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

Livia S. Machado, Anna Kozak, Adviye Ergul, David C. Hess, Cesario V. Borlongan, Susan C. Fagan

Research output: Contribution to journalArticle

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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 contralateral 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 μg/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 a ctivity 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.

Original languageEnglish (US)
Article number56
JournalBMC Neuroscience
Volume7
DOIs
StatePublished - Jul 17 2006

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Minocycline
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Matrix Metalloproteinases
Ischemia
Stroke
Peptide Hydrolases
Thrombolytic Therapy
Brain
Gelatin
Tetracycline
Blood-Brain Barrier
Basement Membrane
Brain Injuries
Reperfusion
Extracellular Matrix
Wistar Rats

ASJC Scopus subject areas

  • Neuroscience(all)
  • Cellular and Molecular Neuroscience

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Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke. / Machado, Livia S.; Kozak, Anna; Ergul, Adviye; Hess, David C.; Borlongan, Cesario V.; Fagan, Susan C.

In: BMC Neuroscience, Vol. 7, 56, 17.07.2006.

Research output: Contribution to journalArticle

Machado, Livia S. ; Kozak, Anna ; Ergul, Adviye ; Hess, David C. ; Borlongan, Cesario V. ; Fagan, Susan C. / Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke. In: BMC Neuroscience. 2006 ; Vol. 7.
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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 contralateral 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 μg/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 a ctivity 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.",
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