Abstract
The purpose of the present study was to investigate whether cilostazol, a phosphodiesterase-III inhibitor and antiplatelet drug, would prevent tPA-associated hemorrhagic transformation. Mice subjected to 6-h middle cerebral artery occlusion were treated with delayed tPA alone at 6 h, with combined tPA plus cilostazol at 6 h, or with vehicle at 6 h. We used multiple imaging (electron microscopy, spectroscopy), histological and neurobehavioral measures to assess the effects of the treatment at 18 h and 7 days after the reperfusion. To further investigate the mechanism of cilostazol to beneficial effect, we also performed an in vitro study with tPA and a phosphodiesterase-III inhibitor in human brain microvascular endothelial cells, pericytes, and astrocytes. Combination therapy with tPA plus cilostazol prevented development of hemorrhagic transformation, reduced brain edema, prevented endothelial injury via reduction MMP-9 activity, and prevented the blood-brain barrier opening by inhibiting decreased claudin-5 expression. These changes significantly reduced the morbidity and mortality at 18 h and 7 days after the reperfusion. Also, the administration of both drugs prevented injury to brain human endothelial cells and human brain pericytes. The present study indicates that a phosphodiesterase-III inhibitor prevents the hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tPA.
Highlights
Accumulating evidence suggests that, for acute ischemic brain attack, it is a fact that thrombolysis is beneficial for patients with an ischemic stroke if given during the first 4.5 h of symptoms (NINDS, ECASS III) [1,2]
We have previously reported that cilostazol monotherapy reduced the infarct volume, hemorrhagic area, and brain edema in mice subjected to middle cerebral artery (MCA) occlusion and reperfusion [11]
We examined whether cilostazol prevented the hemorrhagic transformation induced by tissue plasminogen activator (tPA) and found that cilostazol reduced the extent of hemoglobin content, water content, and matrix metalloproteinases (MMP)-9 activity in mice subjected to MCA occlusion and reperfusion, supporting the idea that cilostazol limits or prevents blood-brain barrier (BBB) disruption after the ischemic injury
Summary
Accumulating evidence suggests that, for acute ischemic brain attack, it is a fact that thrombolysis is beneficial for patients with an ischemic stroke if given during the first 4.5 h of symptoms (NINDS, ECASS III) [1,2]. Beyond this time window, delayed tissue plasminogen activator (tPA) does not appear to be as beneficial and increases the risk of serious side effects. Cilostazol has been approved and used as a vasodilating antiplatelet drug for the treatment of ischemic symptoms in chronic peripheral arterial obstruction or intermittent claudication and for secondary prevention of cerebral infarction (CSPS I) [6]. Cilostazol has been shown to be a more effective and safer alternative to aspirin for long-term prevention of the recurrence of ischemic stroke in patients with chronic ischemic stroke [8]
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