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

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.

• Authors: 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
• Journal: Stroke (Stroke) Vol. 40 Issue 9 Pg. 3028-33 (Sep 2009) ISSN: 1524-4628 [Electronic] United States
• PMID: 19628804 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Anti-Bacterial Agents
• Neuroprotective Agents
• Tissue Plasminogen Activator
• Matrix Metalloproteinase 2
• Mmp2 protein, rat
• Matrix Metalloproteinase 9
• Minocycline

Topics

• Animals
• Anti-Bacterial Agents (pharmacology)
• Blood-Brain Barrier (metabolism)
• Brain Ischemia (chemically induced, drug therapy, metabolism)
• Cerebral Hemorrhage (chemically induced, drug therapy, metabolism)
• Drug Evaluation, Preclinical
• Fibrinolysis (drug effects)
• Gene Expression Regulation (drug effects)
• Male
• Matrix Metalloproteinase 2 (biosynthesis)
• Matrix Metalloproteinase 9 (biosynthesis)
• Minocycline (pharmacology)
• Neuroprotective Agents (pharmacology)
• Rats
• Rats, Wistar
• Stroke (chemically induced, drug therapy, metabolism)
• Tissue Plasminogen Activator (adverse effects, pharmacology)