilepsy: proof-of-principle in a rat model of temporal lobe epilepsy. Neurobiol Dis 24(1):202–211PubMedGoogle Scholar
  41. Brenn A, Grube M, Peters M, Fischer A, Jedlitschky G, Kroemer HK, Warzok RW, Vogelgesang S (2011) Beta-amyloid downregulates MDR1-P-glycoprotein (Abcb1) expression at the blood–brain barrier in mice. Int J Alzheimers Dis 2011:690121PubMedCentralPubMedGoogle Scholar
  42. Britschgi M, Wyss-Coray T (2007) Immune cells may fend off Alzheimer disease. Nat Med 13:408–409PubMedGoogle Scholar
  43. Brownless J, Williams CH (1993) Peptidases, peptides and the mammalian blood–brain barrier. J Neurochem 60:1089–1096Google Scholar
  44. Bulbarelli A, Lonati E, Brambilla A, Orlando A, Cazzaniga E, Piazza F, Ferrarese C, Masserini M, Sancini G (2012) Aβ42 production in brain capillary endothelial cells after oxygen and glucose deprivation. Mol Cell Neurosci 49(4):415–422PubMedGoogle Scholar
  45. Chalbot S, Zetterberg H, Blennow K, Fladby T, Andreasen N, Grundke-Iqbal I, Iqbal K (2011) Blood-cerebrospinal fluid barrier permeability in Alzheimer's disease. J Alzheimers Dis 25(3):505–515PubMedCentralPubMedGoogle Scholar
  46. Cheng T, Petraglia AL, Li Z, Thiyagarajan M, Zhong Z, Wu Z, Liu D, Maggirwar SB, Deane R, Fernandez JA, LaRue B, Griffin JH, Chopp M, Zlokovic BV (2006) Activated protein C inhibits tissue plasminogen activator-induced brain hemorrhage. Nat Med 12:1278–1285PubMedGoogle Scholar
  47. Cheng Z, Zhang J, Liu H, Li Y, Zhao Y, Yang E (2010) Central nervous system penetration for small molecule therapeutic agents does not increase in multiple sclerosis- and Alzheimer's disease-related animal models despite reported blood–brain barrier disruption. Drug Metab Dispos 38(8):1355–1361PubMedGoogle Scholar
  48. Chodobski A, Zink BJ, Szmydynger-Chodobska J (2011) Blood–brain barrier pathophysiology in traumatic brain injury. Transl Stroke Res 2(4):492–516PubMedCentralPubMedGoogle Scholar
  49. Cholerton B, Baker LD, Craft S (2011) Insulin resistance and pathological brain ageing. Diabet Med 28(12):1463–1475PubMedGoogle Scholar
  50. Chopra V, Fox JH, Lieberman G, Dorsey K, Matson W, Waldmeier P, Housman DE, Kazantsev A, Young AB, Hersch S (2007) A small-molecule therapeutic lead for Huntington's disease: preclinical pharmacology and efficacy of C2-8 in the R6/2 transgenic mouse. Proc Natl Acad Sci U S A 104(42):16685–16689PubMedCentralPubMedGoogle Scholar
  51. Christensen J (2012) Traumatic brain injury: Risks of epilepsy and implications for medicolegal assessment. Epilepsia 53(Suppl 4):43–47PubMedGoogle Scholar
  52. Christensen J, Højskov CS, Dam M, Poulsen JH (2001) Plasma concentration of topiramate correlates with cerebrospinal fluid concentration. Ther Drug Monit 23(5):529–535PubMedGoogle Scholar
  53. Chun JT, Wang L, Pasinetti GM, Finch CE, Zlokovic BV (1999) Glycoprotein 330/megalin (LRP-2) has low prevalence as mRNA and protein in brain microvessels and choroid plexus. Exp Neurol 157(1):194–201PubMedGoogle Scholar
  54. Chun HS, Son JJ, Son JH (2000) Identification of potential compounds promoting BDNF production in nigral dopaminergic neurons: clinical implication in Parkinson's disease. Neuroreport 11(3):511–514PubMedGoogle Scholar
  55. Clinckers R, Smolders I, Meurs A, Ebinger G, Michotte Y (2005a) Quantitative in vivo microdialysis study on the influence of multidrug transporters on the blood–brain barrier passage of oxcarbazepine: concomitant use of hippocampal monoamines as pharmacodynamic markers for the anticonvulsant activity. J Pharmacol Exp Ther 314(2):725–731PubMedGoogle Scholar
  56. Clinckers R, Smolders I, Meurs A, Ebinger G, Michotte Y (2005b) Hippocampal dopamine and serotonin elevations as pharmacodynamic markers for the anticonvulsant efficacy of oxcarbazepine and 10,11-dihydro-10-hydroxycarbamazepine. Neurosci Lett 390(1):48–53PubMedGoogle Scholar
  57. Clinckers R, Smolders I, Michotte Y, Ebinger G, Danhof M, Voskuyl RA, Della PO (2008) Impact of efflux transporters and of seizures on the pharmacokinetics of oxcarbazepine metabolite in the rat brain. Br J Pharmacol 155(7):1127–1138PubMedGoogle Scholar
  58. Cohen-Kashi MK, Cooper I, Teichberg VI (2009) Closing the gap between the in-vivo and in-vitro blood–brain barrier tightness. Brain Res 1284:12–21Google Scholar
  59. Confavreux C, Vukusic S (2006) Accumulation of irreversible disability in multiple sclerosis: from epidemiology to treatment. Clin Neurol Neurosurg 108(3):327–332PubMedGoogle Scholar
  60. Contestabile A (2001) Oxidative stress in neurodegeneration: mechanisms and therapeutic perspectives. Curr Top Med Chem 1(6):553–568PubMedGoogle Scholar
  61. Cope EC, Morris DR, Levenson CW (2012) Improving treatments and outcomes: an emerging role for zinc in traumatic brain injury. Nutr Rev 70(7):410–413PubMedCentralPubMedGoogle Scholar
  62. Coppedè F, Mancuso M, Siciliano G, Migliore L, Murri L (2006) Genes and the environment in neurodegeneration. Biosci Rep 26(5):341–367PubMedGoogle Scholar
  63. Cowan CM, Raymond LA (2006) Selective neuronal degeneration in Huntington’s disease. Curr Top Dev Biol 75:25–71PubMedGoogle Scholar
  64. Dalkara T, Gursoy-Ozdemir Y, Yemisci M (2011) Brain microvascular pericytes in health and disease. Acta Neuropathol 122(1):1–9PubMedGoogle Scholar
  65. De Lange EC (2013) The mastermind approach to CNS drug therapy: translational prediction of human brain distribution, target site kinetics, and therapeutic effects. Fluids Barriers CNS 10(1):12PubMedCentralPubMedGoogle Scholar
  66. De Vos KJ, Grierson AJ, Ackerley S, Miller CJJ (2008) Role of axonal transport in neurodegenerative diseases. Annu Rev Neurosci 31:151–173PubMedGoogle Scholar
  67. Deeken JF, Loscher W (2007) The blood–brain barrier and cancer: transporters, treatment, and Trojan horses. Clin Cancer Res 13:1663–1674PubMedGoogle Scholar
  68. Deleu D, Northway MG, Hanssens Y (2002) Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson's disease. Clin Pharmacokinet 41(4):261–309PubMedGoogle Scholar
  69. Deprez F, Zattoni M, Mura ML, Frei K, Fritschy JM (2011) Adoptive transfer of T lymphocytes in immunodeficient mice influences epileptogenesis and neurodegeneration in a model of temporal lobe epilepsy. Neurobiol Dis 44(2):174–184PubMedGoogle Scholar
