title: Recombinant human soluble thrombomodulin ameliorates cerebral ischemic injury through a high-mobility group box 1 inhibitory mechanism without hemorrhagic complications in mice.
abstract: BACKGROUND
  It has been reported that recombinant human soluble thrombomodulin (rhsTM) has a high-mobility group box (HMGB)1 inhibitory effect. Some investigators reported that HMGB1 is associated with ischemic stroke. However, there have been no previous studies to determine whether rhsTM can ameliorate cerebral ischemic injury through its HMGB1 inhibitory mechanism in ischemic stroke. We investigated the effects of rhsTM on cerebral ischemic injury in a 4-h middle cerebral artery occlusion (MCAO) murine model.
  
  
  METHODS
  rhsTM (1 or 5mg/kg, i.v.) was administered immediately after 4-h MCAO. Infarct volume, motor coordination, plasma HMGB1 level, and hemorrhage volume were evaluated 24h after 4-h MCAO.
  
  
  RESULTS
  The infarct volume (P<0.05) was reduced by rhsTM in mice subjected to 4-h MCAO in a dose-dependent manner. Moreover, rhsTM (5mg/kg) significantly improved motor coordination determined by the rotarod test (P<0.05), and significantly decreased plasma HMGB1 level compared with vehicle-treated controls (P<0.001). In addition, there was no difference in hemorrhage volume between vehicle-treated controls and the rhsTM treatment group.
  
  
  CONCLUSIONS
  This represents the first report that rhsTM ameliorates cerebral ischemic injury through an HMGB1 inhibitory mechanism without hemorrhagic complications in mice. Taken together, these observations indicate a palliative effect of rhsTM and suggest new therapeutic possibilities for treatment of ischemic stroke via inhibition of HMGB1.
authors.affiliation: Department of Emergency and Critical Care Medicine, Fukuoka University Hospital, Fukuoka, Japan. Electronic address: pdmxy827@yahoo.co.jp.
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1, Jyonan, Fukuoka 814-0180, Japan; Department of Pharmacy, Fukuoka University Hospital, Fukuoka, Japan. Electronic address: naka0625@fukuoka-u.ac.jp.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Nakano
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1, Jyonan, Fukuoka 814-0180, Japan. Electronic address: kirie@cis.fukuoka-u.ac.jp.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Irie
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1, Jyonan, Fukuoka 814-0180, Japan. Electronic address: ksano@fukuoka-u.ac.jp.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Sano
authors.affiliation: Department of Emergency and Critical Care Medicine, Fukuoka University Hospital, Fukuoka, Japan. Electronic address: junichi0927@gmail.com.
authors.forename: Junichi
authors.initials: J
authors.lastname: Tanaka
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1, Jyonan, Fukuoka 814-0180, Japan. Electronic address: pd141002@cis.fukuoka-u.ac.jp.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Yamashita
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1, Jyonan, Fukuoka 814-0180, Japan. Electronic address: satho@fukuoka-u.ac.jp.
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Satho
authors.affiliation: Department of Pharmaceutical and Health Care Management, Faculty of Pharmaceutical Sciences, Fukuoka University, Fukuoka, Japan. Electronic address: ko1matsuo@fukuoka-u.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuo
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1, Jyonan, Fukuoka 814-0180, Japan; Institute of Aging and Brain Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Japan. Electronic address: mfujioka_2000_99@yahoo.co.jp.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujioka
authors.affiliation: Department of Emergency and Critical Care Medicine, Fukuoka University Hospital, Fukuoka, Japan. Electronic address: ishikurah@fukuoka-u.ac.jp.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ishikura
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1, Jyonan, Fukuoka 814-0180, Japan; Institute of Aging and Brain Sciences, Faculty of Pharmaceutical Sciences, Fukuoka University, Japan. Electronic address: kenichi@fukuoka-u.ac.jp.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Mishima
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002544:Cerebral Infarction / Q000209:etiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D024243:HMGB1 Protein / Q000097:blood*; D006470:Hemorrhage / Q000209:etiology*; D006801:Humans; D002546:Ischemic Attack, Transient / Q000097:blood* / Q000188:drug therapy*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009460:Neurologic Examination; D011994:Recombinant Proteins / Q000494:pharmacology; D018180:Thrombomodulin / Q000627:therapeutic use*
chemical_list: D024243:HMGB1 Protein; D011994:Recombinant Proteins; D018180:Thrombomodulin
keywords: Cerebral ischemia; High-mobility group box 1(HMGB1); Stroke; Thrombomodulin