This Article Full Text Full Text (PDF) All Versions of this Article: 40/9/3028    most recent STROKEAHA.109.556852v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Machado, L. S. Articles by Fagan, S. C. PubMed PubMed Citation Articles by Machado, L. S. Articles by Fagan, S. C. Related Collections Animal models of human disease Fibrinolysis Acute Cerebral Infarction Neuroprotectors Thrombolysis Other Vascular biology

(Stroke. 2009;40:3028.)
© 2009 American Heart Association, Inc.

Original Contributions

Minocycline and Tissue-Type Plasminogen Activator for Stroke

Assessment of Interaction Potential

Livia S. Machado, PhD; Irina Y. Sazonova, PhD; Anna Kozak, MS; Daniel C. Wiley, BS; Azza B. El-Remessy, PhD, RPh; Adviye Ergul, MD, PhD; David C. Hess, MD; Jennifer L. Waller, PhD Susan C. Fagan, PharmD

From the Program in Clinical and Experimental Therapeutics, Department of Clinical and Administrative Pharmacy (L.S.M., A.K., D.C.W., A.B.E., A.E., D.C.H., S.C.F.), College of Pharmacy, University of Georgia; Charlie Norwood Veteran’s Affairs Medical Center (L.S.M., A.K., D.C.W., A.B.E., S.C.F.); and the Departments of Medicine (I.Y.S.), Neurology (D.C.H., S.C.F.), Physiology (A.E.), and Biostatistics (J.L.W.), Medical College of Georgia, Augusta, Ga.

Correspondence to Susan C. Fagan, PharmD, University of Georgia College of Pharmacy, HM-1200, 1120 15th St, Augusta, GA 30912-2450. E-mail sfagan{at}mail.mcg.edu

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-1 (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.

Key Words: cerebral ischemia • minocycline • t-PA • matrix metalloproteinases • vascular protection • hemorrhagic transformation