The AAPS Journal

, Volume 19, Issue 4, pp 910–920 | Cite as

Hypoxic Stress and Inflammatory Pain Disrupt Blood-Brain Barrier Tight Junctions: Implications for Drug Delivery to the Central Nervous System

  • Jeffrey J. Lochhead
  • Patrick T. Ronaldson
  • Thomas P. DavisEmail author
Review Article Theme: CNS Barriers in Health and Disease
Part of the following topical collections:
  1. Theme: CNS Barriers in Health and Disease


A functional blood-brain barrier (BBB) is necessary to maintain central nervous system (CNS) homeostasis. Many diseases affecting the CNS, however, alter the functional integrity of the BBB. It has been shown that various diseases and physiological stressors can impact the BBB’s ability to selectively restrict passage of substances from the blood to the brain. Modifications of the BBB’s permeability properties can potentially contribute to the pathophysiology of CNS diseases and result in altered brain delivery of therapeutic agents. Hypoxia and/or inflammation are central components of a number of diseases affecting the CNS. A number of studies indicate hypoxia or inflammatory pain increase BBB paracellular permeability, induce changes in the expression and/or localization of tight junction proteins, and affect CNS drug uptake. In this review, we look at what is currently known with regard to BBB disruption following a hypoxic or inflammatory insult in vivo. Potential mechanisms involved in altering tight junction components at the BBB are also discussed. A more detailed understanding of the mediators involved in changing BBB functional integrity in response to hypoxia or inflammatory pain could potentially lead to new treatments for CNS diseases with hypoxic or inflammatory components. Additionally, greater insight into the mechanisms involved in TJ rearrangement at the BBB may lead to novel strategies to pharmacologically increase delivery of drugs to the CNS.


blood-brain barrier drug delivery hypoxia pain tight junctions 



This work was supported by NIH grants 5 RO1 NS 42652 and 5 RO1 DA 11271 awarded to TPD.


  1. 1.
    Abbott NJ. Blood-brain barrier structure and function and the challenges for CNS drug delivery. J Inherit Metab Dis. 2013;36(3):437–49.PubMedCrossRefGoogle Scholar
  2. 2.
    Strazielle N, Ghersi-Egea JF. Physiology of blood-brain interfaces in relation to brain disposition of small compounds and macromolecules. Mol Pharm. 2013;10(5):1473–91.PubMedCrossRefGoogle Scholar
  3. 3.
    Ronaldson PT, Davis TP. Targeting blood-brain barrier changes during inflammatory pain: an opportunity for optimizing CNS drug delivery. Ther Deliv. 2011;2(8):1015–41.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Ronaldson PT, Davis TP. Blood-brain barrier integrity and glial support: mechanisms that can be targeted for novel therapeutic approaches in stroke. Curr Pharm Des. 2012;18(25):3624–44.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Pardridge WM. The blood-brain barrier: bottleneck in brain drug development. Neuro Rx. 2005;2(1):3–14.CrossRefGoogle Scholar
  6. 6.
    Brightman MW, Reese TS. Junctions between intimately apposed cell membranes in the vertebrate brain. J Cell Biol. 1969;40(3):648–77.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Butt AM, Jones HC, Abbott NJ. Electrical resistance across the blood-brain barrier in anaesthetized rats: a developmental study. J Physiol. 1990;429:47–62.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Reese TS, Karnovsky MJ. Fine structural localization of a blood-brain barrier to exogenous peroxidase. J Cell Biol. 1967;34(1):207–17.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Banks WA. Characteristics of compounds that cross the blood-brain barrier. BMC Neurol. 2009;9(Suppl 1):S3.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Ohtsuki S, Terasaki T. 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. 2007;24(9):1745–58.PubMedCrossRefGoogle Scholar
  11. 11.
    Hartz AM, Bauer B. ABC transporters in the CNS—an inventory. Curr Pharm Biotechnol. 2011;12(4):656–73.PubMedCrossRefGoogle Scholar
  12. 12.
    Miller DS. Regulation of ABC transporters blood-brain barrier: the good, the bad, and the ugly. Adv Cancer Res. 2015;125:43–70.PubMedCrossRefGoogle Scholar
  13. 13.
