Phosphodiesterase-III Inhibitor Prevents Hemorrhagic Transformation Induced by Focal Cerebral Ischemia in Mice Treated with tPA
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{"title"=>"Phosphodiesterase-III inhibitor prevents hemorrhagic transformation induced by focal cerebral ischemia in mice treated with tPA", "type"=>"journal", "authors"=>[{"first_name"=>"Mitsunori", "last_name"=>"Ishiguro", "scopus_author_id"=>"37021375100"}, {"first_name"=>"Keisuke", "last_name"=>"Mishiro", "scopus_author_id"=>"37021639200"}, {"first_name"=>"Yasuyuki", "last_name"=>"Fujiwara", "scopus_author_id"=>"7402561831"}, {"first_name"=>"Huayue", "last_name"=>"Chen", "scopus_author_id"=>"8296506700"}, {"first_name"=>"Hiroshi", "last_name"=>"Izuta", "scopus_author_id"=>"24559038900"}, {"first_name"=>"Kazuhiro", "last_name"=>"Tsuruma", "scopus_author_id"=>"6505831524"}, {"first_name"=>"Masamitsu", "last_name"=>"Shimazawa", "scopus_author_id"=>"6602683783"}, {"first_name"=>"Shinichi", "last_name"=>"Yoshimura", "scopus_author_id"=>"55484764800"}, {"first_name"=>"Masahiko", "last_name"=>"Satoh", "scopus_author_id"=>"55552811600"}, {"first_name"=>"Toru", "last_name"=>"Iwama", "scopus_author_id"=>"55699971900"}, {"first_name"=>"Hideaki", "last_name"=>"Hara", "scopus_author_id"=>"56799750000"}], "year"=>2010, "source"=>"PLoS ONE", "identifiers"=>{"scopus"=>"2-s2.0-78650163900", "doi"=>"10.1371/journal.pone.0015178", "sgr"=>"78650163900", "pmid"=>"21151895", "issn"=>"19326203", "pui"=>"360158262"}, "id"=>"e9651c9d-cbb7-3e40-9884-43392725a22e", "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.", "link"=>"http://www.mendeley.com/research/phosphodiesteraseiii-inhibitor-prevents-hemorrhagic-transformation-induced-focal-cerebral-ischemia-m", "reader_count"=>17, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>4, "Researcher"=>2, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>3, "Student > Master"=>3, "Student > Bachelor"=>4}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>4, "Researcher"=>2, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>3, "Student > Master"=>3, "Student > Bachelor"=>4}, "reader_count_by_subject_area"=>{"Biochemistry, Genetics and Molecular Biology"=>2, "Medicine and Dentistry"=>8, "Agricultural and Biological Sciences"=>6, "Psychology"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>8}, "Psychology"=>{"Psychology"=>1}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>6}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}}, "reader_count_by_country"=>{"United States"=>1}, "group_count"=>1}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/814347"], "description"=>"<p>These figures show the effects of tPA and cilostazol on neurobehavioral assessment (A and B) measured at 7 days after MCAO. Combination therapy with tPA plus cilostazol increased the total locomotor activity in the first 120 min of measurement. *P<0.05 vs. tPA (Student's <i>t</i> test, n = 5–7). Data are expressed as means ± SEM.</p>", "links"=>[], "tags"=>["tpa", "cilostazol", "subacute", "injuries", "days"], "article_id"=>484702, "categories"=>["Neuroscience", "Pharmacology"], "users"=>["Mitsunori Ishiguro", "Keisuke Mishiro", "Yasuyuki Fujiwara", "Huayue Chen", "Hiroshi Izuta", "Kazuhiro Tsuruma", "Masamitsu Shimazawa", "Shinichi Yoshimura", "Masahiko Satoh", "Toru Iwama", "Hideaki Hara"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0015178.g004", "stats"=>{"downloads"=>1, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_tPA_and_cilostazol_on_subacute_brain_injuries_at_7_days_after_MCAO_/484702", "title"=>"Effects of tPA and cilostazol on subacute brain injuries at 7 days after MCAO.