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Adverse Effect of Cyclosporin A on Barrier Functions of Cerebral Microvascular Endothelial Cells After Hypoxia-reoxygenation Damage In Vitro

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Abstract

Hypoxia and post-hypoxic reoxygenation induces disruption of the blood–brain barrier (BBB). Alterations of the BBB function after hypoxia/reoxygenation (H/R) injury remain unclear. Cyclosporin A (CsA), a potent immunosuppressant, induces neurotoxic effects by entering the brain, although the transport of CsA across the BBB is restricted by P-glycoprotein (P-gp), a multidrug efflux pump, and tight junctions of the brain capillary endothelial cells. The aim of this study was to evaluate whether the BBB after H/R damage is vulnerable to CsA-induced BBB dysfunction. We attempted to establish a pathophysiological BBB model with immortalized mouse brain capillary endothelial (MBEC4) cells. The effects of CsA on permeability and P-gp activity of the MBEC4 cells were then examined. Exposure to hypoxia for 4 h and reoxygenation for 1 h (H/R (4 h/1 h)) produced a significant decrease in P-gp function of MBEC4 cells, without changing cell viability and permeability for sodium fluorescein and Evan’s blue-albumin at 7 days after H/R (4 h/1 h). CsA-induced hyperpermeability and P-gp dysfunction in MBEC4 monolayers at 7 days after H/R (4 h/1 h) were exacerbated. The possibility that CsA penetrates the BBB with incomplete functions in the vicinity of cerebral infarcts to induce neurotoxicity has to be considered.

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References

  • Abbruscato TJ, Davis TP (1999) Combination of hypoxia/aglycemia compromises in vitro blood-brain barrier integrity. J Pharmacol Exp Ther 289:668–675

    PubMed  CAS  Google Scholar 

  • Brillault J, Berezowski V, Cecchelli R, Dehouck MP (2002) Intercommunications between brain capillary endothelial cells and glial cells increase the transcellular permeability of the blood-brain barrier during ischemia. J Neurochem 83:807–817

    Article  PubMed  CAS  Google Scholar 

  • de Groen PC, Aksamit AJ, Rakela J, Forbes GS, Krom RAF (1987) Central nerves system toxicity after liver transplantation. N Engl J Med 317:861–866

    Article  PubMed  Google Scholar 

  • Dehouck MP, Jolliet-Riant P, Brée F, Fruchart JC, Cecchelli R, Tillement J-P (1992) Drug transfer across the blood-brain barrier: correlation between in vitro and in vivo models. J Neurochem 58:1790–1797

    Article  PubMed  CAS  Google Scholar 

  • Dimitrijevic OB, Stamatovic SM, Keep RF, Andjelkovic AV (2007) Absence of the chemokine receptor CCR2 protects against cerebral ischemia/reperfusion injury in mice. Stroke 38:1345–1353

    Article  PubMed  CAS  Google Scholar 

  • Dobbin J, Crockard HA, Ross-Russell R (1989) Transient blood-brain barrier permeability following profound temporary global ischaemia: an experimental study using 14C-AIB. J Cereb Blood Flow Metab 9:71–78

    PubMed  CAS  Google Scholar 

  • Dohgu S, Yamauchi A, Nakagawa S, Takata F, Kai M, Egawa T, Naito M, Tsuruo T, Sawada Y, Niwa M, Kataoka Y (2004) Nitric oxide mediates cyclosporine-induced impairment of the blood-brain barrier in cocultures of mouse brain endothelial cells and rat astrocytes. Eur J Pharmacol 505:51–59

    Article  PubMed  CAS  Google Scholar 

  • Dohgu S, Kataoka Y, Ikesue H, Naito M, Tsuruo T, Oishi R, Sawada Y (2000) Involvement of glial cells in cyclosporine-increased permeability of brain endothelial cells. Cell Mol Neurobiol 20:781–786

    Article  PubMed  CAS  Google Scholar 

  • Erer B, Polchi P, Lucarelli G, Angelucci E, Baronciani D, Galimberti M, Giardini C, Gaziev D, Maiello A (1996) CsA-associatied neurotoxicity and ineffective prophylaxis with clonazepam in patients transplanted for thalassemia major: analysis of risk factors. Bone Marrow Transpl 18:157–162

    CAS  Google Scholar 

  • Fleegal MA, Hom S, Borg LK, Davis TP (2005) Activation of PKC modulates blood-brain barrier endothelial cell permeability changes induced by hypoxia and posthypoxic reoxygenation. Am J Physiol Heart Circ Physiol 289:H2012–H2019

    Article  PubMed  CAS  Google Scholar 

  • Fontaine M, Elmquist WF, Miller DW (1996) Use of rhodamine 123 to examine the functional activity of P-glycoprotein in primary cultured brain microvessel endothelial cell monolayers. Life Sci 59:1521–1531