  70. Desai BS, Monahan AJ, Carvey PM, Hendey B (2007) Blood–brain barrier pathology in Alzheimer's and Parkinson's disease: implications for drug therapy. Cell Transplant 16(3):285–299PubMedGoogle Scholar
  71. Dimitrijevic OB, Stamatovic SM, Keep RF, Andjelkovic AV (2007) Absence of the chemokine receptor CCR2 protects against cerebral ischemia/reperfusion injury in mice. Stroke 38(4):1345–1353PubMedGoogle Scholar
  72. Dombrowski SM, Desai SY, Marroni M, Cucullo L, Goodrich K, Bingaman W, Mayberg MR, Bengez L, Janigro D (2001) Overexpression of multiple drug resistance genes in endothelial cells from patients with refractory epilepsy. Epilepsia 42(12):1501–1506PubMedGoogle Scholar
  73. Dore-Duffy P, Cleary K (2011) Morphology and properties of pericytes. Methods Mol Biol 686:49–68PubMedGoogle Scholar
  74. Drake CT, Iadecola C (2007) The role of neuronal signaling in controlling cerebral blood flow. Brain Lang 102:141–152PubMedGoogle Scholar
  75. Duran-Vilaregut J, del Valle J, Manich G, Camins A, Pallàs M, Vilaplana J, Pelegrí C (2011) Role of matrix metalloproteinase-9 (MMP-9) in striatal blood–brain barrier disruption in a 3-nitropropionic acid model of Huntington's disease. Neuropathol Appl Neurobiol 37(5):525–537PubMedGoogle Scholar
  76. Dutheil F, Jacob A, Dauchy S, Beaune P, Scherrmann JM, Declèves X, Loriot MA (2010) ABC transporters and cytochromes P450 in the human central nervous system: influence on brain pharmacokinetics and contribution to neurodegenerative disorders. Expert Opin Drug Metab Toxicol 6(10):1161–1174PubMedGoogle Scholar
  77. Engelhardt B, Ransohoff R (2005) The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol 26:485–495PubMedGoogle Scholar
  78. Erickson AC, Couchman JR (2000) Still more complexity in mammalian basement membranes. J Histochem Cytochem 48(10):1291–1306PubMedGoogle Scholar
  79. Erickson MA, Hartvigson PE, Morofuji Y, Owen JB, Butterfield DA, Banks WA (2012) Lipopolysaccharide impairs amyloid beta efflux from brain: altered vascular sequestration, cerebrospinal fluid reabsorption, peripheral clearance and transporter function at the blood–brain barrier. J Neuroinflammation 9(1):150PubMedCentralPubMedGoogle Scholar
  80. Fan J, Cowan CM, Zhang LY, Hayden MR, Raymond LA (2009) Interaction of postsynaptic density protein-95 with NMDA receptors influences excitotoxicity in the yeast artificial chromosome mouse model of Huntington's disease. J Neurosci 29(35):10928–10938PubMedGoogle Scholar
  81. Feng MR, Turluck D, Burleigh J, Lister R, Fan C, Middlebrook A, Taylor C, Su T (2001) Brain microdialysis and PK/PD correlation of pregabalin in rats. Eur J Drug Metab Pharmacokinet 26(1–2):123–128PubMedGoogle Scholar
  82. Feng S, Cen J, Huang Y, Shen H, Yao L, Wang Y, Chen Z (2011) Matrix metalloproteinase-2 and −9 secreted by leukemic cells increase the permeability of blood–brain barrier by disrupting tight junction proteins. PLoS One 6(8):e20599PubMedCentralPubMedGoogle Scholar
  83. Filippi M, Rocca MA (2005) MRI evidence for multiple sclerosis as a diffuse disease of the central nervous system. J Neurol 252(Suppl 5):v16–v24PubMedGoogle Scholar
  84. Finder VH (2010) Alzheimer's disease: a general introduction and pathomechanism. J Alzheimers Dis 22(Suppl 3):5–19PubMedGoogle Scholar
  85. Freeman LR, Keller JN (2012) Oxidative stress and cerebral endothelial cells: regulation of the blood–brain-barrier and antioxidant based interventions. Biochim Biophys Acta 1822(5):822–829PubMedCentralPubMedGoogle Scholar
  86. Frigo M, Cogo MG, Fusco ML, Gardinetti M, Frigeni B (2012) Glutamate and multiple sclerosis. Curr Med Chem 19(9):1295–1299PubMedGoogle Scholar
  87. Fukushima H, Fujimoto M, Ide M (1990) Quantitative detection of blood–brain barrier-associated enzymes in cultured endothelial cells of porcine brain microvessels. In Vitro Cell Dev Biol 26(6):612–620PubMedGoogle Scholar
  88. Tudor AF, Elson-Schwab I, Khurana V, Steinhilb ML, Spires TL, Hyman BT, Feany MB (2007) Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo. Nat Cell Biol 9:139–148Google Scholar
  89. Gaillard PJ, Appeldoorn CC, Rip J, Dorland R, van der Pol SM, Kooij G, de Vries HE, Reijerkerk A (2012) Enhanced brain delivery of liposomal methylprednisolone improved therapeutic efficacy in a model of neuroinflammation. J Control Release 164(3):364–369PubMedGoogle Scholar
  90. Ghosh C, Puvenna V, Gonzalez-Martinez J, Janigro D, Marchi N (2011) Blood–brain barrier P450 enzymes and multidrug transporters in drug resistance: a synergistic role in neurological diseases. Curr Drug Metab 12(8):742–749PubMedGoogle Scholar
  91. Girouard H, Bonev AD, Hannah RM, Meredith A, Aldrich RW, Nelson MT (2010) Astrocytic endfoot Ca2+ and BK channels determine both arteriolar dilation and constriction. Proc Natl Acad Sci U S A 107(8):3811–3816PubMedCentralPubMedGoogle Scholar
  92. Gorman AM (2008) Neuronal cell death in neurodegenerative diseases: recurring themes around protein handling. J Cell Mol Med 12(6A):2263–2280PubMedGoogle Scholar
  93. Götz ME, Künig G, Riederer P, Youdim MB (1994) Oxidative stress: free radical production in neural degeneration. Pharmacol Ther 63(1):37–122PubMedGoogle Scholar
  94. Greenhalgh AD, Ogungbenro K, Rothwell NJ, Galea JP (2011) Translational pharmacokinetics: challenges of an emerging approach to drug development in stroke. Expert Opin Drug Metab Toxicol 7(6):681–695PubMedGoogle Scholar
  95. Grünblatt E, Mandel S, Youdim MB (2000) MPTP and 6-hydroxydopamine-induced neurodegeneration as models for Parkinson's disease: neuroprotective strategies. J Neurol 247(Suppl 2):II95–II102PubMedGoogle Scholar
  96. Guo X, Geng M, Du G (2005) Glucose transporter 1, distribution in the brain and in neural disorders: its relationship with transport of neuroactive drugs through the blood–brain barrier. Biochem Genet 43(3–4):175–187PubMedGoogle Scholar
  97. Haass C, Selkoe DJ (2007) Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide. Nat Rev Mol Cell Biol 8(2):101–112PubMedGoogle Scholar
