Blood-brain barrier permeability and tPA-mediated neurotoxicity.
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.
Abu Fanne
Rami
R
Department of Clinical Biochemistry, Hebrew University - Hadassah Medical Center, Jerusalem, Israel.
Nassar
Taher
T
Yarovoi
Sergei
S
Rayan
Anwar
A
Lamensdorf
Itschak
I
Karakoveski
Michael
M
Vadim
Polianski
P
Jammal
Mahmud
M
Cines
Douglas B
DB
Higazi
Abd Al-Roof
AA
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
D005343:Fibrinolytic Agents; D058258:Serpin E2; C511869:Serpine2 protein, mouse; D015843:Serpins; D010447:Peptide Hydrolases; D010959:Tissue Plasminogen Activator