title: SMTP-7, a new thrombolytic agent, decreases hemorrhagic transformation after transient middle cerebral artery occlusion under warfarin anticoagulation in mice.
abstract: Stachybotrys microspora triprenyl phenol-7 (SMTP-7) is a new thrombolytic agent that exhibits anti-inflammatory effects. We previously demonstrated that the hemorrhagic transformation was fewer with SMTP-7 than with recombinant tissue plasminogen activator (rt-PA) following ischemia-reperfusion in animal models. We hypothesized that SMTP-7 may decrease hemorrhagic transformation after ischemia-reperfusion under the warfarin-treated condition. Transient middle cerebral artery occlusion (MCAO) was induced for 3h using an intraluminal suture in warfarin-treated mice to produce hemorrhagic transformation. Warfarin was administered orally for a 24-h feeding period before MCAO through bottled drinking water (5mg in 375 ml tap water), resulting in a mean INR of 5.6±0.2. Mice were treated with vehicle, rt-PA, or SMTP-7 5h before reperfusion. Twenty percent of vehicle-treated and 50.0% of rt-PA-treated mice died 24h after reperfusion, while all SMTP-7-treated mice survived. Hemorrhagic severity in SMTP-7-treated mice was significantly lower than that in rt-PA-treated mice. Neurological deficit was significantly lower in SMTP-7-treated mice than vehicle- and rt-PA-treated mice. These results indicate that SMTP-7 decreases mortality, hemorrhagic transformation, and neurological deficits, and can be a safe thrombolytic agent following MCAO under the warfarin-treated condition.
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Ito
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan. Electronic address: niizuma@nsg.med.tohoku.ac.jp.
authors.forename: Kuniyasu
authors.initials: K
authors.lastname: Niizuma
authors.affiliation: Department of Neurosurgery, Akita University School of Medicine, Akita, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Miki
authors.initials: M
authors.lastname: Fujimura
authors.affiliation: Department of Applied Biological Science, Tokyo University of Agriculture and Technology, Tokyo, Japan; TMS Co., Ltd., Tokyo, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Hasumi
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Teiji
authors.initials: T
authors.lastname: Tominaga
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D001578:Benzopyrans / Q000494:pharmacology / Q000627:therapeutic use*; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism; D002543:Cerebral Hemorrhage / Q000150:complications / Q000188:drug therapy*; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications* / Q000188:drug therapy; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011760:Pyrrolidinones / Q000494:pharmacology / Q000627:therapeutic use*; D014859:Warfarin / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D001578:Benzopyrans; D005343:Fibrinolytic Agents; D011760:Pyrrolidinones; C409191:SMTP 7; D014859:Warfarin; D020780:Matrix Metalloproteinase 9
keywords: Cerebral infarction; Focal ischemia; Hemorrhagic transformation; Recombinant tissue plasminogen activator; Thrombolysis; Warfarin