  98. Hartz AM, Miller DS, Bauer B (2010) Restoring blood–brain barrier P-glycoprotein reduces brain amyloid-beta in a mouse model of Alzheimer's disease. Mol Pharmacol 77(5):715–723PubMedGoogle Scholar
  99. Hawkins BT, Davis TP (2005) The blood–brain barrier/neurovascular unit in health and disease. Pharmacol Rev 57(2):173–185PubMedGoogle Scholar
  100. Healy DP, Wilk S (1993) Localization of immunoreactive glutamyl aminopeptidase in rat brain. II. Distribution and correlation with angiotensin II. Brain Res 606:295–303PubMedGoogle Scholar
  101. Hefti F (1994) Neurotrophic factor therapy for nervous system degenerative diseases. J Neurobiol 25(11):1418–1435PubMedGoogle Scholar
  102. Hendriks JJ, Teunissen CE, de Vries HE, Dijkstra CD (2005) Macrophages and neurodegeneration. Brain Res Brain Res Rev 48(2):185–195PubMedGoogle Scholar
  103. Hermann DM, Bassetti CL (2007) Implications of ATP-binding cassette transporters for brain pharmacotherapies. Trends Pharmacol Sci 28:128–134PubMedGoogle Scholar
  104. Hernández-Romero MC, Delgado-Cortés MJ, Sarmiento M, de Pablos RM, Espinosa-Oliva AM, Argüelles S, Bández MJ, Villarán RF, Mauriño R, Santiago M, Venero JL, Herrera AJ, Cano J, Machado A (2012) Peripheral inflammation increases the deleterious effect of CNS inflammation on the nigrostriatal dopaminergic system. Neurotoxicology 33(3):347–360PubMedGoogle Scholar
  105. Hoffmann K, Löscher W (2007) Upregulation of brain expression of P-glycoprotein in MRP2-deficient TR(−) rats resembles seizure-induced up-regulation of this drug efflux transporter in normal rats. Epilepsia 48(4):631–645PubMedGoogle Scholar
  106. Hoffmann K, Gastens AM, Volk HA, Löscher W (2006) Expression of the multidrug transporter MRP2 in the blood–brain barrier after pilocarpine-induced seizures in rats. Epilepsy Res 69(1):1–14, Epub 2006 Feb 28PubMedGoogle Scholar
  107. Holman DW, Klein RS, Ransohoff RM (2011) The blood–brain barrier, chemokines and multiple sclerosis. Biochim Biophys Acta 1812(2):220–230PubMedCentralPubMedGoogle Scholar
  108. Holtzman DM, Zlokovic BV (2007) Role of Ab transport and clearance in the pathogenesis and treatment of Alzheimer’s disease. In: Sisodia S, Tanzi RE (eds) Alzheimer’s disease: advances in genetics, molecular and cellular biology. Springer, New York, pp 179–198Google Scholar
  109. Hossmann KA (1994) Viability thresholds and the penumbra of focal ischemia. Ann Neurol 36:557–565PubMedGoogle Scholar
  110. Hynes RO, Lander AD (1992) Contact and adhesive specificities in the associations, migrations, and targeting of cells and axons. Cell 68(2):303–322PubMedGoogle Scholar
  111. Iadecola C (2010) The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia. Acta Neuropathol 120(3):287–296PubMedCentralPubMedGoogle Scholar
  112. Jellinger KA (2012) Interaction between pathogenic proteins in neurodegenerative disorders. J Cell Mol Med 16(6):1166–1183PubMedGoogle Scholar
  113. Kalaria RN (2010) Vascular basis for brain degeneration: faltering controls and risk factors for dementia. Nutr Rev 68(Suppl 2):S74–S87PubMedCentralPubMedGoogle Scholar
  114. Kamouchi M, Ago T, Kuroda J, Kitazono T (2012) The possible roles of brain pericytes in brain ischemia and stroke. Cell Mol Neurobiol 32(2):159–165PubMedGoogle Scholar
  115. Kannan P, John C, Zoghbi SS, Halldin C, Gottesman MM, Innis RB, Hall MD (2009) Imaging the function of P-glycoprotein with radiotracers: pharmacokinetics and in vivo applications. Clin Pharmacol Ther 86(4):368–377PubMedCentralPubMedGoogle Scholar
  116. Kaya M, Ahishali B (2011) Assessment of permeability in barrier type of endothelium in brain using tracers: Evans blue, sodium fluorescein, and horseradish peroxidase. Methods Mol Biol 763:369–382PubMedGoogle Scholar
  117. Kaya M, Gurses C, Kalayci R, Ekizoglu O, Ahishali B, Orhan N, Oku B, Arican N, Ustek D, Bilgic B, Elmas I, Kucuk M, Kemikler G (2008) Morphological and functional changes of blood–brain barrier in kindled rats with cortical dysplasia. Brain Res 1208:181–191PubMedGoogle Scholar
  118. Kerr IG, Zimm S, Collins JM, O'Neill D, Poplack DG (1984) Effect of intravenous dose and schedule on cerebrospinal fluid pharmacokinetics of 5-fluorouracil in the monkey. Cancer Res 44:4929–4932PubMedGoogle Scholar
  119. Kirk J, Plumb J, Mirakhur M, McQuaid S (2003) Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood–brain barrier leakage and active demyelination. J Pathol 201:319–327PubMedGoogle Scholar
  120. Kooij G, Backer R, Koning JJ, Reijerkerk A, van Horssen J, van der Pol SM, Drexhage J, Schinkel A, Dijkstra CD, den Haan JM, Geijtenbeek TB, de Vries HE (2009) P-glycoprotein acts as an immunomodulator during neuroinflammation. PLoS One 4(12):e8212PubMedCentralPubMedGoogle Scholar
  121. Kooij G, van Horssen J, de Lange EC, Reijerkerk A, van der Pol SM, van Het Hof B, Drexhage J, Vennegoor A, Killestein J, Scheffer G, Oerlemans R, Scheper R, van der Valk P, Dijkstra CD, de Vries HE (2010) T lymphocytes impair P-glycoprotein function during neuroinflammation. J Autoimmun 34(4):416–425PubMedGoogle Scholar
  122. Krantic S, Mechawar N, Reix S, Quirion R (2005) Molecular basis of programmed cell death involved in neurodegeneration. Trends Neurosci 28(12):670–676PubMedGoogle Scholar
  123. Krueger M, Bechmann I (2010) CNS pericytes: concepts, misconceptions, and a way out. Glia 58(1):1–10PubMedGoogle Scholar
  124. Kuhnke D, Jedlitschky G, Grube M, Krohn M, Jucker M, Mosyagin I, Cascorbi I, Walker LC, Kroemer HK, Warzok RW, Vogelgesang S (2007) MDR1-P-glycoprotein (ABCB1) mediates transport of Alzheimer's amyloid-beta peptides–implications for the mechanisms of abeta clearance at the blood–brain barrier. Brain Pathol 17(4):347–353PubMedGoogle Scholar
  125. Kunz J, Krause D, Kremer M, Dermietzel R (1994) The 140 kDa protein of blood–brain barrier-associated pericytes is identical to aminopeptidase N. J Neurochem 62:2375–2386PubMedGoogle Scholar
  126. Kunz J, Krause D, Gehrmann J, Dermietzel R (1995) Changes in the expression pattern of blood–brain barrier-associated pericytic aminopeptidase N (pAPN) in the course of acute experimental auto-immune encephalomyelitis. J Neuroimmunol 59:41–55PubMedGoogle Scholar
