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A Novel Biomarker in Experimental Cerebral Ischemia: Junctional Adhesion Molecule-A

Year 2024, Volume: 25 Issue: 2, 85 - 96, 31.08.2024
https://doi.org/10.69601/meandrosmdj.1522105

Abstract

Objectives: To investigate the role of blood brain barrier biomarkers for the detection of experimental cerebral ischemia in rats.

Methods: Forty adult male Wistar albino rats with a mean age of 4–6 months and an average weight of 350–400 g were used in the study. The rats were divided into five ischemia groups (control, 1.5 h of ischemia, 4.5 h of ischemia, 6 h of ischemia, and 24 h of ischemia). Cerebral ischemia was achieved by unilateral ligating of CCA and ECA at the same time. After surgical preparation and awaiting for appropriate ischemia time we collected blood and brain tissue samples. Then we investigated serum occludin, claudin-5 and JAM-A levels from blood samples and the apoptotic index and percentages of pycnotic nucleus from brain tissues histologically. The obtained data were analyzed using IBM SPSS Statistics software package version 18 and the Jamovi software package.

Results: Serum JAM-A level showed a statistically significant difference in all ischemia groups compared with the control group (p<0.05). Serum claudin-5 level, a statistically significant difference was found between the control group and the 6-h ischemia group (p<0.05), while no significant inter-group differences were determined for the serum occludin level. As a result, in our experimental focal cerebral ischemia model, serum JAM-A showed more significant and rapid increases compared to occluding and claudin-5. (Since four rats of the 24-h ischemia group died before completing their term, these group data were not statistically evaluated.)

Conclusions: Serum JAM-A might be successfully used in the early stages of ischemic stroke. The presence of hemiparesis or hemiplegic effects in all rat ischemia groups and the significant increases in pyknotic and apoptotic cell counts histologically suggest that our model is successful for focal cerebral ischemia.

Ethical Statement

This study was conducted according to the ARRIVE and Guide for the Care and Use of Laboratory Animals.

Supporting Institution

The Committee for Scientific Researches of Adnan Menderes University

Project Number

2020/TPF-20047

Thanks

The authors would like to thank Francisco Jose Lopez Junior, M.D. for his valuable support during the surgical manipulation of the rats.