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 21:59:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/814259"], "description"=>"<p>These figures show the effects of tPA and cilostazol regarding hemorrhage volume (A), blood-brain barrier permeability (B), and MMP-9 expression (C) measured. Combination therapy with tPA plus cilostazol significantly prevented this tPA-associated amplification of cerebral hemorrhage, water content, and MMP-9 activity. *P<0.05 vs. tPA (Welch's <i>t</i> test, n = 7–10). Data are expressed as means ± SEM.</p>", "links"=>[], "tags"=>["tpa", "cilostazol", "acute", "injuries", "18"], "article_id"=>484615, "categories"=>["Neuroscience", "Pharmacology"], "users"=>["Mitsunori Ishiguro", "Keisuke Mishiro", "Yasuyuki Fujiwara", "Huayue Chen", "Hiroshi Izuta", "Kazuhiro Tsuruma", "Masamitsu Shimazawa", "Shinichi Yoshimura", "Masahiko Satoh", "Toru Iwama", "Hideaki Hara"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0015178.g003", "stats"=>{"downloads"=>2, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_tPA_and_cilostazol_on_acute_brain_injuries_at_18_h_after_reperfusion_/484615", "title"=>"Effects of tPA and cilostazol on acute brain injuries at 18 h after reperfusion.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 21:59:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/814041"], "description"=>"<p>TTC-stained coronal sections show infarct tissues (pale unstained region). Brain sections (from extreme left) were acquired from 2 h vehicle, 3 h vehicle, 6 h vehicle, respectively. They were acquired from 2 h tPA (left), 3 h tPA, and 6 h tPA, respectively (A). These figures show the effects of tPA on the cerebral infarct area (B), volume (C), and hemorrhage area (D). tPA at 2 h and 3 h significantly decreased the infarct area and volume. Delayed tPA at 6 h had no effect on infarction but induced cerebral hemorrhage. *P<0.05 vs. vehicle (Welch's <i>t</i> test, n = 5–8). Data are expressed as means ± SEM.</p>", "links"=>[], "tags"=>["tpa", "cerebral", "infarction", "hemorrhage", "18"], "article_id"=>484392, "categories"=>["Neuroscience", "Pharmacology"], "users"=>["Mitsunori Ishiguro", "Keisuke Mishiro", "Yasuyuki Fujiwara", "Huayue Chen", "Hiroshi Izuta", "Kazuhiro Tsuruma", "Masamitsu Shimazawa", "Shinichi Yoshimura", "Masahiko Satoh", "Toru Iwama", "Hideaki Hara"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0015178.g001", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_tPA_on_cerebral_infarction_and_hemorrhage_at_18_h_after_reperfusion_/484392", "title"=>"Effects of tPA on cerebral infarction and hemorrhage at 18 h after reperfusion.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 21:58:14"}
  • {"files"=>["https://ndownloader.figshare.com/files/814573"], "description"=>"<p>Cell damage after 300-µg/ml tPA treatment was assessed by measuring LDH release into the culture medium in endothelial cells (A), pericytes (B), and astrocytes (C). The LDH level was increased by 300-µg/ml tPA treatment, and the increase was reduced by cilostazol at 30 and 100 µM in endothelial cells, and by cilostazol at 100 µM in pericytes. In addition, db-cAMP at 300 and 1000 µM significantly prevented cell damage induced by tPA in endothelial cells. <sup>##</sup>P<0.05 vs. no treatment, *P<0.05, **p<0.01 vs. 300-µg/ml tPA alone (Dunnett's test, n = 4–8). Data are expressed as means ± SEM.</p>", "links"=>[], "tags"=>["cilostazol", "tpa-stimulated", "microvascular", "endothelial"], "article_id"=>484930, "categories"=>["Neuroscience", "Pharmacology"], "users"=>["Mitsunori Ishiguro", "Keisuke Mishiro", "Yasuyuki Fujiwara", "Huayue Chen", "Hiroshi Izuta", "Kazuhiro Tsuruma", "Masamitsu Shimazawa", "Shinichi Yoshimura", "Masahiko Satoh", "Toru Iwama", "Hideaki Hara"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0015178.g006", "stats"=>{"downloads"=>0, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_cilostazol_on_the_tPA_stimulated_human_brain_microvascular_endothelial_cells_pericytes_and_astrocytes_/484930", "title"=>"Effects of cilostazol on the tPA-stimulated human brain microvascular endothelial cells, pericytes, and astrocytes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 22:01:10"}