    Sanchez-Covarrubias L, Slosky LM, Thompson BJ, Davis TP, Ronaldson PT. Transporters at CNS barrier sites: obstacles or opportunities for drug delivery? Curr Pharm Des. 2014;20(10):1422–49.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Sharma HS, Dey PK. Impairment of blood-brain barrier (BBB) in rat by immobilization stress: role of serotonin (5-HT). Indian J Physiol Pharmacol. 1981;25(2):111–22.PubMedGoogle Scholar
  15. 15.
    Sharma HS, Kretzschmar R, Cervos-Navarro J, Ermisch A, Ruhle HJ, Dey PK. Age-related pathophysiology of the blood-brain barrier in heat stress. Prog Brain Res. 1992;91:189–96.PubMedCrossRefGoogle Scholar
  16. 16.
    Sharabi Y, Danon YL, Berkenstadt H, Almog S, Mimouni-Bloch A, Zisman A, et al. Survey of symptoms following intake of pyridostigmine during the Persian Gulf war. Isr J Med Sci. 1991;27(11–12):656–8.PubMedGoogle Scholar
  17. 17.
    Taylor P. Anticholinesterase agents. In: Brunton LLC, B.A.; Knollmann, B.C., editor. Goodman & Gilman’s: the pharmacological basis of therapeutics. 12 ed: The McGraw-Hill Companies, Inc.; 2011.Google Scholar
  18. 18.
    Friedman A, Kaufer D, Shemer J, Hendler I, Soreq H, Tur-Kaspa I. Pyridostigmine brain penetration under stress enhances neuronal excitability and induces early immediate transcriptional response. Nat Med. 1996;2(12):1382–5.PubMedCrossRefGoogle Scholar
  19. 19.
    Hawkins BT, Davis TP. The blood-brain barrier/neurovascular unit in health and disease. Pharmacol Rev. 2005;57(2):173–85.PubMedCrossRefGoogle Scholar
  20. 20.
    Zlokovic BV. The blood-brain barrier in health and chronic neurodegenerative disorders. Neuron. 2008;57(2):178–201.PubMedCrossRefGoogle Scholar
  21. 21.
    Tietz S, Engelhardt B. Brain barriers: crosstalk between complex tight junctions and adherens junctions. J Cell Biol. 2015;209(4):493–506.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Gunzel D, Yu AS. Claudins and the modulation of tight junction permeability. Physiol Rev. 2013;93(2):525–69.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Daneman R, Zhou L, Agalliu D, Cahoy JD, Kaushal A, Barres BA. The mouse blood-brain barrier transcriptome: a new resource for understanding the development and function of brain endothelial cells. PLoS One. 2010;5(10):e13741.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Haseloff RF, Dithmer S, Winkler L, Wolburg H, Blasig IE. Transmembrane proteins of the tight junctions at the blood-brain barrier: structural and functional aspects. Semin Cell Dev Biol. 2015;38:16–25.PubMedCrossRefGoogle Scholar
  25. 25.
    Ohtsuki S, Yamaguchi H, Katsukura Y, Asashima T, Terasaki T. mRNA expression levels of tight junction protein genes in mouse brain capillary endothelial cells highly purified by magnetic cell sorting. J Neurochem. 2008;104(1):147–54.PubMedGoogle Scholar
  26. 26.
    Krause G, Winkler L, Mueller SL, Haseloff RF, Piontek J, Blasig IE. Structure and function of claudins. Biochim Biophys Acta. 2008;1778(3):631–45.PubMedCrossRefGoogle Scholar
  27. 27.
    Nitta T, Hata M, Gotoh S, Seo Y, Sasaki H, Hashimoto N, et al. Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice. J Cell Biol. 2003;161(3):653–60.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Van Itallie CM, Anderson JM. Claudin interactions in and out of the tight junction. Tissue Barriers. 2013;1(3):e25247.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Furuse M, Hirase T, Itoh M, Nagafuchi A, Yonemura S, Tsukita S, et al. Occludin: a novel integral membrane protein localizing at tight junctions. J Cell Biol. 1993;123(6 Pt 2):1777–88.PubMedCrossRefGoogle Scholar
  30. 30.
    Cummins PM. Occludin: one protein, many forms. Mol Cell Biol. 2012;32(2):242–50.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Walter JK, Rueckert C, Voss M, Mueller SL, Piontek J, Gast K, et al. The oligomerization of the coiled coil-domain of occludin is redox sensitive. Ann N Y Acad Sci. 2009;1165:19–27.PubMedCrossRefGoogle Scholar
  32. 32.