  127. Lamas M, González-Mariscal L, Gutiérrez R (2002) Presence of claudins mRNA in the brain. Selective modulation of expression by kindling epilepsy. Brain Res Mol Brain Res 104(2):250–254PubMedGoogle Scholar
  128. Lee G, Bendayan R (2004) Functional expression and localization of P-glycoprotein in the central nervous system: relevance to the pathogenesis and treatment of neurological disorders. Pharm Res 21(8):1313–1330PubMedGoogle Scholar
  129. Leroy C, Roch C, Koning E, Namer IJ, Nehlig A (2003) In the lithium-pilocarpine model of epilepsy, brain lesions are not linked to changes in blood–brain barrier permeability: an autoradiographic study in adult and developing rats. Exp Neurol 182(2):361–372PubMedGoogle Scholar
  130. Lessing D, Bonini NM (2009) Maintaining the brain: insight into human neurodegeneration from Drosophila melanogaster mutants. Nature Rev Genet 10:359–370PubMedCentralPubMedGoogle Scholar
  131. Lindsay RM, Altar CA, Cedarbaum JM, Hyman C, Wiegand SJ (1993) The therapeutic potential of neurotrophic factors in the treatment of Parkinson's disease. Exp Neurol 124(1):103R–118RGoogle Scholar
  132. Lipton SA (2005) The molecular basis of memantine action in Alzheimer’s disease and other neurologic disorders: low-affinity, uncompetitive antagonism. Curr Alzheimer Res 2:155–165PubMedGoogle Scholar
  133. Liu JY, Thom M, Catarino CB, Martinian L, Figarella-Branger D, Bartolomei F, Koepp M, Sisodiya SM (2012) Neuropathology of the blood–brain barrier and pharmacoresistance in human epilepsy. Brain 135(Pt 10):3115–3133PubMedGoogle Scholar
  134. Lo EH, Dalkara T, Moskowitz MA (2003) Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 4:399–415PubMedGoogle Scholar
  135. Lok J, Gupta P, Guo S, Kim WJ, Whalen MJ, van Leyen K, Lo EH (2007) Cell-cell signaling in the neurovascular unit. Neurochem Res 32:2032–2045PubMedGoogle Scholar
  136. Loscher W, Potschka H (2005) Drug resistance in brain diseases and the role of drug efflux transporters. Nat Rev Neurosci 6:591–602PubMedGoogle Scholar
  137. Löscher W, Luna-Tortós C, Römermann K, Fedrowitz M (2011) Do ATP-binding cassette transporters cause pharmacoresistance in epilepsy? Problems and approaches in determining which antiepileptic drugs are affected. Curr Pharm Des 17(26):2808–2828PubMedGoogle Scholar
  138. Lu M, Hu G (2012) Targeting metabolic inflammation in Parkinson's disease: implications for prospective therapeutic strategies. Clin Exp Pharmacol Physiol 39(6):577–585PubMedGoogle Scholar
  139. Luer MS (1999) Interventions to achieve tonic exposure to levodopa: delaying or preventing the onset of motor complications. Pharmacotherapy 19(11 Pt 2):169S–179SPubMedGoogle Scholar
  140. Luessi F, Siffrin V, Zipp F (2012) Neurodegeneration in multiple sclerosis: novel treatment strategies. Expert Rev Neurother 12(9):1061–1077PubMedGoogle Scholar
  141. Luna-Tortós C, Rambeck B, Jürgens UH, Löscher W (2009) The antiepileptic drug topiramate is a substrate for human P-glycoprotein but not multidrug resistance proteins. Pharm Res 26(11):2464–2470PubMedGoogle Scholar
  142. Luna-Tortós C, Fedrowitz M, Löscher W (2010) Evaluation of transport of common antiepileptic drugs by human multidrug resistance-associated proteins (MRP1, 2 and 5) that are overexpressed in pharmacoresistant epilepsy. Neuropharmacology 58(7):1019–1032PubMedGoogle Scholar
  143. Marchi N, Hallene KL, Kight KM, Cucullo L, Moddel G, Bingaman W, Dini G, Vezzani A, Janigro D (2004) Significance of MDR1 and multiple drug resistance in refractory human epileptic brain. BMC Med 2:37PubMedCentralPubMedGoogle Scholar
  144. Marroni M, Marchi N, Cucullo L, Abbott NJ, Signorelli K, Janigro D (2003) Vascular and parenchymal mechanisms in multiple drug resistance: a lesson from human epilepsy. Curr Drug Targets 4(4):297–304PubMedGoogle Scholar
  145. Maxwell K, Berliner JA, Cancilla PA (1987) Induction of gamma glutamyltranspeptidase in cultured cerebral endothelial cells by a product released by astrocytes. Brain Res 410:309–314PubMedGoogle Scholar
  146. Mazarati AM, Sofia RD, Wasterlain CG (2002) Anticonvulsant and antiepileptogenic effects of fluorofelbamate in experimental status epilepticus. Seizure 11(7):423–430PubMedGoogle Scholar
  147. McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50(1):121–127Google Scholar
  148. McIntosh TK, Juhler M, Wieloch T (1998) Novel pharmacologic strategies in the treatment of experimental traumatic brain injury: 1998. J Neurotrauma 15(10):731–769PubMedGoogle Scholar
  149. Merker HJ (1994) Morphology of the basement membrane. Microsc Res Tech 28(2):95–124PubMedGoogle Scholar
  150. Meyer J, Mischek U, Vehyl M, Henzel K, Galla H-J (1990) Blood–brain barrier characteristic enzymatic properties in cultured brain capillary endothelial cells. Brain Res 514:305–309PubMedGoogle Scholar
  151. Michalak Z, Lebrun A, Di Miceli M, Rousset MC, Crespel A, Coubes P, Henshall DC, Lerner-Natoli M, Rigau V (2012) IgG leakage may contribute to neuronal dysfunction in drug-refractory epilepsies with blood–brain barrier disruption. J Neuropathol Exp Neurol 71(9):826–838PubMedGoogle Scholar
  152. Miltiadous P, Stamatakis A, Koutsoudaki PN, Tiniakos DG, Stylianopoulou F (2011) IGF-I ameliorates hippocampal neurodegeneration and protects against cognitive deficits in an animal model of temporal lobe epilepsy. Exp Neurol 231(2):223–235PubMedGoogle Scholar
  153. Minagar A, Maghzi AH, McGee JC, Alexander JS (2012) Emerging roles of endothelial cells in multiple sclerosis pathophysiology and therapy. Neurol Res 34(8):738–745PubMedGoogle Scholar
  154. Miyakawa T (2010) Vascular pathology in Alzheimer's disease. Psychogeriatrics 10(1):39–44PubMedGoogle Scholar
  155. Miyazaki K, Ohta Y, Nagai M, Morimoto N, Kurata T, Takehisa Y, Ikeda Y, Matsuura T, Abe K (2011) Disruption of neurovascular unit prior to motor neuron degeneration in amyotrophic lateral sclerosis. J Neurosci Res 89(5):718–728PubMedGoogle Scholar
  156. Mooradian AD, Chung HC, Shah GN (1997) GLUT-1 expression in the cerebra of patients with Alzheimer’s disease. Neurobiol Aging 18:469–474PubMedGoogle Scholar
