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A novel finding of a low-molecular-weight compound, SMTP-7, having thrombolytic and anti-inflammatory effects in cerebral infarction of mice.

Shibata K, Hashimoto T, Nobe K, Hasumi K, Honda K - Naunyn Schmiedebergs Arch. Pharmacol. (2010)

Bottom Line: SMTP-7 showed plasmin activity in vivo and caused a decreased CBF to recover.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Showa University, Shinagawa-ku, Tokyo, Japan. kshibata@pharm.showa-u.ac.jp

ABSTRACT
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.

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Comparative study of mRNA expression of IL-1β, TNF-α, and IL-6. SMTP-7 and t-PA were administered at 1 or 3 h after ischemia. ASA was administered with t-PA at 3 h after ischemia. Samples were taken at 24 h after ischemia. Data represent the mean ± SEM of six experiments. *P < 0.05 and **P < 0.01 vs ipsilateral hemisphere of sham-operated group. #P < 0.05 and ##P < 0.01 vs ipsilateral hemisphere of control group
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Fig7: Comparative study of mRNA expression of IL-1β, TNF-α, and IL-6. SMTP-7 and t-PA were administered at 1 or 3 h after ischemia. ASA was administered with t-PA at 3 h after ischemia. Samples were taken at 24 h after ischemia. Data represent the mean ± SEM of six experiments. *P < 0.05 and **P < 0.01 vs ipsilateral hemisphere of sham-operated group. #P < 0.05 and ##P < 0.01 vs ipsilateral hemisphere of control group

Mentions: Figure 7 expresses the real-time RT-PCR analysis for IL-1β, TNF-α, and IL-6. In the control group, the levels of the TNF-α (P < 0.01) and IL-6 (P < 0.05) mRNA expression were significantly higher in the ipsilateral hemisphere compared with the sham-operated group. In the case of treatment with t-PA, the expression levels of IL-1β, TNF-α, and IL-6 were not enhanced by administration at 1 h after ischemia. However, the administration of t-PA at 3 h after ischemia significantly enhanced the expressions of IL-1β, TNF-α, and IL-6 (P < 0.01). In contrast, the expression levels of IL-1β, TNF-α, and IL-6 were not increased by the treatment with SMTP-7 not only at 1 h but also at 3 h after ischemia. A combination of t-PA and ASA partially ameliorated inflammatory cytokine mRNA by treatment at 3 h after ischemia. No changes in these levels of mRNA expression were observed in the contralateral hemisphere.Fig. 7


A novel finding of a low-molecular-weight compound, SMTP-7, having thrombolytic and anti-inflammatory effects in cerebral infarction of mice.

Shibata K, Hashimoto T, Nobe K, Hasumi K, Honda K - Naunyn Schmiedebergs Arch. Pharmacol. (2010)

Comparative study of mRNA expression of IL-1β, TNF-α, and IL-6. SMTP-7 and t-PA were administered at 1 or 3 h after ischemia. ASA was administered with t-PA at 3 h after ischemia. Samples were taken at 24 h after ischemia. Data represent the mean ± SEM of six experiments. *P < 0.05 and **P < 0.01 vs ipsilateral hemisphere of sham-operated group. #P < 0.05 and ##P < 0.01 vs ipsilateral hemisphere of control group
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2926440&req=5

Fig7: Comparative study of mRNA expression of IL-1β, TNF-α, and IL-6. SMTP-7 and t-PA were administered at 1 or 3 h after ischemia. ASA was administered with t-PA at 3 h after ischemia. Samples were taken at 24 h after ischemia. Data represent the mean ± SEM of six experiments. *P < 0.05 and **P < 0.01 vs ipsilateral hemisphere of sham-operated group. #P < 0.05 and ##P < 0.01 vs ipsilateral hemisphere of control group
Mentions: Figure 7 expresses the real-time RT-PCR analysis for IL-1β, TNF-α, and IL-6. In the control group, the levels of the TNF-α (P < 0.01) and IL-6 (P < 0.05) mRNA expression were significantly higher in the ipsilateral hemisphere compared with the sham-operated group. In the case of treatment with t-PA, the expression levels of IL-1β, TNF-α, and IL-6 were not enhanced by administration at 1 h after ischemia. However, the administration of t-PA at 3 h after ischemia significantly enhanced the expressions of IL-1β, TNF-α, and IL-6 (P < 0.01). In contrast, the expression levels of IL-1β, TNF-α, and IL-6 were not increased by the treatment with SMTP-7 not only at 1 h but also at 3 h after ischemia. A combination of t-PA and ASA partially ameliorated inflammatory cytokine mRNA by treatment at 3 h after ischemia. No changes in these levels of mRNA expression were observed in the contralateral hemisphere.Fig. 7

Bottom Line: SMTP-7 showed plasmin activity in vivo and caused a decreased CBF to recover.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, Showa University, Shinagawa-ku, Tokyo, Japan. kshibata@pharm.showa-u.ac.jp

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus