title: Recombinant tissue plasminogen activator induces blood-brain barrier breakdown by a matrix metalloproteinase-9-independent pathway after transient focal cerebral ischemia in mouse.
abstract: The role of the inducible matrix metalloproteinase (MMP)-9 in blood-brain barrier (BBB) disruption after ischemic stroke is well accepted. Recombinant tissue plasminogen activator (r-tPA) is the only approved thrombolytic treatment of ischemic stroke but r-tPA is potentially neurotoxic. Vasogenic edema after r-tPA treatment has been linked with an increase in cerebral MMP-9. However, because cerebral ischemia clearly increases the levels of endogenous tPA, the consequence of additional r-tPA may be questionable. In this study, wild type and MMP-9 knockout mice were subjected to 90 min transient middle cerebral artery occlusion and treated with 10 mg/kg r-tPA. At 24 h after occlusion, BBB permeability, hemispheric enlargement, collagen and laminin degradation as well as cerebral infarction were increased in both wild type and MMP-9 knockout treated animals as compared with non-treated animals. Mortality was increased in wild type but reduced in knockout treated mice. Cerebral MMP-9 concentration was not modified by r-tPA. However, pre-treatment with p-aminobenzoyl-gly-pro-D-leu-D-ala-hydroxamate, a broad-spectrum MMP inhibitor, counteracted the effects of r-tPA on the neurovascular unit and decreased mortality in both wild type and knockout mice. MMP inhibition did not modify cerebral infarction in r-tPA-treated animals. Our results suggest that r-tPA toxicity is mainly independent of MMP-9 after transient middle cerebral artery occlusion but could involve some other MMPs. Additionally, our results support the hypothesis of a dissociation between r-tPA-dependent mechanisms of BBB breakdown and cerebral infarction. Due to the importance of r-tPA in thrombolytic treatment of ischemic stroke patients, the MMPs that could participate in r-tPA-induced BBB disruption should be further characterized.
authors: Division of Neurosurgery, University Hospitals of Geneva, Geneva, Switzerland. jean-christophe.copin@unige.ch
authors: Jean-Christophe
authors: JC
authors: Copin
authors: Daniel Jiménez
authors: DJ
authors: Bengualid
authors: Rafaela F
authors: RF
authors: Da Silva
authors: Odysseas
authors: O
authors: Kargiotis
authors: Karl
authors: K
authors: Schaller
authors: Yvan
authors: Y
authors: Gasche
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology*; D024141:Collagen Type IV / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D007797:Laminin / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020521:Stroke / Q000378:metabolism / Q000473:pathology*; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*
chemical_list: D024141:Collagen Type IV; D005343:Fibrinolytic Agents; D007797:Laminin; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9