Dynamic Effects of Ioversol on the Permeability of the Blood-Brain Barrier and the Expression of ZO-1/Occludin in Rats

  • Heying Wang
  • Tao Li
  • Lili Zhao
  • Man Sun
  • Yating Jian
  • Jiao Liu
  • Yiheng Zhang
  • Ye Li
  • Meijuan Dang
  • Guilian ZhangEmail author


Blood-brain barrier (BBB) dysfunction is involved in the pathogenesis of contrast-induced encephalopathy (CIE), which is a rare adverse event following angiography. In this study, we observed the dynamic effect and potential mechanism of ioversol on the BBB in rats. Eighty-one healthy rats were randomly divided into a normal control group (n = 9), ioversol group (n = 36), and 0.9% NaCl group (n = 36); the latter two groups were separately subdivided into four groups based on time points after treatment (0.5, 3, 6, and 24 h) (n = 9/group). Permeability of the BBB was measured by an Evans Blue (EB) assay. Levels of the tight junction (TJ) proteins ZO-1 and occludin were determined by western blot and immunofluorescence staining. EB content increased at 3 h after the administration of ioversol via the carotid artery and reached a peak at 6 h (P < 0.05), whereas it decreased to its normal level at 24 h. Western blot and immunofluorescence staining indicated that the expression of ZO-1 in brain tissues gradually decreased to its lowest level at 3 h, and then increased gradually, but was still lower than that of the normal control group at 24 h (P < 0.05). Occludin was similar, but its lowest expression appeared at 0.5 h. This study demonstrated that the permeability of BBB in rats increased first and then decreased after ioversol was injected into the carotid artery. The mechanism may be related to altered protein expression of TJs, which are important structures in BBB. Early intervention against TJ proteins may be an effective measure to prevent and treat CIE.


Contrast media Blood-brain barrier ZO-1 Occludin Dynamic 



Blood–brain barrier


Contrast-induced encephalopathy


Evans Blue


Tight junction


Zonula occludens-1


Contrast media


Common carotid artery


External carotid artery


Internal carotid artery


Standard deviation



We thank the members of the Laboratory of Neurology, Xijing Hospital, Air Force Military Medical University. We also thank Prof. Ming Shi (Department of Neurology, Xijing Hospital, Air Force Military Medical University) for his advice on our experimental design, as well as Dr. Yajun Shi (Department of Neurology, Xijing Hospital, Air Force Military Medical University) for helping us with our experimental methods.

Author Contribution Statements

Heying Wang and Guilian Zhang wrote the main manuscript text. Heying Wang, Tao Li, Lili Zhao, Jiao Liu, and Guilian Zhang designed the experiment, Heying Wang, Man Sun, Yating Jian, Yiheng Zhang, Ye Li, and Meijuan Dang collected sample and analyzed the data. All authors reviewed the manuscript.


This work was supported by grants from the Shaanxi Science Research Project, China (No. 2010K16-08-02, 2015SF009) and the Second Affiliated Hospital Science Research Project, Xi’an Jiaotong University of China.

Compliance with Ethical Standards

All the study procedures complied with the National Institute of Health Guide for the Care and Use of Laboratory Animals (NIH Publication No. 80-23). The animal experiments were approved by the Committee on the Ethics of Animal Experiments of the Xi’an Jiaotong University College of Medicine.

Conflict of Interest

The authors declare that they have no conflict of interests.