  157. Morgan L, Shah B, Rivers LE, Barden L, Groom AJ, Chung R, Higazi D, Desmond H, Smith T, Staddon JM (2007) Inflammation and dephosphorylation of the tight junction protein occludin in an experimental model of multiple sclerosis. Neuroscience 147:664–673PubMedGoogle Scholar
  158. Mosconi L, Sorbi S, de Leon MJ, Li Y, Nacmias B, Myoung PS, Tsui W, Ginestroni A, Bessi V, Fayyazz M, Caffarra P, Pupi A (2006) Hypometabolism exceeds atrophy in presymptomatic early-onset familial Alzheimer's disease. J Nucl Med 47(11):1778–1786PubMedGoogle Scholar
  159. Mosconi L, De Santi S, Li J, Tsui WH, Li Y, Boppana M, Laska E, Rusinek H, de Leon MJ (2008) Hippocampal hypometabolism predicts cognitive decline from normal aging. Neurobiol Aging 29(5):676–692PubMedCentralPubMedGoogle Scholar
  160. Mulder M, Blokland A, van den Berg DJ, Schulten H, Bakker AHF, Terwel D, Honig W, de Kloet ER, Havekes LM, Steinbusch HWM, de Lange ECM (2001) Apolipoprotein E protects against neuropathology induced by a high-fat diet and maintains the integrity of the blood–brain barrier during aging. Lab Invest 81(7):953–960PubMedGoogle Scholar
  161. Nakagawa S, Deli MA, Nakao S, Honda M, Hayashi K, Nakaoke R, Kataoka Y, Niwa M (2007) Pericytes from brain microvessels strengthen the barrier integrity in primary cultures of rat brain endothelial cells. Cell Mol Neurobiol 27(6):687–694PubMedGoogle Scholar
  162. Navarro A, Boveris A (2010) Brain mitochondrial dysfunction in aging, neurodegeneration, and Parkinson’s disease. Front Aging Neurosci 2:34PubMedCentralPubMedGoogle Scholar
  163. Ndode-Ekane XE, Hayward N, Gröhn O, Pitkänen A (2010) Vascular changes in epilepsy: functional consequences and association with network plasticity in pilocarpine-induced experimental epilepsy. Neuroscience 166(1):312–332PubMedGoogle Scholar
  164. Nico B, Frigeri A, Nicchia GP, Corsi P, Ribatti D, Quondamatteo F, Herken R, Girolamo F, Marzullo A, Svelto M, Svelto M, Roncali L (2003) Severe alterations of endothelial and glial cells in the blood–brain barrier of dystrophic mdx mice. Glia 42:235–251PubMedGoogle Scholar
  165. Ohtsuki S, Terasaki T (2007) Contribution of carrier-mediated transport systems to the blood–brain barrier as a supporting and protecting interface for the brain; importance for CNS drug discovery and development. Pharm Res 24:1745–1758PubMedGoogle Scholar
  166. Okouchi M, Ekshyyan O, Maracine M, Aw TY (2007) Neuronal apoptosis in neurodegeneration. Antioxid Redox Signal 9(8):1059–1096PubMedGoogle Scholar
  167. Owen JB, Sultana R, Aluise CD, Erickson MA, Price TO, Bu G, Banks WA, Butterfield DA (2010) Oxidative modification to LDL receptor-related protein 1 in hippocampus from subjects with Alzheimer disease: implications for Aβ accumulation in AD brain. Free Radic Biol Med 49(11):1798–1803PubMedCentralPubMedGoogle Scholar
  168. Padou V, Boyet S, Nehlig A (1995) Changes in transport of [14C] alpha-aminoisobutyric acid across the blood–brain barrier during pentylenetetrazol-induced status epilepticus in the immature rat. Epilepsy Res 22(3):175–183PubMedGoogle Scholar
  169. Palmer AM (2011) The role of the blood brain barrier in neurodegenerative disorders and their treatment. J Alzheimers Dis 24(4):643–656PubMedGoogle Scholar
  170. Patel NK, Gill SS (2007) GDNF delivery for Parkinson's disease. Acta Neurochir Suppl 97(Pt 2):135–154PubMedGoogle Scholar
  171. Pathan SA, Iqbal Z, Zaidi SM, Talegaonkar S, Vohra D, Jain GK, Azeem A, Jain N, Lalani JR, Khar RK, Ahmad FJ (2009) CNS drug delivery systems: novel approaches. Recent Pat Drug Deliv Formul 3(1):71–89PubMedGoogle Scholar
  172. Paulsson M (1992) Basement membrane proteins: structure, assembly, and cellular interactions. Crit Rev Biochem Mol Biol 27(1–2):93–127PubMedGoogle Scholar
  173. Paweletz CP, Wiener MC, Bondarenko AY, Yates NA, Song Q, Liaw A, Lee AY, Hunt BT, Henle ES, Meng F, Sleph HF, Holahan M, Sankaranarayanan S, Simon AJ, Settlage RE, Sachs JR, Shearman M, Sachs AB, Cook JJ, Hendrickson RC (2010) Application of an end-to-end biomarker discovery platform to identify target engagement markers in cerebrospinal fluid by high resolution differential mass spectrometry. J Proteome Res 9(3):1392–1401PubMedGoogle Scholar
  174. Perez-Pinzon MA, Stetler RA, Fiskum G (2012) Novel mitochondrial targets for neuroprotection. J Cereb Blood Flow Metab 32(7):1362–1376PubMedGoogle Scholar
  175. Persidsky Y, Ramirez SH, Haorah J, Kanmogne GD (2006) Blood–brain barrier: structural components and function under physiologic and pathologic conditions. J Neuroimmune Pharmacol 1(3):223–236PubMedGoogle Scholar
  176. Pflanzner T, Petsch B, André-Dohmen B, Müller-Schiffmann A, Tschickardt S, Weggen S, Stitz L, Korth C, Pietrzik CU (2012) Cellular prion protein participates in amyloid-β transcytosis across the blood–brain barrier. J Cereb Blood Flow Metab 32(4):628–632PubMedGoogle Scholar
  177. Pop V, Badaut J (2011) A neurovascular perspective for long-term changes after brain trauma. Transl Stroke Res 2(4):533–545PubMedCentralPubMedGoogle Scholar
  178. Portelli J, Aourz N, De Bundel D, Meurs A, Smolders I, Michotte Y, Clinckers R (2009) Intrastrain differences in seizure susceptibility, pharmacological response and basal neurochemistry of Wistar rats. Epilepsy Res 87(2–3):234–246PubMedGoogle Scholar
  179. Potschka H, Löscher W (2001a) In vivo evidence for P-glycoprotein-mediated transport of phenytoin at the blood brain barrier of rats. Epilepsia 42:1231–1240PubMedGoogle Scholar
  180. Potschka H, Löscher W (2001b) Multidrug resistance-associated protein is involved in the regulation of extracellular levels of phenytoin in the brain. Neuroreport 12(11):2387–2389PubMedGoogle Scholar
  181. Potschka H, Fedrowitz M, Löscher W (2001) P-glycoprotein and multidrug resistance-associated protein are involved in the regulation of extracellular levels of the major antiepileptic drug carbamazepine in the brain. Neuroreport 12:3557–3560PubMedGoogle Scholar
  182. Potschka H, Fedrowitz M, Loscher W (2002) P-Glycoprotein-mediated efflux of phenobarbital, lamotrigine, and felbamate at the blood–brain barrier, evidence from microdialysis experiments in rats. Neurosci Lett 327(3):173–176PubMedGoogle Scholar
