Blood-brain barrier permeability and tPA-mediated neurotoxicity

Rami Abu Fanne, Taher Nassar, Sergei Yarovoi, Anwar Rayan, Itschak Lamensdorf, Michael Karakoveski, Polianski Vadim, Mahmud Jammal, Douglas B. Cines, Abd Al-Roof Higazi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

70 Scopus citations

Abstract

Tissue type plasminogen activator (tPA) can induce neuronal apoptosis, disrupt the blood-brain barrier (BBB), and promote dilation of the cerebral vasculature. The timing, sequence and contributions of these and other deleterious effects of tPA and their contribution to post-ischemic brain damage after stroke, have not been fully elucidated. To dissociate the effects of tPA on BBB permeability, cerebral vasodilation and protease-dependent pathways, we developed several tPA mutants and PAI-1 derived peptides constructed by computerized homology modeling of tPA. Our data show that intravenous administration of human tPA to rats increases BBB permeability through a non-catalytic process that is associated with reversible neurotoxicity, brain damage, mortality and contributes significantly to its brief therapeutic window. Furthermore, our data show that inhibiting the effect of tPA on BBB function without affecting its catalytic activity, improves outcome and significantly extends its therapeutic window in mechanical as well as in thromboembolic models of stroke.

Original languageAmerican English
Pages (from-to)972-980
Number of pages9
JournalNeuropharmacology
Volume58
Issue number7
DOIs
StatePublished - Jun 2010
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by Grants HLHL077760, NS53410, HD5735501 and HL076406 from the National Institutes of Health and 930/04 from the Israel Science Foundation.

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