References

  • 1. World Health Organization Global Health Estimates: Life expectancy and leading causes of death and disability. Available from: https://www.who.int/data/gho/data/themes/mortality-and-global-health-estimates.
  • 2. Yaghi S, Elkind MS. Cryptogenic stroke: a diagnostic challenge. Neurol Clin Pract 2014; 4(5): 386–393.
  • 3. Zhang J, Yang Y, Sun H, Xing Y. Hemorrhagic transformation after cerebral infarction: current concepts and challenges. Ann Transl Med 2014; 2(8): 81.
  • 4. Lipton P. Ischemic cell death in brain neurons. Physiol Rev. 1999; 79(4): 1431-568.
  • 5. Stone JA, Willey JZ, Keyrouz S, Butera J, McTaggart RA, Cutting S et al. Therapies for hemorrhagic transformation in acute ischemic stroke. Curr Treat Options Neurol 2017; 19(1): 1.
  • 6. Kago T, Takagi N, Date I, Takenaga Y, Takagi K, Takeo S. Cerebral ischemia enhances tyrosine phosphorylation of occludin in brain capillaries. Biochem Biophys Res Commun 2006; 339(4): 1197–203.
  • 7. Jiao H, Wang Z, Liu Y, Wang P, Xue Y. 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 2011; 44(2): 130–9.
  • 8. Yang Y, Rosenberg GA. MMP-mediated disruption of claudin-5 in the blood-brain barrier of rat brain after cerebral ischemia. Methods Mol Biol 2011; 762: 333-45.
  • 9. Shi S, Qi Z, Ma Q, Pan R, Timmins GS, Zhao Y, et al. Normobaric hyperoxia reduces blood occludin fragments in rats and patients with acute ischemic stroke. Stroke 2017; 48(10): 2848-54.
  • 10. Pan R, Yu K, Weatherwax T, Zheng H, Liu W, Liu KJ. Blood occludin level as a potential biomarker for early blood–brain barrier damage following ischemic stroke. Sci Rep 2017; 7: 40331.
  • 11. Kazmierski R, Michalak S, Wencel-Warot A, Nowinski WL. Serum tight-junction proteins predict hemorrhagic transformation in ischemic stroke patients. Neurology 2012; 79(16): 1677–85.
  • 12. Li W, Qi Z, Kang H, Qin X, Song H, Sui X, et al. Serum occludin as a biomarker to predict the severity of acute ischemic stroke, hemorrhagic transformation, and patient prognosis. Aging Dis 2020; 11(6): 1395–1406.
  • 13. Sladojevic N, Stamatovic SM, Keep RF, Grailer JJ, Sarma JV, Ward PA, et al. Inhibition of junctional adhesion molecule-A/LFA interaction attenuates leukocyte trafficking and inflammation in brain ischemia/reperfusion injury. Neurobiol Dis 2014; 67: 57–70.
  • 14. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke. Stroke 2019; 50(12): 3331–2.
  • 15. Janyou A, Wicha P, Jittiwat J, Suksamrarn A, Tocharus C, Tocharus J . Dihydrocapsaicin attenuates blood brain barrier and cerebral damage in focal cerebral ischemia/reperfusion via oxidative stress and inflammatory. Sci Rep 2017, 7(1): 1-11.
  • 16. Yeung D, Manias JL, Stewart DJ, Nag S. Decreased junctional adhesion molecule-A expression during blood–brain barrier breakdown. Acta Neuropathol 2008; 115(6): 635–42.
  • 17. Padden M, Leech S, Craig B, Kirk J, Brankin B, McQuaid S. Differences in expression of junctional adhesion molecule-A and beta-catenin in multiple sclerosis brain tissue: increasing evidence for the role of tight junction pathology. Acta Neuropathol 2007; 113(2): 177–86.
  • 18. Kempuraj D, Ahmed ME, Selvakumar GP, Thangavel R, Raikwar SP, Zaheer SA, et al. Acute traumatic brain injury-induced neuroinflammatory response and neurovascular disorders in the brain. Neurotox Res 2021; 39(2): 359–68.
  • 19. Kago T, Takagi N, Date I, Takenaga Y, Takagi K, Takeo S. Cerebral ischemia enhances tyrosine phosphorylation of occludin in brain capillaries. Biochem Biophys Res Commun. 2006; 339(4): 1197-203.
  • 20. Jiao H, Wang Z, Liu Y, Wang P, Xue Y. 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 2011; 44(2): 130-9.
  • 21. Vannucci RC, Connor JR, Mauger DT, Palmer C, Smith MB, Towfighi J, et al. Rat model of perinatal hypoxic-ischemic brain damage. J Neurosci Res 1999; 55(2): 158–63.
  • 22. Edwards AB, Feindel KW, Cross CL, Anderton RS, Clark VW, Knuckey NW, et al. Modification to the Rice–Vannucci perinatal hypoxic-ischaemic encephalopathy model in the P7 rat improves the reliability of cerebral infarct development after 48 hours. J Neurosci Methods 2017; 288: 62–71.
Year 2024, Volume: 25 Issue: 2, 85 - 96, 31.08.2024
https://doi.org/10.69601/meandrosmdj.1522105

