Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Oncology Letters
      • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Biomedical Reports
      • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • Information for Authors
    • Information for Reviewers
    • Information for Librarians
    • Information for Advertisers
    • Conferences
  • Language Editing
Spandidos Publications Logo
  • About
    • About Spandidos
    • Aims and Scopes
    • Abstracting and Indexing
    • Editorial Policies
    • Reprints and Permissions
    • Job Opportunities
    • Terms and Conditions
    • Contact
  • Journals
    • All Journals
    • Biomedical Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Experimental and Therapeutic Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Epigenetics
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Functional Nutrition
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Molecular Medicine
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • International Journal of Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Medicine International
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular and Clinical Oncology
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Molecular Medicine Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Letters
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • Oncology Reports
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
    • World Academy of Sciences Journal
      • Information for Authors
      • Editorial Policies
      • Editorial Board
      • Aims and Scope
      • Abstracting and Indexing
      • Bibliographic Information
      • Archive
  • Articles
  • Information
    • For Authors
    • For Reviewers
    • For Librarians
    • For Advertisers
    • Conferences
  • Language Editing
Login Register Submit
  • This site uses cookies
  • You can change your cookie settings at any time by following the instructions in our Cookie Policy. To find out more, you may read our Privacy Policy.

    I agree
Search articles by DOI, keyword, author or affiliation
Search
Advanced Search
presentation
Experimental and Therapeutic Medicine
Join Editorial Board Propose a Special Issue
Print ISSN: 1792-0981 Online ISSN: 1792-1015
Journal Cover
September-2018 Volume 16 Issue 3

Full Size Image

Sign up for eToc alerts
Recommend to Library

Journals

International Journal of Molecular Medicine

International Journal of Molecular Medicine

International Journal of Molecular Medicine is an international journal devoted to molecular mechanisms of human disease.

International Journal of Oncology

International Journal of Oncology

International Journal of Oncology is an international journal devoted to oncology research and cancer treatment.

Molecular Medicine Reports

Molecular Medicine Reports

Covers molecular medicine topics such as pharmacology, pathology, genetics, neuroscience, infectious diseases, molecular cardiology, and molecular surgery.

Oncology Reports

Oncology Reports

Oncology Reports is an international journal devoted to fundamental and applied research in Oncology.

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine

Experimental and Therapeutic Medicine is an international journal devoted to laboratory and clinical medicine.

Oncology Letters

Oncology Letters

Oncology Letters is an international journal devoted to Experimental and Clinical Oncology.

Biomedical Reports

Biomedical Reports

Explores a wide range of biological and medical fields, including pharmacology, genetics, microbiology, neuroscience, and molecular cardiology.

Molecular and Clinical Oncology

Molecular and Clinical Oncology

International journal addressing all aspects of oncology research, from tumorigenesis and oncogenes to chemotherapy and metastasis.

World Academy of Sciences Journal

World Academy of Sciences Journal

Multidisciplinary open-access journal spanning biochemistry, genetics, neuroscience, environmental health, and synthetic biology.

International Journal of Functional Nutrition

International Journal of Functional Nutrition

Open-access journal combining biochemistry, pharmacology, immunology, and genetics to advance health through functional nutrition.

International Journal of Epigenetics

International Journal of Epigenetics

Publishes open-access research on using epigenetics to advance understanding and treatment of human disease.

Medicine International

Medicine International

An International Open Access Journal Devoted to General Medicine.

Journal Cover
September-2018 Volume 16 Issue 3

Full Size Image

Sign up for eToc alerts
Recommend to Library

  • Article
  • Citations
    • Cite This Article
    • Download Citation
    • Create Citation Alert
    • Remove Citation Alert
    • Cited By
  • Similar Articles
    • Related Articles (in Spandidos Publications)
    • Similar Articles (Google Scholar)
    • Similar Articles (PubMed)
  • Download PDF
  • Download XML
  • View XML
Article

Activation of EphA4 induced by EphrinA1 exacerbates disruption of the blood‑brain barrier following cerebral ischemia‑reperfusion via the Rho/ROCK signaling pathway

