A novel finding of a low-molecular-weight compound, SMTP-7, having thrombolytic and anti-inflammatory effects in cerebral infarction of mice.
Tissue plasminogen activator (t-PA) has a short therapeutic time window for administration (3 h) and carries a risk of promoting intracerebral hemorrhage. The aim of the present study was to investigate a therapeutic time window and frequency of hemorrhagic region by treatment with Stachybotrys microspora triprenyl phenol-7 (SMTP-7). Thrombotic occlusion was induced by transfer of acetic acid-induced thrombus at the right common carotid artery into the brain of mice. Infarction area, neurological score, edema percentage, and regional cerebral blood flow (CBF) were determined as the index of the efficacy of SMTP-7. In order to evaluate the mechanism of SMTP-7, plasmin activities and the expressions of interleukin (IL)-1beta, tumor necrosis factor-alpha (TNF-alpha), and IL-6 mRNA were examined. SMTP-7 (0.1, 1, 10 mg/kg) dose dependently reduced infarction area, neurological score, and edema percentage. Additionally, its therapeutic time window was longer than that of t-PA, a high-molecular-weight compound. In addition, little hemorrhagic region was induced by treatment with SMTP-7. SMTP-7 showed plasmin activity in vivo and caused a decreased CBF to recover. Furthermore, the expressions of inflammatory cytokine mRNA (IL-1beta, TNF-alpha, IL-6) were increased by t-PA treatment 3 h after ischemia but were not induced by SMTP-7 treatment. These results indicate that SMTP-7 shows potential thrombolytic and anti-inflammatory effects as well as a wide therapeutic time window and little hemorrhagic region compared with that of t-PA. Therefore, this novel low-molecular-weight compound may represent a novel approach for the treatment of cerebral infarction.
Shibata
Keita
K
Department of Pharmacology, Showa University, Shinagawa-ku, Tokyo, Japan. kshibata@pharm.showa-u.ac.jp
Hashimoto
Terumasa
T
Nobe
Koji
K
Hasumi
Keiji
K
Honda
Kazuo
K
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D001578:Benzopyrans / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D002543:Cerebral Hemorrhage / Q000139:chemically induced; D002544:Cerebral Infarction / Q000188:drug therapy* / Q000503:physiopathology; D016207:Cytokines / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D008970:Molecular Weight; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000494:pharmacology / Q000633:toxicity
D000893:Anti-Inflammatory Agents; D001578:Benzopyrans; D016207:Cytokines; D005343:Fibrinolytic Agents; D011760:Pyrrolidinones; C409191:SMTP 7; D010959:Tissue Plasminogen Activator