Phosphodiesterase-III inhibitor prevents hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tPA.

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 t...

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Autores principales:	Mitsunori Ishiguro, Keisuke Mishiro, Yasuyuki Fujiwara, Huayue Chen, Hiroshi Izuta, Kazuhiro Tsuruma, Masamitsu Shimazawa, Shinichi Yoshimura, Masahiko Satoh, Toru Iwama, Hideaki Hara
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2010
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7053b76226584c73bb89169684b171d3
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spelling	oai:doaj.org-article:7053b76226584c73bb89169684b171d32021-11-18T07:02:03ZPhosphodiesterase-III inhibitor prevents hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tPA.1932-620310.1371/journal.pone.0015178https://doaj.org/article/7053b76226584c73bb89169684b171d32010-12-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21151895/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The 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.Mitsunori IshiguroKeisuke MishiroYasuyuki FujiwaraHuayue ChenHiroshi IzutaKazuhiro TsurumaMasamitsu ShimazawaShinichi YoshimuraMasahiko SatohToru IwamaHideaki HaraPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 5, Iss 12, p e15178 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mitsunori Ishiguro Keisuke Mishiro Yasuyuki Fujiwara Huayue Chen Hiroshi Izuta Kazuhiro Tsuruma Masamitsu Shimazawa Shinichi Yoshimura Masahiko Satoh Toru Iwama Hideaki Hara Phosphodiesterase-III inhibitor prevents hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tPA.
description	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.
format	article
author	Mitsunori Ishiguro Keisuke Mishiro Yasuyuki Fujiwara Huayue Chen Hiroshi Izuta Kazuhiro Tsuruma Masamitsu Shimazawa Shinichi Yoshimura Masahiko Satoh Toru Iwama Hideaki Hara
author_facet	Mitsunori Ishiguro Keisuke Mishiro Yasuyuki Fujiwara Huayue Chen Hiroshi Izuta Kazuhiro Tsuruma Masamitsu Shimazawa Shinichi Yoshimura Masahiko Satoh Toru Iwama Hideaki Hara
author_sort	Mitsunori Ishiguro
title	Phosphodiesterase-III inhibitor prevents hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tPA.
title_short	Phosphodiesterase-III inhibitor prevents hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tPA.
title_full	Phosphodiesterase-III inhibitor prevents hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tPA.
title_fullStr	Phosphodiesterase-III inhibitor prevents hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tPA.
title_full_unstemmed	Phosphodiesterase-III inhibitor prevents hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tPA.
title_sort	phosphodiesterase-iii inhibitor prevents hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tpa.
publisher	Public Library of Science (PLoS)
publishDate	2010
url	https://doaj.org/article/7053b76226584c73bb89169684b171d3
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Phosphodiesterase-III inhibitor prevents hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tPA.

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