Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke.

Hdl Handle:
http://hdl.handle.net/10675.2/73
Title:
Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke.
Authors:
Machado, Livia S; Kozak, Anna; Ergul, Adviye; Hess, David C.; Borlongan, Cesar V ( 0000-0002-2966-9782 ) ; Fagan, Susan C.
Abstract:
BACKGROUND: Matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) are increased in the brain after experimental ischemic stroke in rats. These two proteases are involved with the degradation of the basal lamina and loss of stability of the blood brain barrier that occurs after ischemia and that is associated with thrombolytic therapy in ischemic stroke. Minocycline is a lipophilic tetracycline and is neuroprotective in several models of brain injury. Minocycline inhibits inflammation, apoptosis and extracellular matrix degradation. In this study we investigated whether delayed minocycline inhibits brain MMPs activated by ischemia in a model of temporary occlusion in Wistar rats. RESULTS: Both MMP-2 and MMP-9 were elevated in the ischemic tissue as compared to the contra-lateral hemisphere after 3 hours occlusion and 21 hours survival (p < 0.0001 for MMP-9). Intraperitoneal minocycline at 45 mg/kg concentration twice a day (first dose immediately after the onset of reperfusion) significantly reduced gelatinolytic activity of ischemia-elevated MMP-2 and MMP-9 (p < 0.0003). Treatment also reduced protein concentration of both enzymes (p < 0.038 for MMP-9 and p < 0.018 for MMP-2). In vitro incubation of minocycline in concentrations as low as 0.1 mug/ml with recombinant MMP-2 and MMP-9 impaired enzymatic activity and MMP-9 was more sensitive at lower minocycline concentrations (p < 0.05). CONCLUSION: Minocycline inhibits enzymatic activity of gelatin proteases activated by ischemia after experimental stroke and is likely to be selective for MMP-9 at low doses. Minocycline is a potential new therapeutic agent to acute treatment of ischemic stroke.
Citation:
BMC Neurosci. 2006 Jul 17; 7:56
Issue Date:
15-Aug-2006
URI:
http://hdl.handle.net/10675.2/73
DOI:
10.1186/1471-2202-7-56
PubMed ID:
16846501
PubMed Central ID:
PMC1543649
Type:
Journal Article; Research Support, N.I.H., Extramural
ISSN:
1471-2202
Appears in Collections:
Vascular Biology Center: Faculty Research and Publication

Full metadata record

DC FieldValue Language
dc.contributor.authorMachado, Livia Sen_US
dc.contributor.authorKozak, Annaen_US
dc.contributor.authorErgul, Adviyeen_US
dc.contributor.authorHess, David C.en_US
dc.contributor.authorBorlongan, Cesar Ven_US
dc.contributor.authorFagan, Susan C.en_US
dc.date.accessioned2010-09-24T21:44:42Z-
dc.date.available2010-09-24T21:44:42Z-
dc.date.issued2006-08-15en_US
dc.identifier.citationBMC Neurosci. 2006 Jul 17; 7:56en_US
dc.identifier.issn1471-2202en_US
dc.identifier.pmid16846501en_US
dc.identifier.doi10.1186/1471-2202-7-56en_US
dc.identifier.urihttp://hdl.handle.net/10675.2/73-
dc.description.abstractBACKGROUND: Matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9) are increased in the brain after experimental ischemic stroke in rats. These two proteases are involved with the degradation of the basal lamina and loss of stability of the blood brain barrier that occurs after ischemia and that is associated with thrombolytic therapy in ischemic stroke. Minocycline is a lipophilic tetracycline and is neuroprotective in several models of brain injury. Minocycline inhibits inflammation, apoptosis and extracellular matrix degradation. In this study we investigated whether delayed minocycline inhibits brain MMPs activated by ischemia in a model of temporary occlusion in Wistar rats. RESULTS: Both MMP-2 and MMP-9 were elevated in the ischemic tissue as compared to the contra-lateral hemisphere after 3 hours occlusion and 21 hours survival (p < 0.0001 for MMP-9). Intraperitoneal minocycline at 45 mg/kg concentration twice a day (first dose immediately after the onset of reperfusion) significantly reduced gelatinolytic activity of ischemia-elevated MMP-2 and MMP-9 (p < 0.0003). Treatment also reduced protein concentration of both enzymes (p < 0.038 for MMP-9 and p < 0.018 for MMP-2). In vitro incubation of minocycline in concentrations as low as 0.1 mug/ml with recombinant MMP-2 and MMP-9 impaired enzymatic activity and MMP-9 was more sensitive at lower minocycline concentrations (p < 0.05). CONCLUSION: Minocycline inhibits enzymatic activity of gelatin proteases activated by ischemia after experimental stroke and is likely to be selective for MMP-9 at low doses. Minocycline is a potential new therapeutic agent to acute treatment of ischemic stroke.en_US
dc.rightsThe PMC Open Access Subset is a relatively small part of the total collection of articles in PMC. Articles in the PMC Open Access Subset are still protected by copyright, but are made available under a Creative Commons or similar license that generally allows more liberal redistribution and reuse than a traditional copyrighted work. Please refer to the license statement in each article for specific terms of use. The license terms are not identical for all articles in this subset.en_US
dc.subject.meshAnimalsen_US
dc.subject.meshAnti-Inflammatory Agents / administration & dosageen_US
dc.subject.meshApoptosis / drug effects / physiologyen_US
dc.subject.meshBlood-Brain Barrier / drug effects / metabolism / physiopathologyen_US
dc.subject.meshBrain / drug effects / enzymology / physiopathologyen_US
dc.subject.meshBrain Ischemia / drug therapy / enzymology / physiopathologyen_US
dc.subject.meshDisease Models, Animalen_US
dc.subject.meshDrug Administration Scheduleen_US
dc.subject.meshEncephalitis / drug therapy / metabolism / physiopathologyen_US
dc.subject.meshEnzyme Activation / drug effects / physiologyen_US
dc.subject.meshEnzyme Inhibitors / administration & dosageen_US
dc.subject.meshExtracellular Matrix / drug effects / metabolismen_US
dc.subject.meshMaleen_US
dc.subject.meshMatrix Metalloproteinase 2 / antagonists & inhibitors / metabolismen_US
dc.subject.meshMatrix Metalloproteinase 9 / antagonists & inhibitors / metabolismen_US
dc.subject.meshMatrix Metalloproteinases / antagonists & inhibitors / metabolismen_US
dc.subject.meshMinocycline / administration & dosageen_US
dc.subject.meshNerve Degeneration / drug therapy / metabolism / physiopathologyen_US
dc.subject.meshNeuroprotective Agents / administration & dosageen_US
dc.subject.meshRatsen_US
dc.subject.meshRats, Wistaren_US
dc.subject.meshStroke / drug therapy / enzymology / physiopathologyen_US
dc.subject.meshTime Factorsen_US
dc.subject.meshTreatment Outcomeen_US
dc.titleDelayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke.en_US
dc.typeJournal Articleen_US
dc.typeResearch Support, N.I.H., Extramuralen_US
dc.identifier.pmcidPMC1543649en_US
dc.contributor.corporatenameVascular Biology Centeren_US
dc.contributor.corporatenameDepartment of Neurologyen_US

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