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 language | English (US) |
|---|---|
| Pages (from-to) | 3028-3033 |
| Number of pages | 6 |
| Journal | Stroke; a journal of cerebral circulation |
| Volume | 40 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 2009 |
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ASJC Scopus subject areas
- Clinical Neurology
- Cardiology and Cardiovascular Medicine
- Advanced and Specialized Nursing
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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 journal › Article
}
TY - JOUR
T1 - Minocycline and tissue-type plasminogen activator for stroke
T2 - assessment of interaction potential.
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.
PY - 2009/9
Y1 - 2009/9
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.
UR - http://www.scopus.com/inward/record.url?scp=70349248385&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=70349248385&partnerID=8YFLogxK
U2 - 10.1161/STROKEAHA.109.556852
DO - 10.1161/STROKEAHA.109.556852
M3 - Article
C2 - 19628804
AN - SCOPUS:70349248385
VL - 40
SP - 3028
EP - 3033
JO - Stroke
JF - Stroke
SN - 0039-2499
IS - 9
ER -