  183. Potschka H, Fedrowitz M, Loscher W (2003a) Multidrug resistance protein MRP2 contributes to the blood–brain barrier function and restricts antiepileptic drug activity. J Pharmacol Exp Ther 306:124–131PubMedGoogle Scholar
  184. Potschka H, Fedrowitz M, Loscher W (2003b) Brain access and anticonvulsant efficacy of carbamazepine, lamotrigine, and felbamate in ABCC2/MRP2-deficient TR- rats. Epilepsia 44(12):1479–1486PubMedGoogle Scholar
  185. Potschka H, Baltes S, Loscher W (2004) Inhibition of multidrug transporters by verapamil or probenecid does not alter blood–brain barrier penetration of levetiracetam in rats. Epilepsy Res 58(2–3):85–91PubMedGoogle Scholar
  186. Price DL, Sisodia SS, Borchelt DR (1998) Genetic neurodegenerative diseases: the human illness and transgenic models. Science 282:1079–1083PubMedGoogle Scholar
  187. Prins ML, Giza CC (2006) Induction of monocarboxylate transporter 2 expression and ketone transport following traumatic brain injury in juvenile and adult rats. Dev Neurosci 28(4–5):447–456PubMedGoogle Scholar
  188. Prinz M, Priller J, Sisodia SS, Ransohoff RM (2011) Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat Neurosci 14(10):1227–1235PubMedGoogle Scholar
  189. Ravenstijn PG, Merlini M, Hameetman M, Murray TK, Ward MA, Lewis H, Ball G, Mottart C, de de Ville de Goyet C, Lemarchand T, van Belle K, O'Neill MJ, Danhof M, de Lange EC (2008) The exploration of rotenone as a toxin for inducing Parkinson's disease in rats, for application in BBB transport and PK-PD experiments. J Pharmacol Toxicol Methods 57(2):114–130PubMedGoogle Scholar
  190. Ravenstijn PGM, Drenth H, Baatje MS, O’Neill MJ, Danhof M, de Lange ECM (2012) Evaluation of BBB transport and CNS drug metabolism in diseased and control brain after intravenous l-DOPA in a unilateral rat model of Parkinson’s disease. Fluids Barriers CNS 9:4PubMedCentralPubMedGoogle Scholar
  191. Reale M, Iarlori C, Thomas A, Gambi D, Perfetti B, Di Nicola M, Onofrj M (2009) Peripheral cytokines profile in Parkinson's disease. Brain Behav Immun 23(1):55–63PubMedGoogle Scholar
  192. Romanitan MO, Popescu BO, Winblad B, Bajenaru OA, Bogdanovic N (2007) Occludin is overexpressed in Alzheimer's disease and vascular dementia. J Cell Mol Med 11(3):569–579PubMedGoogle Scholar
  193. Ronaldson PT, Davis TP (2012) Blood–brain barrier integrity and glial support: mechanisms that can be targeted for novel therapeutic approaches in stroke. Curr Pharm Des 18(25):3624–3644PubMedGoogle Scholar
  194. Rosenberg GA, Yang Y (2007) Vasogenic edema due to tight junction disruption by matrix metalloproteinases in cerebral ischemia. Neurosurg Focus 22:E4PubMedGoogle Scholar
  195. Rosenfeld JV, Maas AI, Bragge P, Morganti-Kossmann MC, Manley GT, Gruen RL (2012) Early management of severe traumatic brain injury. Lancet 380(9847):1088–1098PubMedGoogle Scholar
  196. Sagare AP, Deane R, Zlokovic BV (2012) Low-density lipoprotein receptor-related protein 1: A physiological Aβ homeostatic mechanism with multiple therapeutic opportunities. Pharmacol Ther 136(1):94–105PubMedCentralPubMedGoogle Scholar
  197. Sahin D, Ilbay G, Ates N (2003) Changes in the blood–brain barrier permeability and in the brain tissue trace element concentrations after single and repeated pentylenetetrazole-induced seizures in rats. Pharmacol Res 48(1):69–73PubMedGoogle Scholar
  198. Samuraki M, Matsunari I, Chen WP, Yajima K, Yanase D, Fujikawa A, Takeda N, Nishimura S, Matsuda H, Yamada M (2007) Partial volume effect-corrected FDG PET and grey matter volume loss in patients with mild Alzheimer’s disease. Eur J Nucl Med Mol Imaging 34:1658–1669PubMedGoogle Scholar
  199. Sánchez-Pérez AM, Montoliu C, Felipo V (2003) Trialkylglycines: a new family of compounds with in vivo neuroprotective activity. CNS Drug Rev 9(3):263–274PubMedGoogle Scholar
  200. Sandoval KE, Witt KA (2008) Blood–brain barrier tight junction permeability and ischemic stroke. Neurobiol Dis 32(2):200–219PubMedGoogle Scholar
  201. Sayre LM, Perry G, Smith MA (2008) Oxidative stress and neurotoxicity. Chem Res Toxicol 21(1):172–188PubMedGoogle Scholar
  202. Schinkel A, Smit J, van Tellingen O, Beijnen J, Wagenaar E, van Deemter L et al (1994) Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood–brain barrier and to increased sensitivity to drugs. Cell 77:491–502PubMedGoogle Scholar
  203. Schneider A, Mandelkow E (2008) Tau-based treatment strategies in neurodegenerative diseases. Neurotherapeutics 5(3):443–457PubMedGoogle Scholar
  204. Scism JL, Powers KM, Artru AA, Lewis L, Shen DD (2000) Probenecid-inhibitable efflux transport of valproic acid in the brain parenchymal cells of rabbits: a microdialysis study. Brain Res 884(1–2):77–86PubMedGoogle Scholar
  205. Selkoe DJ (2011) Alzheimer's disease. Cold Spring Harb Perspect Biol 1:3–7Google Scholar
  206. Serrano GE, Lelutiu N, Rojas A, Cochi S, Shaw R, Makinson CD, Wang D, FitzGerald GA, Dingledine R (2011) Ablation of cyclooxygenase-2 in forebrain neurons is neuroprotective and dampens brain inflammation after status epilepticus. J Neurosci 31(42):14850–14860PubMedGoogle Scholar
  207. Sharma HS, Castellani RJ, Smith MA, Sharma A (2012) The blood–brain barrier in Alzheimer's disease: novel therapeutic targets and nanodrug delivery. Int Rev Neurobiol 102:47–90PubMedGoogle Scholar
  208. Sheng ZH, Cai Q (2012) Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration. Nat Rev Neurosci 13:77–93PubMedGoogle Scholar
  209. Shepardson NE, Shankar GM, Selkoe DJ (2011) Cholesterol level and statin use in Alzheimer disease: II. Review of human trials and recommendations. Arch Neurol 68(11):1385–1392PubMedCentralPubMedGoogle Scholar
  210. Shlosberg D, Benifla M, Kaufer D, Friedman A (2010) Blood–brain barrier breakdown as a therapeutic target in traumatic brain injury. Nat Rev Neurol 6(7):393–403PubMedCentralPubMedGoogle Scholar
  211. Shoham S, Youdim MB (2004) Nutritional iron deprivation attenuates kainate-induced neurotoxicity in rats: implications for involvement of iron in neurodegeneration. Ann N Y Acad Sci 1012:94–114PubMedGoogle Scholar