    Wittchen ES, Haskins J, Stevenson BR. Protein interactions at the tight junction: actin has multiple binding partners, and ZO-1 forms independent complexes with ZO-2 and ZO-3. J Biol Chem. 1999;274(49):35179–85.PubMedCrossRefGoogle Scholar
  33. 33.
    Itoh M, Furuse M, Morita K, Kubota K, Saitou M, Tsukita S. Direct binding of three tight junction-associated MAGUKs, ZO-1, ZO-2, and ZO-3, with the COOH termini of claudins. J Cell Biol. 1999;147(6):1351–63.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    McCaffrey G, Staatz WD, Quigley CA, Nametz N, Seelbach MJ, Campos CR, et al. Tight junctions contain oligomeric protein assembly critical for maintaining blood-brain barrier integrity in vivo. J Neurochem. 2007;103(6):2540–55.PubMedCrossRefGoogle Scholar
  35. 35.
    Saitou M, Furuse M, Sasaki H, Schulzke JD, Fromm M, Takano H, et al. Complex phenotype of mice lacking occludin, a component of tight junction strands. Mol Biol Cell. 2000;11(12):4131–42.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Ikenouchi J, Furuse M, Furuse K, Sasaki H, Tsukita S, Tsukita S. Tricellulin constitutes a novel barrier at tricellular contacts of epithelial cells. J Cell Biol. 2005;171(6):939–45.PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Steed E, Rodrigues NT, Balda MS, Matter K. Identification of Marvel D3 as a tight junction-associated transmembrane protein of the occludin family. BMC Cell Biol. 2009;10:95.PubMedPubMedCentralCrossRefGoogle Scholar
  38. 38.
    Krug SM, Amasheh S, Richter JF, Milatz S, Gunzel D, Westphal JK, et al. Tricellulin forms a barrier to macromolecules in tricellular tight junctions without affecting ion permeability. Mol Biol Cell. 2009;20(16):3713–24.PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Bauer H, Zweimueller-Mayer J, Steinbacher P, Lametschwandtner A, Bauer HC. The dual role of zonula occludens (ZO) proteins. J Biomed Biotechnol. 2010;2010:402593.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Furuse M, Sasaki H, Fujimoto K, Tsukita S. A single gene product, claudin-1 or -2, reconstitutes tight junction strands and recruits occludin in fibroblasts. J Cell Biol. 1998;143(2):391–401.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Stevenson BR, Siliciano JD, Mooseker MS, Goodenough DA. Identification of ZO-1: a high molecular weight polypeptide associated with the tight junction (zonula occludens) in a variety of epithelia. J Cell Biol. 1986;103(3):755–66.PubMedCrossRefGoogle Scholar
  42. 42.
    Gumbiner B, Lowenkopf T, Apatira D. Identification of a 160-kDa polypeptide that binds to the tight junction protein ZO-1. Proc Natl Acad Sci U S A. 1991;88(8):3460–4.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Hom S, Fleegal MA, Egleton RD, Campos CR, Hawkins BT, Davis TP. Comparative changes in the blood-brain barrier and cerebral infarction of SHR and WKY rats. Am J Physiol Regul Integr Comp Physiol. 2007;292(5):R1881–92.PubMedCrossRefGoogle Scholar
  44. 44.
    Mark KS, Davis TP. Cerebral microvascular changes in permeability and tight junctions induced by hypoxia-reoxygenation. Am J Physiol Heart Circ Physiol. 2002;282(4):H1485–94.PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Inoko A, Itoh M, Tamura A, Matsuda M, Furuse M, Tsukita S. Expression and distribution of ZO-3, a tight junction MAGUK protein, in mouse tissues. Genes Cells. 2003;8(11):837–45.PubMedCrossRefGoogle Scholar
  46. 46.
    Sugawara T, Fujimura M, Noshita N, Kim GW, Saito A, Hayashi T, et al. Neuronal death/survival signaling pathways in cerebral ischemia. Neuro Rx. 2004;1(1):17–25.CrossRefGoogle Scholar
  47. 47.
    Raz L, Knoefel J, Bhaskar K. The neuropathology and cerebrovascular mechanisms of dementia. J Cereb Blood Flow Metab. 2016;36(1):172–86.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Lavie L, Polotsky V. Cardiovascular aspects in obstructive sleep apnea syndrome—molecular issues, hypoxia and cytokine profiles. Respiration. 2009;78(4):361–70.PubMedCrossRefGoogle Scholar
  49. 49.
