Published Online
on October 16, 2008

A more recent version of this article appeared on December 1, 2008

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Submitted on January 10, 2008
Accepted on February 7, 2008

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; and 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.

^* To whom correspondence should be addressed. 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

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