  212. Shoulson I (1998) Experimental therapeutics of neurodegenerative disorders: unmet needs. Science 282(5391):1072–1074PubMedGoogle Scholar
  213. Siddiqui A, Kerb R, Weale ME, Brinkmann U, Smith A, Goldstein DB, Wood NW, Sisodiya SM (2003) Association of multidrug resistance in epilepsy with a polmorhism in the drug-transporter gene ABCB1. N Engl J Med 348:1442–1448PubMedGoogle Scholar
  214. Sills GJ, Kwan P, Butler E, de Lange EC, van den Berg DJ, Brodie MJ (2002) P-glycoprotein-mediated efflux of antiepileptic drugs: preliminary studies in mdr1a knockout mice. Epilepsy Behav 3(5):427–432PubMedGoogle Scholar
  215. Simpson IA, Carruthers A, Vannucci SJ (2007) Supply and demand in cerebral energy metabolism: the role of nutrient transporters. J Cereb Blood Flow Metab 27(11):1766–1791PubMedCentralPubMedGoogle Scholar
  216. Sisodiya SM, Mefford HC (2011) Genetic contribution to common epilepsies. Curr Opin Neurol 24(2):140–145PubMedGoogle Scholar
  217. Sivanandam TM, Thakur MK (2012) Traumatic brain injury: a risk factor for Alzheimer's disease. Neurosci Biobehav Rev 36(5):1376–1381PubMedGoogle Scholar
  218. Soto C (2008) Endoplasmic reticulum stress, PrP trafficking, and neurodegeneration. Dev Cell 15(3):339–341PubMedCentralPubMedGoogle Scholar
  219. Soto C, Estrada LD (2008) Protein misfolding and neurodegeneration. Arch Neurol 65(2):184–189PubMedGoogle Scholar
  220. Spector R (2009) Nutrient transport systems in brain: 40 years of progress. J Neurochem 111(2):315–320PubMedGoogle Scholar
  221. Spector R, Johanson CE (2007) Vitamin transport and homeostasis in mammalian brain: focus on Vitamins B and E. J Neurochem 103:425–438PubMedGoogle Scholar
  222. Stangel M (2012) Neurodegeneration and neuroprotection in multiple sclerosis. Curr Pharm Des 18(29):4471–4474PubMedGoogle Scholar
  223. Stokin GB, Goldstein LSB (2006) Axonal transport and Alzheimer’s disease. Annu Rev Biochem 75:607–627PubMedGoogle Scholar
  224. Syvänen S, Luurtsema G, Molthoff CF, Windhorst AD, Huisman MC, Lammertsma AA, Voskuyl RA, de Lange EC (2011) (R)-[11C]verapamil PET studies to assess changes in P-glycoprotein expression and functionality in rat blood–brain barrier after exposure to kainate-induced status epilepticus. BMC Med Imaging 11:1PubMedCentralPubMedGoogle Scholar
  225. Syvänen S, Schenke M, van den Berg DJ, Voskuyl RA, de Lange EC (2012) Alteration in P-glycoprotein functionality affects intrabrain distribution of quinidine more than brain entry-a study in rats subjected to status epilepticus by kainate. AAPS J 14(1):87–96PubMedGoogle Scholar
  226. Takano T, Tian GF, Peng W, Lou N, Libionka W, Han X, Nedergaard M (2006) Astrocyte-mediated control of cerebral blood flow. Nat Neurosci 9:260–267PubMedGoogle Scholar
  227. Takano T, Han X, Deane R, Zlokovic B, Nedergaard M (2007) Two-photon imaging of astrocytic Ca2+ signaling and the microvasculature in experimental mice models of Alzheimer’s disease. Ann N Y Acad Sci 1097:40–50PubMedGoogle Scholar
  228. Tanzi RE, Moir RD, Wagner SL (2004) Clearance of Alzheimer’s A beta peptide: the many roads to perdition. Neuron 43:605–608PubMedGoogle Scholar
  229. Tate SK, Sisodiya SM (2007) Multidrug resistance in epilepsy: a pharmacogenomic update. Expert Opin Pharmacother 8:1441–1449PubMedGoogle Scholar
  230. Tayarani I, Cloez I, Clément M, Bourre JM (1989) Antioxidant enzymes and related trace elements in aging brain capillaries and choroid plexus. J Neurochem 53:817–824PubMedGoogle Scholar
  231. Vallejo-Illarramendi A, Domercq M, Pérez-Cerdá F, Ravid R, Matute C (2006) Increased expression and function of glutamate transporters in multiple sclerosis. Neurobiol Dis 21(1):154–164PubMedGoogle Scholar
  232. Van Assema DM, Goos JD, van der Flier WM, Lubberink M, Boellaard R, Windhorst AD, Scheltens P, Lammertsma AA, van Berckel BN (2012) No evidence for additional blood–brain barrier P-glycoprotein dysfunction in Alzheimer's disease patients with microbleeds. J Cereb Blood Flow Metab 32(8):1468–1471PubMedGoogle Scholar
  233. Van Damme P, Dewil M, Robberecht W, Van Den Bosch L (2005) Excitotoxicity and amyotrophic lateral sclerosis. Neurodegener Dis 2:147–159PubMedGoogle Scholar
  234. Van der Schyf CJ, Gal S, Geldenhuys WJ, Youdim MB (2006) Multifunctional neuroprotective drugs targeting monoamine oxidase inhibition, iron chelation, adenosine receptors, and cholinergic and glutamatergic action for neurodegenerative diseases. Expert Opin Investig Drugs 15(8):873–886PubMedGoogle Scholar
  235. Van Raamsdonk JM, Warby SC, Hayden MR (2007) Selective degeneration in YAC mouse models of Huntington disease. Brain Res Bull 72(2–3):124–131PubMedGoogle Scholar
  236. Van Vliet EA, van Schaik R, Edelbroek PM, Voskuyl RA, Redeker S, Aronica E, Wadman WJ, Gorter JA (2007) Region-specific overexpression of P-glycoprotein at the blood–brain barrier affects brain uptake of phenytoin in epileptic rats. J Pharmacol Exp Ther 322(1):141–147PubMedGoogle Scholar
  237. Van Vliet EA, Zibell G, Pekcec A, Schlichtiger J, Edelbroek PM, Holtman L, Aronica E, Gorter JA (2010) Potschka. COX-2 inhibition controls P-glycoprotein expression and promotes brain delivery of phenytoin in chronic epileptic rats. Neuropharmacology 58(2):404–412PubMedGoogle Scholar
  238. Vautier S, Milane A, Fernandez C, Chacun H, Lacomblez L, Farinotti R (2009) Role of two efflux proteins, ABCB1 and ABCG2 in blood–brain barrier transport of bromocriptine in a murine model of MPTP-induced dopaminergic degeneration. J Pharm Pharm Sci 12(2):199–208PubMedGoogle Scholar
  239. Vigeveno RM, Wiebenga OT, Wattjes MP, Geurts JJ, Barkhof F (2012) Shifting imaging targets in multiple sclerosis: from inflammation to neurodegeneration. J Magn Reson Imaging 36(1):1–19PubMedGoogle Scholar
  240. Viggars AP, Wharton SB, Simpson JE, Matthews FE, Brayne C, Savva GM, Garwood C, Drew D, Shaw PJ, Ince PG (2011) Alterations in the blood brain barrier in ageing cerebral cortex in relationship to Alzheimer-type pathology: a study in the MRC-CFAS population neuropathology cohort. Neurosci Lett 505(1):25–30PubMedGoogle Scholar
  241. Vogelgesang S, Jedlitschky G, Brenn A, Walker LC (2011) The role of the ATP-binding cassette transporter P-glycoprotein in the transport of β-amyloid across the blood–brain barrier. Curr Pharm Des 17(26):2778–2786PubMedGoogle Scholar
