title: Distinct effects of tissue-type plasminogen activator and SMTP-7 on cerebrovascular inflammation following thrombolytic reperfusion.
abstract: OBJECTIVE
  Thrombolysis therapy using tissue-type plasminogen activator (t-PA) is occasionally accompanied by harmful outcomes, including intracerebral hemorrhage. We have reported that Stachybotrys microspora triprenyl phenol-7 (SMTP-7), a candidate thrombolytic drug, has excellent therapeutic effect on cerebral infarction in embolic stroke model in mice; however, little is known regarding whether this agent influences cerebrovascular inflammation following thrombolytic reperfusion. The current study aimed to compare the effects of recombinant t-PA (rt-PA) and SMTP-7 on cerebrovascular inflammation.
  
  
  METHODS
  The impact of rt-PA- and SMTP-7-induced thrombolytic reperfusion on leukocyte dynamics was investigated in a photochemically induced thrombotic middle cerebral artery occlusion (tMCAo) model in mice.
  
  
  RESULTS
  Both rt-PA and SMTP-7 administration in tMCAo mice (each 10 mg/kg) resulted in thrombolytic reperfusion. The SMTP-7-administered mice showed relatively mild rolling and attachment of leukocytes to the vascular wall in the middle cerebral vein, with weak peroxynitrite reactions and proinflammatory gene expression (IL-1β, TNF-α, ICAM-1, and VCAM-1); thus, a small infarct volume compared with rt-PA-administered mice. In vitro study suggested that rt-PA at 20 μg/mL, but not SMTP-7 at a similar concentration, promotes cytokine-induced reactive oxygen species generation in cultured endothelial cells; moreover, SMTP-7 suppressed cytokine-induced VCAM-1 induction in the cells and leukocyte/ endothelial cell adhesions.
  
  
  CONCLUSIONS
  Relatively mild cerebrovascular inflammation and cerebral infarction in the SMTP-7 mice, compared with in rt-PA mice, is thought to be caused at least in part by direct antioxidative actions of SMTP-7 in ECs.
authors.affiliation: Department of Pharmacology, School of Pharmacy, Showa University, 1-5-8 Hatanodai Shinagawa-ku, Tokyo, 142-8555 Japan. taku@pharm.showa-u.ac.jp
authors.forename: Takuro
authors.initials: T
authors.lastname: Miyazaki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kimura
authors.forename: Hisayuki
authors.initials: H
authors.lastname: Ohata
authors.forename: Terumasa
authors.initials: T
authors.lastname: Hashimoto
authors.forename: Keita
authors.initials: K
authors.lastname: Shibata
authors.forename: Keiji
authors.initials: K
authors.lastname: Hasumi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Honda
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000037:antagonists & inhibitors / Q000633:toxicity*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology / Q000209:etiology; D020766:Intracranial Embolism / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D007834:Lasers; D008297:Male; D051379:Mice; D011760:Pyrrolidinones / Q000037:antagonists & inhibitors / Q000633:toxicity*; D015427:Reperfusion Injury / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D015912:Thrombolytic Therapy / Q000379:methods; D010959:Tissue Plasminogen Activator / Q000037:antagonists & inhibitors / Q000633:toxicity*
chemical_list: D001578:Benzopyrans; D011760:Pyrrolidinones; C409191:SMTP 7; D010959:Tissue Plasminogen Activator