    Article  PubMed  CAS  Google Scholar 

  • Gijitenbeek JMM, van den Bent MJ, Vecht ChJ (1999) Cyclosporine neurotoxicity: a review. J Neurol 246:339–346

    Article  Google Scholar 

  • Gumerlock MK (1989) Cerebrovascular disease and the blood-brain barrier. In: Neuwelt EA (ed) The clinical impact of the blood-brain barrier and its manipulation. Plenum Press, New York, pp 495–565

    Google Scholar 

  • Hauben M (1996) Cyclosporine neurotoxicity. Pharmacotherapy 16:576–583

    PubMed  CAS  Google Scholar 

  • Hayashi K, Nakao S, Nakaoke R, Nakagawa S, Kitagawa N, Niwa M (2004) Effects of hypoxia on endothelial/pericytic co-culture model of the blood-brain barrier. Regul Pept 123:77–83

    Article  PubMed  CAS  Google Scholar 

  • Hawkins BT, Davis TP (2005) The blood-brain barrier/neurovascular unit in health and disease. Pharmacol. Rev 57:173–185

    Article  PubMed  CAS  Google Scholar 

  • Huber JD, Egleton RD, Davis TP (2001) Molecular physiology and pathophysiology of tight junctions in the blood-brain barrier. Trends Neurosci 24:719–725

    Article  PubMed  CAS  Google Scholar 

  • Ikesue H, Kataoka Y, Kawachi R, Dohgu S, Shuto H, Oishi R (2000) Cyclosporine enhances α1-adrenoceptor-mediated nitric oxide production in C6 glioma cells. Eur J Pharmacol 407:221–226

    Article  PubMed  CAS  Google Scholar 

  • Jansen O, Krieger D, Krieger S, Sartor K (1996) Cortical hyperintensity on proton density-weighted images: an MR sign of cyclosporine-related encephalopathy. Am J Neuroradiol 17:337–344

    PubMed  CAS  Google Scholar 

  • Kochi S, Takanaga H, Matsuo H, Naito M, Tsuruo T, Sawada Y (1999) Effect of cyclosporine A or tacrolimus on the function of blood-brain barrier cells. Eur J Pharmacol 372:287–295

    Article  PubMed  CAS  Google Scholar 

  • Lenzser G, Kis B, Bari F, Busija DW (2005) Diazoxide preconditioning attenuates global cerebral ischemia-induced blood-brain barrier permeability. Brain Res 1051:72–80

    Article  PubMed  CAS  Google Scholar 

  • Mark KS, Davis TP (2002) Cerebral microvascular changes in permeability and tight junctions induced by hypxia-reoxygenation. Am J Physiol Heart Circ Physiol 282:H1485–H1495

    PubMed  CAS  Google Scholar 

  • Nishioku T, Takata F, Yamauchi A, Sumi N, Yamamoto I, Fujino A, Naito M, Tsuruo T, Shuto H, Kataoka Y (2007) Protective action of indapamide, a thiazide-like diuretic, on ischemia-induced injury and barrier dysfunction in mouse brain microvascular endothelial cells. J Pharmacol Sci 103:323–327

    Article  PubMed  CAS  Google Scholar 

  • Plateel M, Teisseir E, Cecchelli R (1997) Hypoxia dramatically increases the nonspecific transport of blood-borne proteins to the brain. J Neurochem 68:874–877

    Article  PubMed  CAS  Google Scholar 

  • Samoto K, Ikezaki K, Yokoyama N, Fukui M (1994) P-glycoprotein expression in brain capillary endothelial cells after focal ischemia in rat. Acta Neurochir Suppl 60:257–260

    CAS  Google Scholar 

  • Serkova NJ, Christians U, Benet LZ (2004) Biochemical mecahisms of cyclosporine neurotoxicity. Mol Interv 4:97–107

    Article  PubMed  CAS  Google Scholar 

  • Shuto H, Kataoka Y, Kanaya A, Matsunaga K, Sueyasu M, Oishi R (1998) Enhancement of serotonergic neural activity contributes to cyclosporine-induced tremors in mice. Eur J Pharmacol 341:33–37

    Article  PubMed  CAS  Google Scholar 

  • Shuto H, Kataoka Y, Fujisaki K, Nakao T, Sueyasu M, Miura I, Watanabe Y, Fujiwara M, Oishi R (1999) Inhibition of GABA system involved in cyclosporine-induced convulsions. Life Sci 65:879–887

    Article  PubMed  CAS  Google Scholar 

  • Takata F, Dohgu S, Yamauchi A, Nakagawa S, Naito M, Tsuruo T, Shuto H, Kataoka Y (2007) Inhibition of transforming growth factor-β production in brain pericytes contributes to cyclosporin A-induced dysfunction of the blood-brain barrier. Cell Mol Neurobiol 27:317–328