    Davies AL, Desai RA, Bloomfield PS, McIntosh PR, Chapple KJ, Linington C, et al. Neurological deficits caused by tissue hypoxia in neuroinflammatory disease. Ann Neurol. 2013;74(6):815–25.PubMedCrossRefGoogle Scholar
  50. 50.
    Wilson MH, Newman S, Imray CH. The cerebral effects of ascent to high altitudes. Lancet Neurol. 2009;8(2):175–91.PubMedCrossRefGoogle Scholar
  51. 51.
    Kalogeris T, Bao Y, Korthuis RJ. Mitochondrial reactive oxygen species: a double edged sword in ischemia/reperfusion vs preconditioning. Redox Biol. 2014;2:702–14.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Sandoval KE, Witt KA. Blood-brain barrier tight junction permeability and ischemic stroke. Neurobiol Dis. 2008;32(2):200–19.PubMedCrossRefGoogle Scholar
  53. 53.
    Engelhardt S, Patkar S, Ogunshola OO. Cell-specific blood-brain barrier regulation in health and disease: a focus on hypoxia. Br J Pharmacol. 2014;171(5):1210–30.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Witt KA, Mark KS, Hom S, Davis TP. Effects of hypoxia-reoxygenation on rat blood-brain barrier permeability and tight junctional protein expression. Am J Physiol Heart Circ Physiol. 2003;285(6):H2820–31.PubMedCrossRefGoogle Scholar
  55. 55.
    Takasato Y, Rapoport SI, Smith QR. An in situ brain perfusion technique to study cerebrovascular transport in the rat. Am J Phys. 1984;247(3 Pt 2):H484–93.Google Scholar
  56. 56.
    Bhattacharjee AK, Nagashima T, Kondoh T, Tamaki N. Quantification of early blood-brain barrier disruption by in situ brain perfusion technique. Brain Res Brain Res Protoc. 2001;8(2):126–31.PubMedCrossRefGoogle Scholar
  57. 57.
    Knowland D, Arac A, Sekiguchi KJ, Hsu M, Lutz SE, Perrino J, et al. Stepwise recruitment of transcellular and paracellular pathways underlies blood-brain barrier breakdown in stroke. Neuron. 2014;82(3):603–17.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Ben-Zvi A, Lacoste B, Kur E, Andreone BJ, Mayshar Y, Yan H, et al. Mfsd 2a is critical for the formation and function of the blood-brain barrier. Nature. 2014;509(7501):507–11.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Witt KA, Mark KS, Sandoval KE, Davis TP. Reoxygenation stress on blood-brain barrier paracellular permeability and edema in the rat. Microvasc Res. 2008;75(1):91–6.PubMedCrossRefGoogle Scholar
  60. 60.
    Fleegal MA, Hom S, Borg LK, Davis TP. Activation of PKC modulates blood-brain barrier endothelial cell permeability changes induced by hypoxia and posthypoxic reoxygenation. Am J Physiol Heart Circ Physiol. 2005;289(5):H2012–9.PubMedCrossRefGoogle Scholar
  61. 61.
    Willis CL, Meske DS, Davis TP. Protein kinase C activation modulates reversible increase in cortical blood-brain barrier permeability and tight junction protein expression during hypoxia and posthypoxic reoxygenation. J Cereb Blood Flow Metab. 2010;30(11):1847–59.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Lochhead JJ, McCaffrey G, Quigley CE, Finch J, DeMarco KM, Nametz N, et al. Oxidative stress increases blood-brain barrier permeability and induces alterations in occludin during hypoxia-reoxygenation. J Cereb Blood Flow Metab. 2010;30(9):1625–36.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    McCaffrey G, Willis CL, Staatz WD, Nametz N, Quigley CA, Hom S, et al. Occludin oligomeric assemblies at tight junctions of the blood-brain barrier are altered by hypoxia and reoxygenation stress. J Neurochem. 2009;110(1):58–71.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Suidan GL, Brill A, De Meyer SF, Voorhees JR, Cifuni SM, Cabral JE, et al. Endothelial Von Willebrand factor promotes blood-brain barrier flexibility and provides protection from hypoxia and seizures in mice. Arterioscler Thromb Vasc Biol. 2013;33(9):2112–20.PubMedCrossRefGoogle Scholar
  65. 65.
