Abstract TP98: SMTP-7, A Novel Thrombolytic With An Anti-inflammatory Potential, Improves Thrombotic Stroke With Little Bleeding Risk

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.