  • Authors:
    • Fangbin Chen
    • Zhiyang Liu
    • Wei Peng
    • Zhiqin Gao
    • Hui Ouyang
    • Tongjun Yan
    • Songbai Ding
    • Zhankui Cai
    • Bin Zhao
    • Longjin Mao
    • Zhiyong Cao
  • View Affiliations / Copyright

    Affiliations: Institute of Psychiatry, The 102nd Hospital of PLA, Changzhou, Jiangsu 213003, P.R. China, Department of Psychiatry, The 92nd Hospitial of PLA, Nanping, Fujian 353000, P.R. China
  • Pages: 2651-2658
    |
    Published online on: July 17, 2018
       https://doi.org/10.3892/etm.2018.6460
  • Expand metrics +
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )
Cited By (CrossRef): 0 citations Loading Articles...

This article is mentioned in:



Abstract

Vascular dementia (VD) is a syndrome characterized by progressive cognitive decline. According to previous studies, stroke is considered to be a risk factor for VD. The disruption of the blood‑brain barrier (BBB) is pivotal to the pathology of stroke, as it contributes to post‑stroke inflammation and edema. It has been reported that the Eph/Ephrin signaling pathway serves an important role in central nervous system injury. However, the role of EphrinA1/EphA4 signaling in BBB damage following ischemic stroke has not yet been reported. Oxygen‑glucose deprivation/reperfusion was performed to detect changes in EphrinA1 and EphA4 expression in human brain microvascular endothelial cells (HBMECs). Male mice were randomly divided into four groups [Sham, ischemia‑reperfusion (I/R), I/R+EphrinA1 and I/R+EphA4] to observe the role of EphrinA1 and EphA4 under I/R conditions in vivo. The results of the present study revealed that the expression of EphrinA1 and EphA4 was significantly increased following I/R in vitro and in vivo. The administration of soluble ligand EphrinA1 enhanced CD68+ cell accumulation, brain edema and dysfunction of the BBB, with lower expression levels of zonula occludens‑1 (ZO‑1) and Claudin‑5. In addition, EphrinA1‑treated mice had a higher level of caspase‑3 and a lower level of phosphorylated‑protein kinase B. However, the effects of EphrinA1 were abolished by EphA4‑Fc, an inhibitor of EphA4. These results suggested that EphrinA1 exerted its effects on I/R injury via the activated EphA4 receptor. In addition, EphrinA1 decreased ZO‑1 and Claudin‑5 expression through the Rho/Rho associated kinase (ROCK) signaling pathway, which was attenuated by the pharmacological inhibition of Rho (C3 transferase) or ROCK (Y‑27632). In conclusion, the present study provides evidence that the activation of EphA4 induced by EphrinA1 contributes to BBB damage following ischemic stroke through the Rho/ROCK signaling pathway, which highlights a potential therapeutic strategy for ischemic stroke and may help the development of preventative interventions for VD.
View Figures

Figure 1

Figure 2

Figure 3

Figure 4

View References

1 

Plassman BL, Langa KM, Fisher GG, Heeringa SG, Weir DR, Ofstedal MB, Burke JR, Hurd MD, Potter GG, Rodgers WL, et al: Prevalence of dementia in the United States: The aging, demographics and memory study. Neuroepidemiology. 29:125–132. 2007. View Article : Google Scholar : PubMed/NCBI

2 

Erkinjuntti T: Diagnosis and management of vascular cognitive impairment and dementia. J Neural Transm Suppl. 1–109. 2002.