    Bauer AT, Burgers HF, Rabie T, Marti HH. Matrix metalloproteinase-9 mediates hypoxia-induced vascular leakage in the brain via tight junction rearrangement. J Cereb Blood Flow Metab. 2010;30(4):837–48.PubMedCrossRefGoogle Scholar
  66. 66.
    Huber JD, Witt KA, Hom S, Egleton RD, Mark KS, Davis TP. Inflammatory pain alters blood-brain barrier permeability and tight junctional protein expression. Am J Physiol Heart Circ Physiol. 2001;280(3):H1241–8.PubMedGoogle Scholar
  67. 67.
    Huber JD, Hau VS, Borg L, Campos CR, Egleton RD, Davis TP. Blood-brain barrier tight junctions are altered during a 72-h exposure to lambda-carrageenan-induced inflammatory pain. Am J Physiol Heart Circ Physiol. 2002;283(4):H1531–7.PubMedCrossRefGoogle Scholar
  68. 68.
    McCaffrey G, Seelbach MJ, Staatz WD, Nametz N, Quigley C, Campos CR, et al. Occludin oligomeric assembly at tight junctions of the blood-brain barrier is disrupted by peripheral inflammatory hyperalgesia. J Neurochem. 2008;106(6):2395–409.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Brooks TA, Hawkins BT, Huber JD, Egleton RD, Davis TP. Chronic inflammatory pain leads to increased blood-brain barrier permeability and tight junction protein alterations. Am J Physiol Heart Circ Physiol. 2005;289(2):H738–43.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Brooks TA, Ocheltree SM, Seelbach MJ, Charles RA, Nametz N, Egleton RD, et al. Biphasic cytoarchitecture and functional changes in the BBB induced by chronic inflammatory pain. Brain Res. 2006;1120(1):172–82.PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Brooks TA, Nametz N, Charles R, Davis TP. Diclofenac attenuates the regional effect of lambda-carrageenan on blood-brain barrier function and cytoarchitecture. J Pharmacol Exp Ther. 2008;325(2):665–73.PubMedCrossRefGoogle Scholar
  72. 72.
    Campos CR, Ocheltree SM, Hom S, Egleton RD, Davis TP. Nociceptive inhibition prevents inflammatory pain induced changes in the blood-brain barrier. Brain Res. 2008;1221:6–13.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Ronaldson PT, Demarco KM, Sanchez-Covarrubias L, Solinsky CM, Davis TP. Transforming growth factor-beta signaling alters substrate permeability and tight junction protein expression at the blood-brain barrier during inflammatory pain. J Cereb Blood Flow Metab. 2009;29(6):1084–98.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Lochhead JJ, McCaffrey G, Sanchez-Covarrubias L, Finch JD, Demarco KM, Quigley CE, et al. Tempol modulates changes in xenobiotic permeability and occludin oligomeric assemblies at the blood-brain barrier during inflammatory pain. Am J Physiol Heart Circ Physiol. 2012;302(3):H582–93.PubMedCrossRefGoogle Scholar
  75. 75.
    Awad AS. Role of AT1 receptors in permeability of the blood-brain barrier in diabetic hypertensive rats. Vasc Pharmacol. 2006;45(3):141–7.CrossRefGoogle Scholar
  76. 76.
    Borges N, Shi F, Azevedo I, Audus KL. Changes in brain microvessel endothelial cell monolayer permeability induced by adrenergic drugs. Eur J Pharmacol. 1994;269(2):243–8.PubMedCrossRefGoogle Scholar
  77. 77.
    Kuang F, Wang BR, Zhang P, Fei LL, Jia Y, Duan XL, et al. Extravasation of blood-borne immunoglobulin G through blood-brain barrier during adrenaline-induced transient hypertension in the rat. Int J Neurosci. 2004;114(6):575–91.PubMedCrossRefGoogle Scholar
  78. 78.
    Murphy VA, Johanson CE. Adrenergic-induced enhancement of brain barrier system permeability to small nonelectrolytes: choroid plexus versus cerebral capillaries. J Cereb Blood Flow Metab. 1985;5(3):401–12.PubMedCrossRefGoogle Scholar
  79. 79.