Abstract

Project Number

2020/TPF-20047

References

  • 1. World Health Organization Global Health Estimates: Life expectancy and leading causes of death and disability. Available from: https://www.who.int/data/gho/data/themes/mortality-and-global-health-estimates.
  • 2. Yaghi S, Elkind MS. Cryptogenic stroke: a diagnostic challenge. Neurol Clin Pract 2014; 4(5): 386–393.
  • 3. Zhang J, Yang Y, Sun H, Xing Y. Hemorrhagic transformation after cerebral infarction: current concepts and challenges. Ann Transl Med 2014; 2(8): 81.
  • 4. Lipton P. Ischemic cell death in brain neurons. Physiol Rev. 1999; 79(4): 1431-568.
  • 5. Stone JA, Willey JZ, Keyrouz S, Butera J, McTaggart RA, Cutting S et al. Therapies for hemorrhagic transformation in acute ischemic stroke. Curr Treat Options Neurol 2017; 19(1): 1.
  • 6. Kago T, Takagi N, Date I, Takenaga Y, Takagi K, Takeo S. Cerebral ischemia enhances tyrosine phosphorylation of occludin in brain capillaries. Biochem Biophys Res Commun 2006; 339(4): 1197–203.
  • 7. Jiao H, Wang Z, Liu Y, Wang P, Xue Y. 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 2011; 44(2): 130–9.
  • 8. Yang Y, Rosenberg GA. MMP-mediated disruption of claudin-5 in the blood-brain barrier of rat brain after cerebral ischemia. Methods Mol Biol 2011; 762: 333-45.
  • 9. Shi S, Qi Z, Ma Q, Pan R, Timmins GS, Zhao Y, et al. Normobaric hyperoxia reduces blood occludin fragments in rats and patients with acute ischemic stroke. Stroke 2017; 48(10): 2848-54.
  • 10. Pan R, Yu K, Weatherwax T, Zheng H, Liu W, Liu KJ. Blood occludin level as a potential biomarker for early blood–brain barrier damage following ischemic stroke. Sci Rep 2017; 7: 40331.
  • 11. Kazmierski R, Michalak S, Wencel-Warot A, Nowinski WL. Serum tight-junction proteins predict hemorrhagic transformation in ischemic stroke patients. Neurology 2012; 79(16): 1677–85.
  • 12. Li W, Qi Z, Kang H, Qin X, Song H, Sui X, et al. Serum occludin as a biomarker to predict the severity of acute ischemic stroke, hemorrhagic transformation, and patient prognosis. Aging Dis 2020; 11(6): 1395–1406.
  • 13. Sladojevic N, Stamatovic SM, Keep RF, Grailer JJ, Sarma JV, Ward PA, et al. Inhibition of junctional adhesion molecule-A/LFA interaction attenuates leukocyte trafficking and inflammation in brain ischemia/reperfusion injury. Neurobiol Dis 2014; 67: 57–70.
  • 14. Powers WJ, Rabinstein AA, Ackerson T, Adeoye OM, Bambakidis NC, Becker K, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke. Stroke 2019; 50(12): 3331–2.
  • 15. Janyou A, Wicha P, Jittiwat J, Suksamrarn A, Tocharus C, Tocharus J . Dihydrocapsaicin attenuates blood brain barrier and cerebral damage in focal cerebral ischemia/reperfusion via oxidative stress and inflammatory. Sci Rep 2017, 7(1): 1-11.
  • 16. Yeung D, Manias JL, Stewart DJ, Nag S. Decreased junctional adhesion molecule-A expression during blood–brain barrier breakdown. Acta Neuropathol 2008; 115(6): 635–42.
  • 17. Padden M, Leech S, Craig B, Kirk J, Brankin B, McQuaid S. Differences in expression of junctional adhesion molecule-A and beta-catenin in multiple sclerosis brain tissue: increasing evidence for the role of tight junction pathology. Acta Neuropathol 2007; 113(2): 177–86.
  • 18. Kempuraj D, Ahmed ME, Selvakumar GP, Thangavel R, Raikwar SP, Zaheer SA, et al. Acute traumatic brain injury-induced neuroinflammatory response and neurovascular disorders in the brain. Neurotox Res 2021; 39(2): 359–68.
  • 19. Kago T, Takagi N, Date I, Takenaga Y, Takagi K, Takeo S. Cerebral ischemia enhances tyrosine phosphorylation of occludin in brain capillaries. Biochem Biophys Res Commun. 2006; 339(4): 1197-203.
  • 20. Jiao H, Wang Z, Liu Y, Wang P, Xue Y. 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 2011; 44(2): 130-9.
  • 21. Vannucci RC, Connor JR, Mauger DT, Palmer C, Smith MB, Towfighi J, et al. Rat model of perinatal hypoxic-ischemic brain damage. J Neurosci Res 1999; 55(2): 158–63.
  • 22. Edwards AB, Feindel KW, Cross CL, Anderton RS, Clark VW, Knuckey NW, et al. Modification to the Rice–Vannucci perinatal hypoxic-ischaemic encephalopathy model in the P7 rat improves the reliability of cerebral infarct development after 48 hours. J Neurosci Methods 2017; 288: 62–71.
There are 22 citations in total.

Details

Primary Language English
Subjects Emergency Medicine
Journal Section Research Article
Authors

Gül Taşlı Yeşilçayır 0000-0002-0394-4168

Yunus Emre Özlüer 0000-0001-8297-7525

Ozge Cevik 0000-0002-9325-3757

Erkan Gümüş 0000-0001-6432-7457

Project Number 2020/TPF-20047
Early Pub Date August 28, 2024
Publication Date August 31, 2024
Submission Date July 25, 2024
Acceptance Date August 14, 2024
Published in Issue Year 2024 Volume: 25 Issue: 2

Cite

EndNote Taşlı Yeşilçayır G, Özlüer YE, Cevik O, Gümüş E (August 1, 2024) A Novel Biomarker in Experimental Cerebral Ischemia: Junctional Adhesion Molecule-A. Meandros Medical And Dental Journal 25 2 85–96.