3 

Iadecola C: The pathobiology of vascular dementia. Neuron. 80:844–866. 2013. View Article : Google Scholar : PubMed/NCBI

4 

Bowler JV: Vascular cognitive impairment. Stroke. 35:386–388. 2004. View Article : Google Scholar : PubMed/NCBI

5 

Nyenhuis DL and Gorelick PB: Vascular dementia: A contemporary review of epidemiology, diagnosis, prevention and treatment. J Ame Geriat Soc. 46:1437–1448. 1998. View Article : Google Scholar

6 

Farooq MU and Gorelick PB: Vascular cognitive impairment. Curr Atheroscler Rep. 15:3302013. View Article : Google Scholar : PubMed/NCBI

7 

Jacquin A, Binquet C, Rouaud O, Graule-Petot A, Daubail B, Osseby GV, Bonithon-Kopp C, Giroud M and Béjot Y: Post-stroke cognitive impairment: High prevalence and determining factors in a cohort of mild stroke. J Alzheimers Dis. 40:1029–1038. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Imfeld P, Bodmer M, Schuerch M, Jick SS and Meier CR: Risk of incident stroke in patients with Alzheimer disease or vascular dementia. Neurology. 81:910–919. 2013. View Article : Google Scholar : PubMed/NCBI

9 

Pendlebury ST and Rothwell PM: Prevalence, incidence and factors associated with pre-stroke and post-stroke dementia: A systematic review and meta-analysis. Lancet Neurol. 8:1006–1018. 2009. View Article : Google Scholar : PubMed/NCBI

10 

Yang Y and Rosenberg GA: Blood-brain barrier breakdown in acute and chronic cerebrovascular disease. Stroke. 42:3323–3328. 2011. View Article : Google Scholar : PubMed/NCBI

11 

Kamada H, Yu F, Nito C and Chan PH: Influence of hyperglycemia on oxidative stress and matrix metalloproteinase-9 activation after focal cerebral ischemia/reperfusion in rats: Relation to blood-brain barrier dysfunction. Stroke. 38:1044–1049. 2007. View Article : Google Scholar : PubMed/NCBI

12 

Khatri R, McKinney AM, Swenson B and Janardhan V: Blood-brain barrier, reperfusion injury and hemorrhagic transformation in acute ischemic stroke. Neurology. 79 13 Suppl 1:S52–S57. 2012. View Article : Google Scholar : PubMed/NCBI

13 

Weekman EM and Wilcock DM: Matrix metalloproteinase in blood-brain barrier breakdown in dementia. J Alzheimers Dis. 49:893–903. 2016. View Article : Google Scholar : PubMed/NCBI

14 

Rochfort KD and Cummins PM: The blood-brain barrier endothelium: A target for pro-inflammatory cytokines. Biochem Soc Trans. 43:702–706. 2015. View Article : Google Scholar : PubMed/NCBI

15 

Blanchette M and Daneman R: Formation and maintenance of the BBB. Mech Dev. 138:8–16. 2015. View Article : Google Scholar : PubMed/NCBI

16 

Haseloff RF, Dithmer S, Winkler L, Wolburg H and Blasig IE: Transmembrane proteins of the tight junctions at the blood-brain barrier: Structural and functional aspects. Semin Cell Dev Biol. 38:16–25. 2015. View Article : Google Scholar : PubMed/NCBI

17 

Abbott NJ, Patabendige AA, Dolman DE, Yusof SR and Begley DJ: Structure and function of the blood-brain barrier. Neurobiol Dis. 37:13–25. 2010. View Article : Google Scholar : PubMed/NCBI

18 

Stamatovic SM, Keep RF and Andjelkovic AV: Brain endothelial cell-cell junctions: How to ‘open’ the blood brain barrier. Curr Neuropharmacol. 6:179–192. 2008. View Article : Google Scholar : PubMed/NCBI

19 

Sandoval KE and Witt KA: Blood-brain barrier tight junction permeability and ischemic stroke. Neurobiol Dis. 32:200–219. 2008. View Article : Google Scholar : PubMed/NCBI

20 

Lucke-Wold BP, Logsdon AF, Turner RC, Rosen CL and Huber JD: Aging, the metabolic syndrome and ischemic stroke: redefining the approach for studying the blood-brain barrier in a complex neurological disease. Adv Pharmacol. 71:411–449. 2014. View Article : Google Scholar : PubMed/NCBI

21 

Lisabeth EM, Falivelli G and Pasquale EB: Eph receptor signaling and ephrins. Cold Spring Harb Perspect Biol. 5:a0091592013. View Article : Google Scholar : PubMed/NCBI