    Article  PubMed  CAS  Google Scholar 

  • Tatsuta T, Naito M, Oh-hara T, Sugawara I, Tsuruo T (1992) Functional involvement of P-glycoprotein in blood-brain barrier. J Biol Chem 267:20383–20391

    PubMed  CAS  Google Scholar 

  • Thompson CB, June CH, Sullivan KM, Thomas ED (1984) Association between cyclosporine neurotoxicity and hypomagnesia. Lancet 2:1116–1120

    Article  PubMed  CAS  Google Scholar 

  • Tsuji A, Tamai I, Sakata A, Tenda Y, Terasaki T (1993) Restricted transport of cyclosporin A across the blood-brain barrier by a multidrug transporter P-glycoprotein. Biochem Pharmacol 46:1096–1099

    Article  PubMed  CAS  Google Scholar 

  • Utepbergenov DI, Mertsch K, Sporbert A, Tenz K, Paul M, Haseloff RF, Blasig IE (1998) Nitric oxide protects blood-brain barrier in vitro from hypxia/reoxygenation-mediated injury. FEBS Lett 424:197–201

    Article  PubMed  CAS  Google Scholar 

  • Wachtel M, Frei K, Ehler E, Bauer C, Gassmann M, Gloor SM (2002) Extracellular signal-regulated protein kinase activation during reoxygenation is required to restore ischaemia-induced endothelial barrier failure. Biochem J 367:873–879

    Article  PubMed  CAS  Google Scholar 

  • Wardlaw JM, Sandercock PA, Dennis MS, Starr J (2003) Is breakdown of the blood-brain barrier responsible for lacunar stroke, leukoaraiosis, and dementia? Stroke 34:806–812

    Article  PubMed  CAS  Google Scholar 

  • Wartenberg M, Ling FC, Schallenberg M, Baumer AT, Petrat K, Hescheler J, Sauer H (2001) Down-regulation of intrinsic P-glycoprotein expression in multicellular prostate tumor spheroids by reactive oxygen species. J Biol Chem 276:17420–17428

    Article  PubMed  CAS  Google Scholar 

  • Yamauchi A, Dohgu S, Nishioku T, Shuto H, Naito M, Tsuruo T, Sawada Y, Kataoka Y (2007) An inhibitory role of nitric oxide in the dynamic regulation of the blood-brain barrier function. Cell Mol Neurobiol 27:263–270

    Article  PubMed  CAS  Google Scholar 

  • Yamauchi A, Shuto H, Dohgu S, Nakano Y, Egawa T, Kataoka Y (2005) Cyclosporin A aggravates electroshock-induced convulsions in mice with a transient middle cerebral artery occlusion. Cell Mol Neurobiol 25:923–928

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported, in part, by Grants-in-Aid for Scientific Research [(B) 17390159], Grants-in-Aid for Young Scientists [(Start-up) 18890227], Grants-in-Aid for Young Scientists [(B) 19790199] from JSPS, Japan and the Ministry of Health, Labor and Welfare of Japan (H19-nanchi-ippan-006). The authors thank Dr. Mária A. Deli (Institute of Biophysics, Biological Research Centre of the Hungarian Academy of Sciences) and Dr. Masami Niwa (Nagasaki University School of Medicine) for pertinent comments on the manuscript.

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Authors and Affiliations

  1. Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka, 814-0180, Japan

    Shinya Dohgu, Tsuyoshi Nishioku, Noriko Sumi, Fuyuko Takata, Atsushi Yamauchi, Hideki Shuto & Yasufumi Kataoka

  2. Department of Pharmacology 1, Graduate School of Medicine, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan

    Shinsuke Nakagawa

  3. Institute of Molecular and Cellular Biosciences, University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo, 113-0032, Japan

    Mikihiko Naito & Takashi Tsuruo

  4. Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-10-6 Ariake, Koto-ku, Tokyo, 135-8550, Japan

    Takashi Tsuruo

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  1. Shinya Dohgu
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  2. Tsuyoshi Nishioku
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  3. Noriko Sumi
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  4. Fuyuko Takata
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  5. Shinsuke Nakagawa
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  6. Mikihiko Naito
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  7. Takashi Tsuruo
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  8. Atsushi Yamauchi
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  9. Hideki Shuto
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  10. Yasufumi Kataoka
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Correspondence to Yasufumi Kataoka.

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Dohgu, S., Nishioku, T., Sumi, N. et al. Adverse Effect of Cyclosporin A on Barrier Functions of Cerebral Microvascular Endothelial Cells After Hypoxia-reoxygenation Damage In Vitro. Cell Mol Neurobiol 27, 889–899 (2007). https://doi.org/10.1007/s10571-007-9209-2

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  • DOI: https://doi.org/10.1007/s10571-007-9209-2

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