title: Blood-brain barrier permeability and tPA-mediated neurotoxicity.
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.
authors.affiliation: Department of Clinical Biochemistry, Hebrew University - Hadassah Medical Center, Jerusalem, Israel.
authors.forename: Rami
authors.initials: R
authors.lastname: Abu Fanne
authors.forename: Taher
authors.initials: T
authors.lastname: Nassar
authors.forename: Sergei
authors.initials: S
authors.lastname: Yarovoi
authors.forename: Anwar
authors.initials: A
authors.lastname: Rayan
authors.forename: Itschak
authors.initials: I
authors.lastname: Lamensdorf
authors.forename: Michael
authors.initials: M
authors.lastname: Karakoveski
authors.forename: Polianski
authors.initials: P
authors.lastname: Vadim
authors.forename: Mahmud
authors.initials: M
authors.lastname: Jammal
authors.forename: Douglas B
authors.initials: DB
authors.lastname: Cines
authors.forename: Abd Al-Roof
authors.initials: AA
authors.lastname: Higazi
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000473:pathology; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D002199:Capillary Permeability / Q000187:drug effects*; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000633:toxicity; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D009154:Mutation; D010447:Peptide Hydrolases / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D058258:Serpin E2; D015843:Serpins / Q000235:genetics / Q000633:toxicity; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000188:drug therapy / Q000473:pathology; D013923:Thromboembolism / Q000188:drug therapy / Q000473:pathology; D010959:Tissue Plasminogen Activator / Q000235:genetics / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D005343:Fibrinolytic Agents; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D015843:Serpins; D010447:Peptide Hydrolases; D010959:Tissue Plasminogen Activator