Minocycline and tissue-type plasminogen activator for stroke: assessment of interaction potential.

Livia S. Machado, Irina Y. Sazonova, Anna Kozak, Daniel C. Wiley, Azza B. El-Remessy, Adviye Ergul, David C. Hess, Jennifer L. Waller, Susan C. Fagan

Research output: Contribution to journalArticle

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Abstract

BACKGROUND AND PURPOSE: New treatment strategies for acute ischemic stroke must be evaluated in the context of effective reperfusion. Minocycline is a neuroprotective agent that inhibits proteolytic enzymes and therefore could potentially both inactivate the clot lysis effect and decrease the damaging effects of tissue-type plasminogen activator (t-PA). This study aimed to determine the effect of minocycline on t-PA clot lysis and t-PA-induced hemorrhage formation after ischemia. METHODS: Fibrinolytic and amidolytic activities of t-PA were investigated in vitro over a range of clinically relevant minocycline concentrations. A suture occlusion model of 3-hour temporary cerebral ischemia in rats treated with t-PA and 2 different minocycline regimens was used. Blood-brain barrier basal lamina components, matrix metalloproteinases (MMPs), hemorrhage formation, infarct size, edema, and behavior outcome were assessed. RESULTS: Minocycline did not affect t-PA fibrinolysis. However, minocycline treatment at 3 mg/kg IV decreased total protein expression of both MMP-2 (P=0.0034) and MMP-9 (P=0.001 for 92 kDa and P=0.0084 for 87 kDa). It also decreased the incidence of hemorrhage (P=0.019), improved neurologic outcome (P=0.0001 for Bederson score and P=0.0391 for paw grasp test), and appeared to decrease mortality. MMP inhibition was associated with decreased degradation in collagen IV and laminin-alpha1 (P=0.0001). CONCLUSIONS: Combination treatment with minocycline is beneficial in t-PA-treated animals and does not compromise clot lysis. These results also suggest that neurovascular protection by minocycline after stroke may involve direct protection of the blood-brain barrier during thrombolysis with t-PA.

Original languageEnglish (US)
Pages (from-to)3028-3033
Number of pages6
JournalStroke; a journal of cerebral circulation
Volume40
Issue number9
DOIs
StatePublished - Sep 2009

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Minocycline
Tissue Plasminogen Activator
Plasminogen Activators
Stroke
Hemorrhage
Blood-Brain Barrier
Matrix Metalloproteinases
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Hand Strength
Neuroprotective Agents
Fibrinolysis
Brain Ischemia
Basement Membrane
Sutures
Nervous System
Reperfusion
Edema
Peptide Hydrolases
Collagen

ASJC Scopus subject areas

  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine
  • Advanced and Specialized Nursing

Cite this

Machado, L. S., Sazonova, I. Y., Kozak, A., Wiley, D. C., El-Remessy, A. B., Ergul, A., ... Fagan, S. C. (2009). Minocycline and tissue-type plasminogen activator for stroke: assessment of interaction potential. Stroke; a journal of cerebral circulation, 40(9), 3028-3033. https://doi.org/10.1161/STROKEAHA.109.556852

Minocycline and tissue-type plasminogen activator for stroke : assessment of interaction potential. / Machado, Livia S.; Sazonova, Irina Y.; Kozak, Anna; Wiley, Daniel C.; El-Remessy, Azza B.; Ergul, Adviye; Hess, David C.; Waller, Jennifer L.; Fagan, Susan C.

In: Stroke; a journal of cerebral circulation, Vol. 40, No. 9, 09.2009, p. 3028-3033.

Research output: Contribution to journalArticle

Machado, Livia S. ; Sazonova, Irina Y. ; Kozak, Anna ; Wiley, Daniel C. ; El-Remessy, Azza B. ; Ergul, Adviye ; Hess, David C. ; Waller, Jennifer L. ; Fagan, Susan C. / Minocycline and tissue-type plasminogen activator for stroke : assessment of interaction potential. In: Stroke; a journal of cerebral circulation. 2009 ; Vol. 40, No. 9. pp. 3028-3033.
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AU - Machado, Livia S.