  1. Bassett RC, Rogers JS, Cherry GR, Cruzhit C (1953) The effect of contrast media on the blood-brain-barrier. J Neurosurg 10(1):38–47CrossRefGoogle Scholar
  2. Beckett KR, Moriarity AK, Langer JM (2015) Safe use of contrast media: what the radiologist needs to know. Radiographics 35:1738–1750. CrossRefGoogle Scholar
  3. Broman T, Olsson O (1948) The tolerance of cerebral blood-vessels to a contrast medium of the diorast group: an experimental study of the effect on the blood-brain-barrier. Acta Radiol 30:326–342CrossRefGoogle Scholar
  4. Cardoso FL, Brites D, Brito MA (2010) Looking at the blood-brain barrier: molecular anatomy and possible investigation approaches. Brain Res Rev 64:328–363. CrossRefGoogle Scholar
  5. Clark BA, Kim D, Epstein FH (1997) Endothelin and atrial natriuretic peptide levels following radiocontrast exposure in humans. Am J Kidney Dis 30:82–86. CrossRefGoogle Scholar
  6. Dattani A, Au L, Tay K, Davey P (2018) Contrast-induced encephalopathy following coronary angiography with no radiological features: a case report and literature review. Cardiology 139:197–201. CrossRefGoogle Scholar
  7. Franke RP, Fuhrmann R, Hiebl B, Jung F (2008) Influence of various radiographic contrast media on the buckling of endothelial cells. Microvasc Res 76:110–113. CrossRefGoogle Scholar
  8. Frye RE, Newburger JW, Nugent A, Sahin M (2005) Focal seizure and cerebral contrast retention after cardiac catheterization. Pediatr Neurol 32:213–216. CrossRefGoogle Scholar
  9. Gonsette RE, Liesenborgh L (1980) New contrast media in cerebral angiography: animal experiments and preliminary clinical studies. Investig Radiol 15:S270–S274CrossRefGoogle Scholar
  10. Greene C, Campbell M (2016) Tight junction modulation of the blood brain barrier: CNS delivery of small molecules. Tissue Barriers 4:e1138017. CrossRefGoogle Scholar
  11. Haley EC Jr (1984) Encephalopathy following arteriography: a possible toxic effect of contrast agents. Ann Neurol 15:100–102. CrossRefGoogle Scholar
  12. Haseloff RF, Dithmer S, Winkler L, Wolburg H, Blasig IE (2015) Transmembrane proteins of the tight junctions at the blood-brain barrier: structural and functional aspects. Semin Cell Dev Biol 38:16–25. CrossRefGoogle Scholar
  13. Heyman SN, Clark BA, Kaiser N, Spokes K, Rosen S, Brezis M, Epstein FH (1992) Radiocontrast agents induce endothelin release in vivo and in vitro. J Am Soc Nephrol 3:58–65Google Scholar
  14. Jiao H, Wang Z, Liu Y, Wang P, Xue Y (2011) Specific role of tight junction proteins claudin-5, occludin, and ZO-1 of the blood-brain barrier in a focal cerebral ischemic insult. J Mol Neurosci 44:130–139. CrossRefGoogle Scholar
  15. Junck L, Marshall WH (1983) Neurotoxicity of radiological contrast agents. Ann Neurol 13(5):469–484CrossRefGoogle Scholar
  16. Keaney J, Campbell M (2015) The dynamic blood-brain barrier. FEBS J 282:4067–4079. CrossRefGoogle Scholar
  17. Khatri P, Broderick JP, Khoury JC, Carrozzella JA, Tomsick TA, Investigators III (2008) Microcatheter contrast injections during intra-arterial thrombolysis may increase intracranial hemorrhage risk. Stroke 39:3283–3287. CrossRefGoogle Scholar
  18. Khatri R, McKinney AM, Swenson B, Janardhan V (2012) Blood-brain barrier, reperfusion injury, and hemorrhagic transformation in acute ischemic stroke. Neurology 79:S52–S57. CrossRefGoogle Scholar
  19. Knowland D, Arac A, Sekiguchi KJ, Hsu M, Lutz SE, Perrino J, Steinberg GK, Barres BA, Nimmerjahn A, Agalliu D (2014) Stepwise recruitment of transcellular and paracellular pathways underlies blood-brain barrier breakdown in stroke. Neuron 82:603–617. CrossRefGoogle Scholar