22 

Ieguchi K: Eph as a target in inflammation. Endocr Metab Immune Disord Drug Targets. 15:119–128. 2015. View Article : Google Scholar : PubMed/NCBI

23 

Jellinghaus S, Poitz DM, Ende G, Augstein A, Weinert S, Stütz B, Braun-Dullaeus RC, Pasquale EB and Strasser RH: Ephrin-A1/EphA4-mediated adhesion of monocytes to endothelial cells. Biochim Biophys Acta. 1833:2201–2211. 2013. View Article : Google Scholar : PubMed/NCBI

24 

Gliem M, Schwaninger M and Jander S: Protective features of peripheral monocytes/macrophages in stroke. Biochim Biophys Acta. 1862:329–338. 2016. View Article : Google Scholar : PubMed/NCBI

25 

Moskowitz MA, Lo EH and Iadecola C: The science of stroke: Mechanisms in search of treatments. Neuron. 67:181–198. 2010. View Article : Google Scholar : PubMed/NCBI

26 

Thundyil J, Manzanero S, Pavlovski D, Cully TR, Lok KZ, Widiapradja A, Chunduri P, Jo DG, Naruse C, Asano M, et al: Evidence that the EphA2 receptor exacerbates ischemic brain injury. PLoS One. 8:e535282013. View Article : Google Scholar : PubMed/NCBI

27 

Choi JS, Kim SJ, Shin JA, Lee KE and Park EM: Effects of estrogen on temporal expressions of IL-1beta and IL-1ra in rat organotypic hippocampal slices exposed to oxygen-glucose deprivation. Neurosci Lett. 438:233–237. 2008. View Article : Google Scholar : PubMed/NCBI

28 

Khedr EM, Hamed SA, El-Shereef HK, Shawky OA, Mohamed KA, Awad EM, Ahmed MA, Shehata GA and Eltahtawy MA: Cognitive impairment after cerebrovascular stroke: Relationship to vascular risk factors. Neuropsychiatr Dis Treat. 5:103–116. 2009.PubMed/NCBI

29 

del Ser T, Barba R, Morin MM, Domingo J, Cemillan C, Pondal M and Vivancos J: Evolution of cognitive impairment after stroke and risk factors for delayed progression. Stroke. 36:2670–2675. 2005. View Article : Google Scholar : PubMed/NCBI

30 

van de Haar HJ, Burgmans S, Hofman PA, Verhey FR, Jansen JF and Backes WH: Blood-brain barrier impairment in dementia: Current and future in vivo assessments. Neurosci Biobehav Rev. 49:71–81. 2015. View Article : Google Scholar : PubMed/NCBI

31 

Borlongan CV, Rodrigues AA Jr and Oliveira MC: Breaking the barrier in stroke: What should we know? A mini-review. Curr Pharm Des. 18:3615–3623. 2012. View Article : Google Scholar : PubMed/NCBI

32 

Hafner C, Schmitz G, Meyer S, Bataille F, Hau P, Langmann T, Dietmaier W, Landthaler M and Vogt T: Differential gene expression of Eph receptors and ephrins in benign human tissues and cancers. Clin Chem. 50:490–499. 2004. View Article : Google Scholar : PubMed/NCBI

33 

Julian L and Olson MF: Rho-associated coiled-coil containing kinases (ROCK): Structure, regulation and functions. Small GTPases. 5:e298462014. View Article : Google Scholar : PubMed/NCBI

34 

Shin HK, Salomone S and Ayata C: Targeting cerebrovascular Rho-kinase in stroke. Exp Opin Ther Targets. 12:1547–1564. 2008. View Article : Google Scholar

35 

Gibson CL, Srivastava K, Sprigg N, Bath PM and Bayraktutan U: Inhibition of Rho-kinase protects cerebral barrier from ischaemia-evoked injury through modulations of endothelial cell oxidative stress and tight junctions. J Neurochem. 129:816–826. 2014. View Article : Google Scholar : PubMed/NCBI

