Abstract
Extending the time window for acute stroke therapies is important in increasing the number of stroke patients who might benefit from treatment. SMTP-7, a novel small-molecule plasminogen modulator, has a time window of ~6 h in thrombotic stroke in animal experiments. The excellent activity of SMTP-7 is attributable to an anti-inflammatory action as well as thrombolysis due to plasminogen modulation. We recently identified soluble epoxide hydrolase (sEH) as an intracellular target of the anti-inflammatory action of SMTP-7. SMTP-7 inhibits sEH that hydrolyzes anti-inflammatory fatty acid epoxides, and this action possibly plays a role in the protection of nervous tissues from inflammatory damage. We report here that SMTP-7 treats thrombotic stroke with little bleeding risk. In thrombotic stroke models of monkey and mouse, SMTP-7 (10 mg/kg) significantly ameliorated neurological deficits, cerebral infarct, and hemorrhage transformation. The efficacy of SMTP-7 in thrombolysis at 10 mg/kg was comparable to that of t-PA at 0.55 mg/kg in a rat carotid artery thrombosis model. In a mouse tail amputation assay, SMTP-7 at < 30 mg/kg did not prolong bleeding time, and bleeding was observed at 100 mg/kg. t-PA significantly prolonged bleeding time at >0.1 mg/kg. These effects of SMTP-7 and t-PA were canceled by tranexamic acid, an inhibitor of fibrinolysis. Thus, at the pharmacological thrombolytic dose, t-PA but not SMTP-7 increases bleeding time. The difference can be explained by that, unlike t-PA that directly activates plasminogen, SMTP-7 is a plasminogen modulator that alters plasminogen conformation to be susceptible to proteolytic activation by endogenous plasminogen activators, and acts through a physiological on-demand system coping with thrombotic events. In addition, anti-inflammatory action of SMTP-7 through an sEH inhibition may contribute to lower risk of hemorrhagic transformation.
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