Distinct Effects of Tissue-Type Plasminogen Activator and SMTP-7 on Cerebrovascular Inflammation Following Thrombolytic Reperfusion

作者：Miyazaki Takuro^*; Kimura Yuji; Ohata Hisayuki; Hashimoto Terumasa; Shibata Keita; Hasumi Keiji; Honda Kazuo

来源：Stroke, 2011, 42(4): 1097-1104.

DOI：10.1161/STROKEAHA.110.598359

• focal ischemia
• tPA
• thrombolysis
• vasculitis
• endothelium
• SMTP-7

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-1 beta, TNF-alpha, 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 mu g/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. (Stroke. 2011;42:1097-1104.)

• 出版日期2011-4