    Nag S, Harik SI. Cerebrovascular permeability to horseradish peroxidase in hypertensive rats: effects of unilateral locus ceruleus lesion. Acta Neuropathol. 1987;73(3):247–53.PubMedCrossRefGoogle Scholar
  80. 80.
    Hau VS, Huber JD, Campos CR, Davis RT, Davis TP. Effect of lambda-carrageenan-induced inflammatory pain on brain uptake of codeine and antinociception. Brain Res. 2004;1018(2):257–64.PubMedCrossRefGoogle Scholar
  81. 81.
    Seelbach MJ, Brooks TA, Egleton RD, Davis TP. Peripheral inflammatory hyperalgesia modulates morphine delivery to the brain: a role for P-glycoprotein. J Neurochem. 2007;102(5):1677–90.PubMedCrossRefGoogle Scholar
  82. 82.
    King M, Su W, Chang A, Zuckerman A, Pasternak GW. Transport of opioids from the brain to the periphery by P-glycoprotein: peripheral actions of central drugs. Nat Neurosci. 2001;4(3):268–74.PubMedCrossRefGoogle Scholar
  83. 83.
    Tome ME, Schaefer CP, Jacobs LM, Zhang Y, Herndon JM, Matty FO, et al. Identification of P-glycoprotein co-fractionating proteins and specific binding partners in rat brain microvessels. J Neurochem. 2015;134(2):200–10.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Thompson BJ, Sanchez-Covarrubias L, Slosky LM, Zhang Y, Laracuente ML, Ronaldson PT. Hypoxia/reoxygenation stress signals an increase in organic anion transporting polypeptide 1a4 (Oatp 1a4) at the blood-brain barrier: relevance to CNS drug delivery. J Cereb Blood Flow Metab. 2014;34(4):699–707.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Ronaldson PT, Finch JD, Demarco KM, Quigley CE, Davis TP. Inflammatory pain signals an increase in functional expression of organic anion transporting polypeptide 1a4 at the blood-brain barrier. J Pharmacol Exp Ther. 2011;336(3):827–39.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Ronaldson PT, Davis TP. Gabapentin and diclofenac reduce opioid consumption in patients undergoing tonsillectomy: a result of altered CNS drug delivery? Arch Trauma Res. 2013;2(2):97–8.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Yeganeh Mogadam A, Fazel MR, Parviz S. Comparison of analgesic effect between gabapentin and diclofenac on post-operative pain in patients undergoing tonsillectomy. Arch Trauma Res. 2012;1(3):108–11.PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Sanchez-Covarrubias L, Slosky LM, Thompson BJ, Zhang Y, Laracuente ML, DeMarco KM, et al. P-glycoprotein modulates morphine uptake into the CNS: a role for the non-steroidal anti-inflammatory drug diclofenac. PLoS One. 2014;9(2):e88516.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    DosSantos MF, Holanda-Afonso RC, Lima RL, DaSilva AF, Moura-Neto V. The role of the blood-brain barrier in the development and treatment of migraine and other pain disorders. Front Cell Neurosci. 2014;8:302.PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Dreier JP, Jurkat-Rott K, Petzold GC, Tomkins O, Klingebiel R, Kopp UA, et al. Opening of the blood-brain barrier preceding cortical edema in a severe attack of FHM type II. Neurology. 2005;64(12):2145–7.PubMedCrossRefGoogle Scholar
  91. 91.
    Schankin CJ, Maniyar FH, Seo Y, Kori S, Eller M, Chou DE, et al. Ictal lack of binding to brain parenchyma suggests integrity of the blood-brain barrier for 11C-dihydroergotamine during glyceryl trinitrate-induced migraine. Brain. 2016;139(Pt 7):1994–2001.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Gursoy-Ozdemir Y, Qiu J, Matsuoka N, Bolay H, Bermpohl D, Jin H, et al. Cortical spreading depression activates and upregulates MMP-9. J Clin Invest. 2004;113(10):1447–55.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Olah G, Heredi J, Menyhart A, Czinege Z, Nagy D, Fuzik J, et al. Unexpected effects of peripherally administered kynurenic acid on cortical spreading depression and related blood-brain barrier permeability. Drug Des Devel Ther. 2013;7:981–7.PubMedPubMedCentralGoogle Scholar
  94. 94.
    Mika J. Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness. Pharmacol Rep. 2008;60(3):297–307.PubMedGoogle Scholar
  95. 95.