AU - Sazonova, Irina Y.

AU - Kozak, Anna

AU - Wiley, Daniel C.

AU - El-Remessy, Azza B.

AU - Ergul, Adviye

AU - Hess, David C.

AU - Waller, Jennifer L.

AU - Fagan, Susan C.

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N2 - BACKGROUND AND PURPOSE: New treatment strategies for acute ischemic stroke must be evaluated in the context of effective reperfusion. Minocycline is a neuroprotective agent that inhibits proteolytic enzymes and therefore could potentially both inactivate the clot lysis effect and decrease the damaging effects of tissue-type plasminogen activator (t-PA). This study aimed to determine the effect of minocycline on t-PA clot lysis and t-PA-induced hemorrhage formation after ischemia. METHODS: Fibrinolytic and amidolytic activities of t-PA were investigated in vitro over a range of clinically relevant minocycline concentrations. A suture occlusion model of 3-hour temporary cerebral ischemia in rats treated with t-PA and 2 different minocycline regimens was used. Blood-brain barrier basal lamina components, matrix metalloproteinases (MMPs), hemorrhage formation, infarct size, edema, and behavior outcome were assessed. RESULTS: Minocycline did not affect t-PA fibrinolysis. However, minocycline treatment at 3 mg/kg IV decreased total protein expression of both MMP-2 (P=0.0034) and MMP-9 (P=0.001 for 92 kDa and P=0.0084 for 87 kDa). It also decreased the incidence of hemorrhage (P=0.019), improved neurologic outcome (P=0.0001 for Bederson score and P=0.0391 for paw grasp test), and appeared to decrease mortality. MMP inhibition was associated with decreased degradation in collagen IV and laminin-alpha1 (P=0.0001). CONCLUSIONS: Combination treatment with minocycline is beneficial in t-PA-treated animals and does not compromise clot lysis. These results also suggest that neurovascular protection by minocycline after stroke may involve direct protection of the blood-brain barrier during thrombolysis with t-PA.

AB - BACKGROUND AND PURPOSE: New treatment strategies for acute ischemic stroke must be evaluated in the context of effective reperfusion. Minocycline is a neuroprotective agent that inhibits proteolytic enzymes and therefore could potentially both inactivate the clot lysis effect and decrease the damaging effects of tissue-type plasminogen activator (t-PA). This study aimed to determine the effect of minocycline on t-PA clot lysis and t-PA-induced hemorrhage formation after ischemia. METHODS: Fibrinolytic and amidolytic activities of t-PA were investigated in vitro over a range of clinically relevant minocycline concentrations. A suture occlusion model of 3-hour temporary cerebral ischemia in rats treated with t-PA and 2 different minocycline regimens was used. Blood-brain barrier basal lamina components, matrix metalloproteinases (MMPs), hemorrhage formation, infarct size, edema, and behavior outcome were assessed. RESULTS: Minocycline did not affect t-PA fibrinolysis. However, minocycline treatment at 3 mg/kg IV decreased total protein expression of both MMP-2 (P=0.0034) and MMP-9 (P=0.001 for 92 kDa and P=0.0084 for 87 kDa). It also decreased the incidence of hemorrhage (P=0.019), improved neurologic outcome (P=0.0001 for Bederson score and P=0.0391 for paw grasp test), and appeared to decrease mortality. MMP inhibition was associated with decreased degradation in collagen IV and laminin-alpha1 (P=0.0001). CONCLUSIONS: Combination treatment with minocycline is beneficial in t-PA-treated animals and does not compromise clot lysis. These results also suggest that neurovascular protection by minocycline after stroke may involve direct protection of the blood-brain barrier during thrombolysis with t-PA.

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