  20. Kopecky KK, Becker GJ, Conces DJ Jr (1989) Ioversol 320: a new nonionic, water-soluble contrast medium for body computed tomography clinical trial. Investig Radiol 24(Suppl 1):S33–S34CrossRefGoogle Scholar
  21. Krueger M, Hartig W, Reichenbach A, Bechmann I, Michalski D (2013) Blood-brain barrier breakdown after embolic stroke in rats occurs without ultrastructural evidence for disrupting tight junctions. PLoS One 8:e56419. CrossRefGoogle Scholar
  22. Kurosawa Y, Lu AG, Khatri P, Carrozzella JA, Clark JF, Khoury J, Tomsick TA (2010) Intra-arterial iodinated radiographic contrast material injection administration in a rat middle cerebral artery occlusion and reperfusion model possible effects on intracerebral hemorrhage. Stroke 41:1013–1017. CrossRefGoogle Scholar
  23. Leong S, Fanning NF (2012) Persistent neurological deficit from iodinated contrast encephalopathy following intracranial aneurysm coiling: a case report and review of the literature. Interv Neuroradiol 18:33–41. CrossRefGoogle Scholar
  24. Nakamura I, Hori S, Funabiki T, Sekine K, Kimura H, Fujishima S, Aoki K, Kuribayashi S, Aikawa N (2002) Cardiopulmonary arrest induced by anaphylactoid reaction with contrast media. Resuscitation 53:223–226CrossRefGoogle Scholar
  25. Nico B, Ribatti D (2012) Morphofunctional aspects of the blood-brain barrier. Curr Drug Metab 13:50–60CrossRefGoogle Scholar
  26. Niimi Y, Kupersmith MJ, Ahmad S, Song J, Berenstein A (2008) Cortical blindness, transient and otherwise, associated with detachable coil embolization of intracranial aneurysms. AJNR Am J Neuroradiol 29:603–607. CrossRefGoogle Scholar
  27. O’Donnell DH, Moloney MA, Bouchier-Hayes DJ, Lee MJ (2010) Iodinated contrast media alter immune responses in pro-inflammatory states. Acta Radiol 51:635–640. CrossRefGoogle Scholar
  28. Obermeier B, Daneman R, Ransohoff RM (2013) Development, maintenance and disruption of the blood-brain barrier. Nat Med 19:1584–1596. CrossRefGoogle Scholar
  29. Potsi S, Chourmouzi D, Moumtzouoglou A, Nikiforaki A, Gkouvas K, Drevelegas A (2012) Transient contrast encephalopathy after carotid angiography mimicking diffuse subarachnoid haemorrhage. Neurol Sci 33:445–448. CrossRefGoogle Scholar
  30. Spina R, Simon N, Markus R, Muller DW, Kathir K (2017) Recurrent contrast-induced encephalopathy following coronary angiography. Intern Med J 47:221–224. CrossRefGoogle Scholar
  31. Tiwari YV, Lu JF, Shen Q, Cerqueira B, Duong TQ (2017) Magnetic resonance imaging of blood-brain barrier permeability in ischemic stroke using diffusion-weighted arterial spin labeling in rats. J Cere Blood Flow Metab 37:2706–2715. CrossRefGoogle Scholar
  32. Wolburg H, Lippoldt A (2002) Tight junctions of the blood-brain barrier: development, composition and regulation. Vasc Pharmacol 38:323–337CrossRefGoogle Scholar
  33. Yu J, Dangas G (2011) New insights into the risk factors of contrast-induced encephalopathy. J Endovasc Ther 18:545–546. CrossRefGoogle Scholar
  34. Zihni C, Mills C, Matter K, Balda MS (2016) Tight junctions: from simple barriers to multifunctional molecular gates. Nat Rev Mol Cell Biol 17:564–580. CrossRefGoogle Scholar
  35. Zweifler RM, Rothrock JF (1995) Aseptic meningoencephalitis following iohexol myelography. Neuroradiology 37:148–149CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Heying Wang
    • 1
  • Tao Li
    • 1
  • Lili Zhao
    • 1
  • Man Sun
    • 1
  • Yating Jian
    • 1
  • Jiao Liu
    • 1
  • Yiheng Zhang
    • 1
  • Ye Li
    • 1
  • Meijuan Dang
    • 1
  • Guilian Zhang
    • 1
    Email author
  1. 1.Department of Neurology, the Second Affiliated HospitalMedical School of Xi’an Jiaotong UniversityXi’anChina

Personalised recommendations