title: Delayed treatment with ADAMTS13 ameliorates cerebral ischemic injury without hemorrhagic complication.
abstract: Tissue plasminogen activator (tPA) is the only approved therapy for acute ischemic stroke. However, delayed tPA treatment increases the risk of cerebral hemorrhage and can result in exacerbation of nerve injury. ADAMTS13, a von Willebrand factor (VWF) cleaving protease, has a protective effect against ischemic brain injury and may reduce bleeding risk by cleaving VWF. We examined whether ADAMTS13 has a longer therapeutic time window in ischemic stroke than tPA in mice subjected to middle cerebral artery occlusion (MCAO). ADAMTS13 (0.1mg/kg) or tPA (10mg/kg) was administered i.v., immediately after reperfusion of after 2-h or 4-h MCAO for comparison of the therapeutic time windows in ischemic stroke. Infarct volume, hemorrhagic volume, plasma high-mobility group box1 (HMGB1) levels and cerebral blood flow were measured 24h after MCAO. Both ADAMTS13 and tPA improved the infarct volume without hemorrhagic complications in 2-h MCAO mice. On the other hand, ADAMTS13 reduced the infarct volume and plasma HMGB1 levels, and improved cerebral blood flow without hemorrhagic complications in 4-h MCAO mice, but tPA was not effective and these animals showed massive intracerebral hemorrhage. These results indicated that ADAMTS13 has a longer therapeutic time window in ischemic stroke than tPA, and ADAMTS13 may be useful as a new therapeutic agent for ischemic stroke.
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.
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.
authors.forename: Kazuhide
authors.initials: K
authors.lastname: Hayakawa
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1, Jyonan, Fukuoka 814-0180, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Sano
authors.affiliation: Department of Emergency and Critical Care Medicine, Fukuoka University Hospital, Fukuoka, Japan.
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.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1, Jyonan, Fukuoka 814-0180, Japan.
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.
authors.forename: Tomomitsu
authors.initials: T
authors.lastname: Satho
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1, Jyonan, Fukuoka 814-0180, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Fujioka
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1, Jyonan, Fukuoka 814-0180, Japan.
authors.forename: Carl
authors.initials: C
authors.lastname: Muroi
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1, Jyonan, Fukuoka 814-0180, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuo
authors.affiliation: Department of Emergency and Critical Care Medicine, Fukuoka University Hospital, Fukuoka, Japan.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Ishikura
authors.affiliation: Department of Pharmacy, Fukuoka University Hospital, Fukuoka, Japan.
authors.forename: Kojiro
authors.initials: K
authors.lastname: Futagami
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Fukuoka University, Nanakuma 8-19-1, Jyonan, Fukuoka 814-0180, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Mishima
mesh_terms: D051722:ADAM Proteins / Q000627:therapeutic use*; D000071120:ADAMTS13 Protein; D000818:Animals; D002545:Brain Ischemia / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D002543:Cerebral Hemorrhage / Q000188:drug therapy / Q000209:etiology; D002544:Cerebral Infarction / Q000188:drug therapy / Q000209:etiology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D024243:HMGB1 Protein / Q000097:blood; D017078:Laser-Doppler Flowmetry; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009460:Neurologic Examination; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use
chemical_list: D005343:Fibrinolytic Agents; D024243:HMGB1 Protein; D010959:Tissue Plasminogen Activator; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human
keywords: ADAMTS13; Cerebral ischemic stroke; Hemorrhagic complication; Therapeutic time window; Tissue plasminogen activator