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Updated: Jun 4, 2026
A Thrombotic Stroke Model Based On Transient Cerebral Hypoxia-ischemia
Published on: August 18, 2015
Distinct effects of tissue-type plasminogen activator and SMTP-7 on cerebrovascular inflammation following
Takuro Miyazaki1, Yuji Kimura, Hisayuki Ohata
1Department of Pharmacology, School of Pharmacy, Showa University, 1-5-8 Hatanodai Shinagawa-ku, Tokyo, 142-8555 Japan. taku@pharm.showa-u.ac.jp
Background And Purpose:
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.
Insights
Stachybotrys microspora triprenyl phenol-7 (SMTP-7) reduces cerebrovascular inflammation and infarct volume after stroke reperfusion more effectively than recombinant tissue-type plasminogen activator (rt-PA). SMTP-7
Area of Science:
- Neuroscience
- Pharmacology
- Vascular Biology
Background:
- Thrombolysis with recombinant tissue-type plasminogen activator (rt-PA) can cause intracerebral hemorrhage.
- Stachybotrys microspora triprenyl phenol-7 (SMTP-7) shows therapeutic potential for cerebral infarction.
- The effect of SMTP-7 on cerebrovascular inflammation post-thrombolysis is unknown.
Purpose of the Study:
- To compare the effects of rt-PA and SMTP-7 on cerebrovascular inflammation.
- To evaluate the impact of these thrombolytic agents on leukocyte dynamics and infarct size.
Main Methods:
- Photochemically induced thrombotic middle cerebral artery occlusion (tMCAo) model in mice.
- Administration of rt-PA and SMTP-7 (10 mg/kg) to induce thrombolytic reperfusion.
- In vitro studies on endothelial cells to assess reactive oxygen species generation and VCAM-1 induction.
Main Results:
- Both rt-PA and SMTP-7 achieved thrombolytic reperfusion.
- SMTP-7 treatment resulted in reduced leukocyte rolling/attachment, lower peroxynitrite, and decreased pro-inflammatory gene expression (IL-1β, TNF-α, ICAM-1, VCAM-1).
- SMTP-7 treated mice had smaller infarct volumes and suppressed cytokine-induced reactive oxygen species and VCAM-1 in vitro.
Conclusions:
- SMTP-7 demonstrates a milder cerebrovascular inflammatory response and smaller infarct volume compared to rt-PA.
- SMTP-7's antioxidative actions in endothelial cells likely contribute to its beneficial effects.
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