  • {"files"=>["https://ndownloader.figshare.com/files/814427"], "description"=>"<p>Electron microscopic view of microvessels in a peri-infarct area obtained from the sham model (A), the ipsilateral side of the vehicle model (B), tPA (C), and combination therapy with tPA plus cilostazol (D) Although no significant differences were observed in the nuclei of the endothelial cells of the sham and vehicle models at 6 h, the nuclei of the cells with tPA at 6 h significantly had disappeared. On the other hand, combination therapy with tPA plus cilostazol at 6 h significantly prevented the exacerbation induced by tPA (E). **P<0.01 vs. tPA (χ<sup>2</sup> test, n = 11–32). Combination therapy with tPA plus cilostazol significantly decreased this tPA-associated brain edema (F). *P<0.05 vs. tPA (Student's <i>t</i> test, n = 5–10). Western blot analysis measured the levels of claudin-5. tPA alone at 6 h decreased claudin-5 levels. Combination therapy with tPA plus cilostazol prevented this tPA-associated decrease in claudin-5 (G). *P<0.05 vs. tPA (Welch's <i>t</i> test, n = 3–4). Data are expressed as means ± SEM. Ed; edema, En; endothelial cell, V; vessel. Scale bar = 1 µm.</p>", "links"=>[], "tags"=>["tpa", "cilostazol", "endothelial", "cells", "18"], "article_id"=>484778, "categories"=>["Neuroscience", "Pharmacology"], "users"=>["Mitsunori Ishiguro", "Keisuke Mishiro", "Yasuyuki Fujiwara", "Huayue Chen", "Hiroshi Izuta", "Kazuhiro Tsuruma", "Masamitsu Shimazawa", "Shinichi Yoshimura", "Masahiko Satoh", "Toru Iwama", "Hideaki Hara"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0015178.g005", "stats"=>{"downloads"=>1, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_tPA_and_cilostazol_on_endothelial_cells_at_18_h_after_reperfusion_/484778", "title"=>"Effects of tPA and cilostazol on endothelial cells at 18 h after reperfusion.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 22:00:23"}
  • {"files"=>["https://ndownloader.figshare.com/files/814152"], "description"=>"<p>The other figures show the effects of tPA and cilostazol regarding the cerebral infarct volume (A) and hemorrhage area (B). Combination therapy with tPA plus cilostazol at 6 h had no effect on infarction but prevented hemorrhage. *P<0.01 vs. tPA (Welch's <i>t</i> test, n = 8–11). Coronal sections of brains (from extreme left) were acquired from vehicle, tPA, tPA plus cilostazol with no staining (location; 1 mm anterior to bregma) showing hemorrhagic spots in the infarct area (C). 34 animals were treated. Mortality rates were 0% (0/5) in saline-treated mice and 38% (5/13) in the delayed tPA group, whereas combination therapy with tPA plus cilostazol treatments significantly reduced mortality to 6.25% (1/16) at 18 h after reperfusion (D). *P<0.05 vs. tPA (χ<sup>2</sup> test, n = 5–16). Furthermore, combination therapy significantly prevented neurological deficits (E). *P<0.05 vs. vehicle (χ<sup>2</sup> test, n = 5–16). Data are expressed as mean ± SEM.</p>", "links"=>[], "tags"=>["tpa", "cilostazol", "cerebral", "infarction", "hemorrhage", "18"], "article_id"=>484511, "categories"=>["Neuroscience", "Pharmacology"], "users"=>["Mitsunori Ishiguro", "Keisuke Mishiro", "Yasuyuki Fujiwara", "Huayue Chen", "Hiroshi Izuta", "Kazuhiro Tsuruma", "Masamitsu Shimazawa", "Shinichi Yoshimura", "Masahiko Satoh", "Toru Iwama", "Hideaki Hara"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0015178.g002", "stats"=>{"downloads"=>0, "page_views"=>8, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effects_of_tPA_and_cilostazol_on_cerebral_infarction_and_hemorrhage_at_18_h_after_reperfusion_/484511", "title"=>"Effects of tPA and cilostazol on cerebral infarction and hemorrhage at 18 h after reperfusion.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-02-20 21:58:55"}

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Relative Metric

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