Related Articles

  • Abstract
  • View
  • Download
  • Twitter
Copy and paste a formatted citation
Spandidos Publications style
Chen F, Liu Z, Peng W, Gao Z, Ouyang H, Yan T, Ding S, Cai Z, Zhao B, Mao L, Mao L, et al: Activation of EphA4 induced by EphrinA1 exacerbates disruption of the blood‑brain barrier following cerebral ischemia‑reperfusion via the Rho/ROCK signaling pathway. Exp Ther Med 16: 2651-2658, 2018.
APA
Chen, F., Liu, Z., Peng, W., Gao, Z., Ouyang, H., Yan, T. ... Cao, Z. (2018). Activation of EphA4 induced by EphrinA1 exacerbates disruption of the blood‑brain barrier following cerebral ischemia‑reperfusion via the Rho/ROCK signaling pathway. Experimental and Therapeutic Medicine, 16, 2651-2658. https://doi.org/10.3892/etm.2018.6460
MLA
Chen, F., Liu, Z., Peng, W., Gao, Z., Ouyang, H., Yan, T., Ding, S., Cai, Z., Zhao, B., Mao, L., Cao, Z."Activation of EphA4 induced by EphrinA1 exacerbates disruption of the blood‑brain barrier following cerebral ischemia‑reperfusion via the Rho/ROCK signaling pathway". Experimental and Therapeutic Medicine 16.3 (2018): 2651-2658.
Chicago
Chen, F., Liu, Z., Peng, W., Gao, Z., Ouyang, H., Yan, T., Ding, S., Cai, Z., Zhao, B., Mao, L., Cao, Z."Activation of EphA4 induced by EphrinA1 exacerbates disruption of the blood‑brain barrier following cerebral ischemia‑reperfusion via the Rho/ROCK signaling pathway". Experimental and Therapeutic Medicine 16, no. 3 (2018): 2651-2658. https://doi.org/10.3892/etm.2018.6460
Copy and paste a formatted citation
x
Spandidos Publications style
Chen F, Liu Z, Peng W, Gao Z, Ouyang H, Yan T, Ding S, Cai Z, Zhao B, Mao L, Mao L, et al: Activation of EphA4 induced by EphrinA1 exacerbates disruption of the blood‑brain barrier following cerebral ischemia‑reperfusion via the Rho/ROCK signaling pathway. Exp Ther Med 16: 2651-2658, 2018.
APA
Chen, F., Liu, Z., Peng, W., Gao, Z., Ouyang, H., Yan, T. ... Cao, Z. (2018). Activation of EphA4 induced by EphrinA1 exacerbates disruption of the blood‑brain barrier following cerebral ischemia‑reperfusion via the Rho/ROCK signaling pathway. Experimental and Therapeutic Medicine, 16, 2651-2658. https://doi.org/10.3892/etm.2018.6460
MLA
Chen, F., Liu, Z., Peng, W., Gao, Z., Ouyang, H., Yan, T., Ding, S., Cai, Z., Zhao, B., Mao, L., Cao, Z."Activation of EphA4 induced by EphrinA1 exacerbates disruption of the blood‑brain barrier following cerebral ischemia‑reperfusion via the Rho/ROCK signaling pathway". Experimental and Therapeutic Medicine 16.3 (2018): 2651-2658.
Chicago
Chen, F., Liu, Z., Peng, W., Gao, Z., Ouyang, H., Yan, T., Ding, S., Cai, Z., Zhao, B., Mao, L., Cao, Z."Activation of EphA4 induced by EphrinA1 exacerbates disruption of the blood‑brain barrier following cerebral ischemia‑reperfusion via the Rho/ROCK signaling pathway". Experimental and Therapeutic Medicine 16, no. 3 (2018): 2651-2658. https://doi.org/10.3892/etm.2018.6460
Follow us
  • Twitter
  • LinkedIn
  • Facebook
About
  • Spandidos Publications
  • Careers
  • Cookie Policy
  • Privacy Policy
How can we help?
  • Help
  • Live Chat
  • Contact
  • Email to our Support Team