A broad-spectrum matrix metalloproteinase inhibitor prevents hemorrhagic complications induced by tissue plasminogen activator in mice

• Published in: Neuroscience Vol. 205; pp. 39 - 48
• Main Authors: Mishiro, K, Ishiguro, M, Suzuki, Y, Tsuruma, K, Shimazawa, M, Hara, H
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 15.03.2012; Elsevier
• Subjects: Animals; Animals, Outbred Strains; Biological and medical sciences; blood–brain barrier; Cerebral circulation. Blood-brain barrier. Choroid plexus. Cerebrospinal fluid. Circumventricular organ. Meninges; Cerebral Hemorrhage - chemically induced; Cerebral Hemorrhage - enzymology; Cerebral Hemorrhage - prevention & control; Dipeptides - pharmacology; Dipeptides - therapeutic use; Disease Models, Animal; Fibrinolytic Agents - toxicity; Fundamental and applied biological sciences. Psychology; GM6001; Male; Matrix Metalloproteinase 3 - metabolism; Matrix Metalloproteinase Inhibitors - pharmacology; Matrix Metalloproteinase Inhibitors - therapeutic use; matrix metalloproteinases; Mice; Neurology; tissue plasminogen activator; Tissue Plasminogen Activator - antagonists & inhibitors; Tissue Plasminogen Activator - toxicity; Vertebrates: nervous system and sense organs; MCAO; TNF-α converting enzyme; BBB; tissue plasminogen activator; tPA; zona occludens; lactate dehydrogenase; TACE; EDTA; NVU; ethylendiaminetetraacetate; LDH; MMP; blood–brain barrier; tight junction protein; ZO; transendothelial electrical resistance; matrix metalloproteinase; TEER; TJP; matrix metalloproteinases; middle cerebral artery occlusion; GM6001; neurovascular unit; blood-brain barrier; Serine endopeptidases; Enzyme; Rodentia; Central nervous system; Metalloendopeptidases; Blood brain barrier; t-Plasminogen activator; Encephalon; Peptidases; Vertebrata; Mammalia; Mouse; Animal; Hydrolases; Metalloproteinase
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2011.12.042

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.