    Inoue K, Tsuda M. Microglia and neuropathic pain. Glia. 2009;57(14):1469–79.PubMedCrossRefGoogle Scholar
  96. 96.
    Huber JD, Campos CR, Mark KS, Davis TP. Alterations in blood-brain barrier ICAM-1 expression and brain microglial activation after lambda-carrageenan-induced inflammatory pain. Am J Physiol Heart Circ Physiol. 2006;290(2):H732–40.PubMedCrossRefGoogle Scholar
  97. 97.
    Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci. 2006;7(1):41–53.PubMedCrossRefGoogle Scholar
  98. 98.
    Choi HS, Roh DH, Yoon SY, Moon JY, Choi SR, Kwon SG, et al. Microglial interleukin-1beta in the ipsilateral dorsal horn inhibits the development of mirror-image contralateral mechanical allodynia through astrocyte activation in a rat model of inflammatory pain. Pain. 2015;156(6):1046–59.PubMedGoogle Scholar
  99. 99.
    Gao YJ, Ji RR. Targeting astrocyte signaling for chronic pain. Neurotherapeutics. 2010;7(4):482–93.PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Armulik A, Genove G, Mae M, Nisancioglu MH, Wallgard E, Niaudet C, et al. Pericytes regulate the blood-brain barrier. Nature. 2010;468(7323):557–61.PubMedCrossRefGoogle Scholar
  101. 101.
    Al Ahmad A, Taboada CB, Gassmann M, Ogunshola OO. Astrocytes and pericytes differentially modulate blood-brain barrier characteristics during development and hypoxic insult. J Cereb Blood Flow Metab. 2011;31(2):693–705.PubMedCrossRefGoogle Scholar
  102. 102.
    Pan W, Stone KP, Hsuchou H, Manda VK, Zhang Y, Kastin AJ. Cytokine signaling modulates blood-brain barrier function. Curr Pharm Des. 2011;17(33):3729–40.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Zhang WJ, Feng J, Zhou R, Ye LY, Liu HL, Peng L, et al. Tanshinone IIA protects the human blood-brain barrier model from leukocyte-associated hypoxia-reoxygenation injury. Eur J Pharmacol. 2010;648(1–3):146–52.PubMedCrossRefGoogle Scholar
  104. 104.
    Braniste V, Al-Asmakh M, Kowal C, Anuar F, Abbaspour A, Toth M, et al. The gut microbiota influences blood-brain barrier permeability in mice. Sci Transl Med. 2014; 6(263):263ra158.Google Scholar
  105. 105.
    Montagne A, Barnes SR, Sweeney MD, Halliday MR, Sagare AP, Zhao Z, et al. Blood-brain barrier breakdown in the aging human hippocampus. Neuron. 2015;85(2):296–302.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid beta. Sci Transl Med. 2012;4(147):147ra11.CrossRefGoogle Scholar
  107. 107.
    Nathoo N, Jalal H, Natah SS, Zhang Q, Wu Y, Dunn JF. Hypoxia and inflammation-induced disruptions of the blood-brain and blood-cerebrospinal fluid barriers assessed using a novel T1-based MRI method. Acta Neurochir Suppl. 2016;121:23–8.PubMedCrossRefGoogle Scholar
  108. 108.
    Echeverry S, Shi XQ, Rivest S, Zhang J. Peripheral nerve injury alters blood-spinal cord barrier functional and molecular integrity through a selective inflammatory pathway. J Neurosci. 2011;31(30):10819–28.PubMedCrossRefGoogle Scholar
  109. 109.
    Sharma HS, Winkler T. Assessment of spinal cord pathology following trauma using early changes in the spinal cord evoked potentials: a pharmacological and morphological study in the rat. Muscle Nerve Suppl. 2002;11:S83–91.PubMedCrossRefGoogle Scholar
  110. 110.
    Hu J, Yu Q, Xie L, Zhu H. Targeting the blood-spinal cord barrier: a therapeutic approach to spinal cord protection against ischemia-reperfusion injury. Life Sci. 2016;158:1–6.PubMedCrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2017

Authors and Affiliations

  • Jeffrey J. Lochhead
    • 1
  • Patrick T. Ronaldson
    • 1
  • Thomas P. Davis
    • 1
    Email author
  1. 1.Department of PharmacologyUniversity of ArizonaTucsonUSA

Personalised recommendations