  242. Volk B, Hettmansperger U, Papp TH, Amelizad Z, Oesch F, Knoth R (1991) Mapping of phenytoin-inducible cytochrome P450 immunoreactivity in the mouse central nervous system. Neuroscience 42:215–235PubMedGoogle Scholar
  243. Volk HA, Arabadzisz D, Fritschy JM, Brandt C, Bethmann K, Löscher W (2006) Antiepileptic drug-resistant rats differ from drug-responsive rats in hippocampal neurodegeneration and GABA(A) receptor ligand binding in a model of temporal lobe epilepsy. Neurobiol Dis 21(3):633–646PubMedGoogle Scholar
  244. Von Tell D, Armulik A, Betsholtz C (2006) Pericytes and vascular stability. Exp Cell Res 312:623–629Google Scholar
  245. Vorbrodt AW (1988) Ultrastructural cytochemistry of blood–brain barrier endothelia. Prog Histochem Cytochem 18:1–99PubMedGoogle Scholar
  246. Weaver SM, Chau A, Portelli JN, Grafman J (2012) Genetic polymorphisms influence recovery from traumatic brain injury. Neuroscientist 18(6):631–644PubMedGoogle Scholar
  247. Weber JT (2012) Altered calcium signaling following traumatic brain injury. Front Pharmacol 3:60PubMedCentralPubMedGoogle Scholar
  248. Weinreb O, Amit T, Bar-Am O, Youdim MB (2007a) Induction of neurotrophic factors GDNF and BDNF associated with the mechanism of neurorescue action of rasagiline and ladostigil: new insights and implications for therapy. Ann N Y Acad Sci 1122:155–168PubMedGoogle Scholar
  249. Weinreb O, Drigues N, Sagi Y, Reznick AZ, Amit T, Youdim MB (2007b) The application of proteomics and genomics to the study of age-related neurodegeneration and neuroprotection. Antioxid Redox Signal 9(2):169–179PubMedGoogle Scholar
  250. Weiss HR (1988) Measurement of cerebral capillary perfusion with a fluorescent label. Microvasc Res 36:172–180PubMedGoogle Scholar
  251. Wenk GL (2003) Neuropathologic changes in Alzheimer's disease. J Clin Psychiatry 64(Suppl 9):7–10PubMedGoogle Scholar
  252. Whitton PS (2007) Inflammation as a causative factor in the aetiology of Parkinson’s disease. Br J Pharmacol 150:963–976PubMedGoogle Scholar
  253. Williams SK, Gillis JF, Matthews MA, Wagnert RC, Bitensky MW (1980) Isolation and characterization of brain endothelial cells: morphology and enzyme activity. J Neurochem 35(2):374–381PubMedGoogle Scholar
  254. Winkler EA, Bell RD, Zlokovic BV (2011) Central nervous system pericytes in health and disease. Nat Neurosci 14(11):1398–1405PubMedGoogle Scholar
  255. Winkler EA, Sengillo JD, Sullivan JS, Henkel JS, Appel SH, Zlokovic BV (2013) Blood-spinal cord barrier breakdown and pericyte reductions in amyotrophic lateral sclerosis. Acta Neuropathol 125(1):111–120PubMedCentralPubMedGoogle Scholar
  256. Witt KA, Gillespie TJ, Huber JD, Egleton RD, Davis TP (2001) Peptide drug modifications to enhance bioavailability and blood–brain barrier permeability. Peptides 22:2329–2343PubMedGoogle Scholar
  257. Wolburg H (2006) The endothelial frontier. In: Dermietzel R, Spray DC, Nedergaard M (eds) Blood–brain interface: from ontogeny to artificial barriers. Wiley, Weinheim, pp 77–109Google Scholar
  258. Wolburg H, Noell S, Mack A, Wolburg-Buchholz K, Fallier-Becker P (2009) Brain endothelial cells and the glio-vascular complex. Cell Tissue Res 335(1):75–96PubMedGoogle Scholar
  259. Wu Z, Guo H, Chow N, Sallstrom J, Bell RD, Deane R, Brooks AI, Kanagala S, Rubio A, Sagare A, Liu D, Li F, Armstrong D, Gasiewicz T, Zidovetzki R, Song X, Hofman F, Zlokovic BV (2005) Role of the MEOX2 homeobox gene in neurovascular dysfunction in Alzheimer disease. Nat Med 11(9):959–965PubMedGoogle Scholar
  260. Wyss-Coray T, Lin C, Sanan DA, Mucke L, Masliah E (2000) Chronic overproduction of transforming growth factor-beta1 by astrocytes promotes Alzheimer's disease-like microvascular degeneration in transgenic mice. Am J Pathol 156(1):139–150PubMedGoogle Scholar
  261. Yang Y, Rosenberg GA (2011) MMP-mediated disruption of claudin-5 in the blood–brain barrier of rat brain after cerebral ischemia. Methods Mol Biol 762:333–345PubMedGoogle Scholar
  262. Yang J, Lunde LK, Nuntagij P, Oguchi T, Camassa LM, Nilsson LN, Lannfelt L, Xu Y, Amiry-Moghaddam M, Ottersen OP, Torp R (2011) Loss of astrocyte polarization in the tg-ArcSwe mouse model of Alzheimer's disease. J Alzheimers Dis 27(4):711–722PubMedGoogle Scholar
  263. Youdim MB, Buccafusco JJ (2005) Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders. Trends Pharmacol Sci 26(1):27–35PubMedGoogle Scholar
  264. Yu F, Wang Z, Tchantchou F, Chiu CT, Zhang Y, Chuang DM (2012) Lithium ameliorates neurodegeneration, suppresses neuroinflammation, and improves behavioral performance in a mouse model of traumatic brain injury. J Neurotrauma 29(2):362–374PubMedGoogle Scholar
  265. Zattoni M, Mura ML, Deprez F, Schwendener RA, Engelhardt B, Frei K, Fritschy JM (2011) Brain infiltration of leukocytes contributes to the pathophysiology of temporal lobe epilepsy. J Neurosci 31(11):4037–4050PubMedGoogle Scholar
  266. Zhang XM, Mao XJ, Zhang HL, Zheng XY, Pham T, Adem A, Winblad B, Mix E, Zhu J (2012) Overexpression of apolipoprotein E4 increases kainic-acid-induced hippocampal neurodegeneration. Exp Neurol 233(1):323–332PubMedGoogle Scholar
  267. Zlokovic BV, Yamada S, Holtzman D, Ghiso J, Frangione B (2000) Clearance of amyloid beta-peptide from brain: transport or metabolism? Nat Med 6(7):718–719PubMedGoogle Scholar
  268. Zlokovic BV (2006) Remodeling after stroke. Nat Med 12:390–391PubMedGoogle Scholar
  269. Zlokovic BV (2008) The blood–brain barrier in health and chronic neurodegenerative disorders. Neuron 57(2):178–201PubMedGoogle Scholar
  270. Zlokovic BV (2010) Neurodegeneration and the neurovascular unit. Nat Med 16:1370–1371PubMedGoogle Scholar
  271. Zlokovic BV (2011) Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci 12(12):723–738PubMedGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2014

Authors and Affiliations

  1. 1.Gorlaeus Laboratories, Division of Pharmacology, Leiden Academic Center for Drug ResearchLeiden UniversityLeidenThe Netherlands

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