title: A broad-spectrum matrix metalloproteinase inhibitor prevents hemorrhagic complications induced by tissue plasminogen activator in mice.
abstract: Delayed activation of tissue plasminogen activator (tPA) can lead to the disruption of the blood-brain barrier (BBB), resulting in hemorrhagic complications. In the present study, we focused on tight junction proteins (TJPs), occludin, zona occludens (ZO)-1, and claudin-5, which are important structural components of the BBB, and investigated whether inhibition of matrix metalloproteinases (MMPs) provides a protective effect against hemorrhagic complications induced by tPA. We subjected mice to 6-h filamental middle cerebral artery occlusion (MCAO) with vehicle, delayed tPA alone, or combined tPA (10 mg/kg, i.v.) plus GM6001 (100 mg/kg, i.p.), a broad-spectrum MMP inhibitor. We evaluated brain hemoglobin and the expression of MMP-9 and TJPs by immunoblotting. GM6001 significantly reduced tPA-elevated brain hemoglobin, MMP-9, and inhibited the degradation of occludin and ZO-1 induced by tPA, but not claudin-5. Treatment with GM6001 also significantly prevented the decrease in the survival rate and the reduction in locomotor activity caused by tPA at 7 days after ischemia/reperfusion. Furthermore, GM6001 treatment also significantly prevented cell damage, determined by release of lactase dehydrogenase (LDH) activity, and the decrease in transendothelial electrical resistance (TEER) induced by tPA. These findings indicate that GM6001 prevented the hemorrhagic complications and improved the behavioral abnormalities induced by tPA, partly via protection of TJPs. This suggests that GM6001 may be a useful candidate for combination therapy against the hemorrhagic complications induced by tPA.
authors.affiliation: Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu 501-1196, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Mishiro
authors.forename: M
authors.initials: M
authors.lastname: Ishiguro
authors.forename: Y
authors.initials: Y
authors.lastname: Suzuki
authors.forename: K
authors.initials: K
authors.lastname: Tsuruma
authors.forename: M
authors.initials: M
authors.lastname: Shimazawa
authors.forename: H
authors.initials: H
authors.lastname: Hara
mesh_terms: D000818:Animals; D021461:Animals, Outbred Strains; D002543:Cerebral Hemorrhage / Q000139:chemically induced* / Q000201:enzymology / Q000517:prevention & control*; D004151:Dipeptides / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000633:toxicity*; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051379:Mice; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors* / Q000633:toxicity*
chemical_list: D004151:Dipeptides; D005343:Fibrinolytic Agents; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D010959:Tissue Plasminogen Activator; D019278:Matrix Metalloproteinase 3