TY - JOUR
T1 - Blood-brain barrier permeability and tPA-mediated neurotoxicity
AU - Fanne, Rami Abu
AU - Nassar, Taher
AU - Yarovoi, Sergei
AU - Rayan, Anwar
AU - Lamensdorf, Itschak
AU - Karakoveski, Michael
AU - Vadim, Polianski
AU - Jammal, Mahmud
AU - Cines, Douglas B.
AU - Al-Roof Higazi, Abd
N1 - 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.
PY - 2010/6
Y1 - 2010/6
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=77950935919&partnerID=8YFLogxK
U2 - 10.1016/j.neuropharm.2009.12.017
DO - 10.1016/j.neuropharm.2009.12.017
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C2 - 20060006
AN - SCOPUS:77950935919
SN - 0028-3908
VL - 58
SP - 972
EP - 980
JO - Neuropharmacology
JF - Neuropharmacology
IS - 7
ER -
