Glial cells drive preconditioning-induced blood-brain barrier protection

Raffaella Gesuete, Franca Orsini, Elisa R. Zanier, Diego Albani, Maria A. Deli, Gianfranco Bazzoni, Maria Grazia De Simoni

Research output: Contribution to journalArticle

Abstract

BACKGROUND AND PURPOSE-The cerebrovascular contribution to ischemic preconditioning (IPC) has been scarcely explored. Using in vivo and in vitro approaches, we investigated the involvement of the blood-brain barrier and the role of its cellular components. METHODS-Seven-minute occlusion of the right middle cerebral artery, used as in vivo IPC stimulus 4 days before permanent occlusion of the right middle cerebral artery, significantly reduced brain infarct size (8.45±0.7 versus 13.61±0.08 mm3 measured 7 days after injury) and preserved blood-brain barrier function (Evans blue leakage, 0.54±0.1 versus 0.89±0.1 ng/mg). Assessment of neuronal, endothelial, and glial gene expression revealed that IPC specifically increased glial fibrillary acidic protein mRNA, thus showing selective astrocyte activation in IPC-protected mice. RESULTS-The blood-brain barrier was modeled by coculturing murine primary brain microvessel endothelial and astroglial cells. One-hour oxygen-glucose deprivation (OGD), delivered 24 hours before a 5-hour OGD, acted as an IPC stimulus, significantly attenuating the reduction in transendothelial electric resistance (199.17±11.7 versus 97.72±3.4 Ωcm2) and the increase in permeability coefficients for sodium fluorescein (0.98±0.11×10-3 versus 1.8±0. 36×10-3 cm/min) and albumin (0.12±0.01×10 -3 versus 0.29±0.07×10-3 cm/min) induced by severe OGD. IPC also prevented the 5-hour OGD-induced disorganization of the tight junction proteins ZO-1 and claudin-5. IPC on glial (but not endothelial) cells alone preserved transendothelial electric resistance, permeability coefficients, and ZO-1 localization after 5 hours of OGD. Astrocyte metabolic inhibition by fluorocitrate abolished IPC protection, confirming the critical role of astrocytes. IPC significantly increased glial fibrillary acidic protein, interleukin-6, vascular endothelial growth factor-a, and ciliary neurotrophic factor gene expression after OGD in glial cells, indicating that multiple pathways mediate the glial contribution to IPC. CONCLUSIONS-Our data show that the blood-brain barrier can be directly preconditioned and that astrocytes are major mediators of IPC protection.

Original languageEnglish
Pages (from-to)1445-1453
Number of pages9
JournalStroke
Volume42
Issue number5
DOIs
Publication statusPublished - May 2011

Fingerprint

Ischemic Preconditioning
Blood-Brain Barrier
Neuroglia
Oxygen
Glucose
Astrocytes
Middle Cerebral Artery Infarction
Glial Fibrillary Acidic Protein
Electric Impedance
Permeability
Claudin-5
Endothelial Cells
Zonula Occludens-1 Protein
Ciliary Neurotrophic Factor
Gene Expression
Evans Blue
Brain
Microvessels
Fluorescein
Vascular Endothelial Growth Factor A

Keywords

  • astrocytes
  • blood-brain barrier
  • ischemia
  • oxygen-glucose deprivation
  • preconditioning

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialised Nursing

Cite this

Glial cells drive preconditioning-induced blood-brain barrier protection. / Gesuete, Raffaella; Orsini, Franca; Zanier, Elisa R.; Albani, Diego; Deli, Maria A.; Bazzoni, Gianfranco; De Simoni, Maria Grazia.

In: Stroke, Vol. 42, No. 5, 05.2011, p. 1445-1453.

Research output: Contribution to journalArticle

Gesuete, Raffaella ; Orsini, Franca ; Zanier, Elisa R. ; Albani, Diego ; Deli, Maria A. ; Bazzoni, Gianfranco ; De Simoni, Maria Grazia. / Glial cells drive preconditioning-induced blood-brain barrier protection. In: Stroke. 2011 ; Vol. 42, No. 5. pp. 1445-1453.
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