Specific role of tight junction proteins claudin-5, occludin and ZO-1 of the blood-brain barrier in a focal cerebral ischemic insult
Abstract
Blood-brain barrier (BBB) leakage plays a key role in cerebral ischemia-reperfusion injury. It is quite necessary to further explore the characteristic and mechanism of BBB leakage during stroke. We induced a focal cerebral ischemia model by transient middle cerebral artery occlusion in male rats for defining the time course of BBB permeability within 120 h following reperfusion and evaluate the specific role of tight junction (TJ) associated proteins claudin-5, occludin, and ZO-1 as well as protein kinase C delta (PKCδ) pathway in BBB leakage induced by reperfusion injury. We verified a bimodal increase in the permeability of the BBB following focal ischemia by Evans blue assay. Two peaks of BBB permeability appeared at 3 h and 72 h of reperfusion after 2 h focal ischemia, respectively. The leak at the endothelial cell was represented at the level of transmission electron microscopy. TTC staining results showed increased infarct size with time after cerebral ischemia reperfusion. The mRNA and protein expression levels of these three TJ associated proteins were significantly decreased compared with the sham-operated group within 120 h of reperfusion, corresponding to the time-dependent change of the biphasic pattern in BBB leakage. The redistribution of claudin-5, occludin, and ZO-1 in ischemia brain microvascular endothelial cells was observed at the same time points. In addition, Western blot assay revealed PKCδ level was also significantly increased in a similar biphasic pattern to above results within 120 h after cerebral ischemia-reperfusion. This study demonstrates the timing of TJ associated proteins claudin-5, occludin, and ZO-1 in light of BBB permeability associated with cerebral ischemia reperfusion, and suggests PKCδ pathway may participate in TJ barrier open and BBB leakage during reperfusion injury in a time-dependent manner.
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Microglial-induced late-phase BBB disruption is due to direct effects on endothelial cells: IL-1β and TNF-α downregulate tight junction protein expression in ECs, and together with IL-6 modulate expression of adhesion molecules ICAM-1 and VCAM.
“Apart from the effects of MMPs, microglial-induced late-phase BBB disruption is due to direct effects on ECs: IL-1β and TNF-α downregulate tight junction proteins expression in ECs (Yamagata et al., 2004; Jiao et al., 2011) and, together with IL-6, modulate the expression of adhesion molecules (ICAM-1 and VCAM; Hallenbeck, 2002).”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Jiao et al., 2011
Blood-derived macrophages and microglia have many functions in the dynamic process of CNS injury and repair, affecting BBB permeabilization, which in turn can aggravate stroke.
“Blood-derived macrophages and microglia appear to have many functions in the dynamic process of CNS injury and repair, affecting BBB permeabilization, which in turn can aggravate stroke (Hallenbeck, 2002; Sandoval and Witt, 2008; Jiao et al., 2011).”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Jiao et al., 2011
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References 36 · Cited by 411
- Authors
- Jiao, H., Wang, Z., Liu, Y., Wang, P., & Xue, Y.
- Affiliations
- China Medical University (CN)
- Sheng Jing Hospital (CN)
- Corresponding author
- Xue, Yixue
- Venue
- Journal of Molecular Neuroscience
- Published
- 2011-02-12
- Volume
- 44
- Issue
- 2
- Pages
- 130-139
- ISSN
- 0895-8696 (ISSN-L)
- 1559-1166
- OpenAlex
- W2025688778
- Cited by
- 411
- References
- 36
- Citations by year
- 2026: 25 · 2025: 37 · 2024: 23 · 2023: 28 · 2022: 38 · 2021: 41 · 2020: 40 · 2019: 28 · 2018: 33 · 2017: 18 · 2016: 24 · 2015: 13 · 2014: 24 · 2013: 22 · 2012: 12
- FWCI
- 11.04
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Journal of Molecular Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China
- Topics
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- blood-brain barrier permeability, tight junction proteins, claudin-5, occludin, ZO-1, cerebral ischemia-reperfusion injury, focal cerebral ischemia, protein kinase C delta, middle cerebral artery occlusion, stroke, infarct size, endothelial cells
- MeSH terms
- Animals, Blood-Brain Barrier, Brain Ischemia, Coloring Agents, Evans Blue, Male, Membrane Proteins, Permeability, Phosphoproteins, Random Allocation, Reperfusion Injury, Rats, Sprague-Dawley, Tight Junctions, Infarction, Middle Cerebral Artery, Rats, Protein Kinase C-delta, Claudin-5, Occludin, Zonula Occludens-1 Protein
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