Phosphodiesterase-III Inhibitor Prevents Hemorrhagic Transformation Induced by Focal Cerebral Ischemia in Mice Treated with tPA

PLoS One

Hiroshi Izuta¹  Keisuke Mishiro²  Masahiko Satoh²  Hideaki Hara²  Huayue Chen³  Toru Iwama³  Yasuyuki Fujiwara⁴  Masamitsu Shimazawa⁴  Mitsunori Ishiguro⁴  Shinichi Yoshimura⁴  Kazuhiro Tsuruma⁴ 

[1] Departments of Anatomy, Gifu University Graduate School of Medicine, Gifu, Japan;Departments of Neurosurgery, Gifu University Graduate School of Medicine, Gifu, Japan;Laboratory of Pharmaceutical Health Sciences, School of Pharmacy, Aichi Gakuin University, Aichi, Japan;Molecular Pharmacology, Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu, Japan

关键词: Endothelial cells;    Brain damage;    Reperfusion;    Cerebral ischemia;    Hemorrhage;    Pericytes;    Astrocytes;    Edema;   

DOI  :  10.1371/journal.pone.0015178

学科分类：医学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY