This Article Full Text Full Text (PDF) All Versions of this Article: 39/12/3372    most recent STROKEAHA.108.514026v1 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 Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Murata, Y. Articles by Lo, E. H. Search for Related Content PubMed PubMed Citation Articles by Murata, Y. Articles by Lo, E. H. Related Collections Animal models of human disease Acute Cerebral Hemorrhage Acute Cerebral Infarction Embolic stroke Other Stroke

(Stroke. 2008;39:3372.)
© 2008 American Heart Association, Inc.

Original Contributions

Extension of the Thrombolytic Time Window With Minocycline in Experimental Stroke

Yoshihiro Murata, MD; Anna Rosell, PhD; Robert H. Scannevin, PhD; Kenneth J. Rhodes, PhD; Xiaoying Wang, PhD Eng H. Lo, PhD

From the Neuroprotection Research Laboratory (Y.M., A.R., X.W., E.H.L.), Departments of Neurology and Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, Mass; and Biogen IDEC (R.H.S., K.J.R.), Cambridge, Mass.

Correspondence to Eng H. Lo, Neuroprotection Res Lab, MGH East 149-2401, Charlestown, MA 02129. E-mail Lo{at}helix.mgh.harvard.edu

Background and Purpose— Thrombolysis with tPA is the only FDA-approved therapy for acute ischemic stroke. But its widespread application remains limited by narrow treatment time windows and the related risks of cerebral hemorrhage. In this study, we ask whether minocycline can prevent tPA-associated cerebral hemorrhage and extend the reperfusion window in an experimental stroke model in rats.

Methods— Spontaneously hypertensive rats were subjected to embolic focal ischemia using homologous clots and treated with: saline at 1 hour; early tPA at 1 hour, delayed tPA at 6 hours; minocycline at 4 hours; combined minocycline at 4 hours plus tPA at 6 hours. Infarct volumes and hemorrhagic transformation were quantified at 24 hours. Gelatin zymography was used to measure blood levels of circulating matrix metalloproteinase-9 (MMP-9).

Results— Early 1-hour thrombolysis restored perfusion and reduced infarction. Late 6-hour tPA did not decrease infarction but instead worsened hemorrhagic conversion. Combining minocycline with delayed 6-hour tPA decreased plasma MMP-9 levels, reduced infarction, and ameliorated brain hemorrhage. Blood levels of MMP-9 were also significantly correlated with volumes of infarction and hemorrhage.

Conclusion— Combination therapy with minocycline may extend tPA treatment time windows in ischemic stroke.

Key Words: cerebral ischemia • hemorrhagic transformation • edema • tPA • neuroprotection

This article has been cited by other articles:

				S. K. Natarajan, K. V. Snyder, A. H. Siddiqui, C. C. Ionita, L. N. Hopkins, and E. I. Levy Safety and Effectiveness of Endovascular Therapy After 8 Hours of Acute Ischemic Stroke Onset and Wake-Up Strokes Stroke, October 1, 2009; 40(10): 3269 - 3274. [Abstract] [Full Text] [PDF]

				L. S. Machado, I. Y. Sazonova, A. Kozak, D. C. Wiley, A. B. El-Remessy, A. Ergul, D. C. Hess, J. L. Waller, and S. C. Fagan Minocycline and Tissue-Type Plasminogen Activator for Stroke: Assessment of Interaction Potential Stroke, September 1, 2009; 40(9): 3028 - 3033. [Abstract] [Full Text] [PDF]

				W. Liu, J. Hendren, X.-J. Qin, and K. J. Liu Normobaric Hyperoxia Reduces the Neurovascular Complications Associated With Delayed Tissue Plasminogen Activator Treatment in a Rat Model of Focal Cerebral Ischemia Stroke, July 1, 2009; 40(7): 2526 - 2531. [Abstract] [Full Text] [PDF]