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.
journal_name
Strokejournal_title
Strokeauthors
Gesuete R,Orsini F,Zanier ER,Albani D,Deli MA,Bazzoni G,De Simoni MGdoi
10.1161/STROKEAHA.110.603266subject
Has Abstractpub_date
2011-05-01 00:00:00pages
1445-53issue
5eissn
0039-2499issn
1524-4628pii
STROKEAHA.110.603266journal_volume
42pub_type
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