Efficacy of SMTP‐7, a small‐molecule anti‐inflammatory thrombolytic, in embolic stroke in monkeys

SMTP‐7 (Stachybotrys microspora triprenyl phenol‐7) is a small molecule that promotes thrombolysis and suppresses inflammation possibly through plasminogen modulation and soluble epoxide hydrolase (sEH) inhibition, respectively. Here, we demonstrate an efficacy of SMTP‐7 in a severe embolic stroke model in monkeys. The middle cerebral artery was embolized by an autologous blood clot. Saline, SMTP‐7, or tissue‐type plasminogen activator (t‐PA) (n = 5 in each group) was given after 3 hours, and neurologic deficit scoring and infarct characterization were performed after 24 hours. Hemorrhagic infarct‐accompanied premature death was observed for two animals in t‐PA group. SMTP‐7 treatment significantly reduced the sizes of infarct by 65%, edema by 37%, and clot by 55% compared to saline treatment. Plasma levels of the products of plasminogen activation (plasmin‐α(2)‐antiplasmin complex) and sEH reaction (dihydroxyeicosatrienoic acid) in SMTP‐7 group were 794% (P < 0.05) and 60% (P = 0.085) compared to saline group, respectively. No significant changes in the plasma levels of MMP‐9, CRP, MCP‐1, and S100B were found. There was an inverse correlation between plasmin‐α(2)‐antiplasmin complex level and infarct volume (r = 0.93, P < 0.05), suggesting a role of thrombolysis in the SMTP‐7 action to limit infarct development. In conclusion, SMTP‐7 is effective in treating severe embolic stroke in monkeys under conditions where t‐PA treatment tends to cause hemorrhagic infarct‐associated premature death.