SMTP-7, a Novel Small-Molecule Thrombolytic for Ischemic Stroke: A Study in Rodents and Primates

Abstract

SMTP-7 (Stachybotrys microspora triprenyl phenol-7), a small molecule that promotes plasminogen activation through the modulation of plasminogen conformation, has excellent therapeutic activity against cerebral infarction in several rodent models. Detailed evaluations of SMTP-7 in a primate stroke model are needed for effective, safe drug development. Here we evaluated SMTP-7 in a monkey photochemical-induced thrombotic middle cerebral artery (MCA) occlusion model (n=6), in which MCA occlusion was followed by recanalization/reocclusion. SMTP-7 (10 mg/kg, intravenous infusion) significantly increased the postinfusion MCA recanalization rate (32.5-fold, P=0.043) and ameliorated the post-24-h neurologic deficit (by 29%, P=0.02), cerebral infarct (by 46%, P=0.033), and cerebral hemorrhage (by 51%, P=0.013) compared with the vehicle control animals. In normal monkeys, SMTP-7 did not affect general physiologic or hemostatic variables, including coagulation and platelet parameters. Investigations in rodent models of transient and permanent focal cerebral ischemia, as well as arterial thrombosis and bleeding tests, suggest a role for SMTP-7's regulated profibrinolytic action and neuroprotective properties in the monkey MCA occlusion model. In conclusion, SMTP-7 is effective in treating thrombotic stroke in monkeys. SMTP-7 is thus a promising candidate for the development of alternative therapy for ischemic stroke.

Soluble Epoxide Hydrolase as an Anti-inflammatory Target of the Thrombolytic Stroke Drug SMTP-7

“…SMTP-7 thus promotes plasmin formation and clot clearance in vivo (14,16), and it has been used to treat thrombotic and embolic strokes in experimental models in rodents and nonhuman primates (17)(18)(19)(20). Unexpectedly, SMTP-7 was demonstrated to reduce hemorrhagic transformation and to have a wide therapeutic time window (17,18,20). These excellent activities are partly explained by the finding that, unlike tissue plasminogen activator, SMTP-7 suppresses inflammatory/oxidative responses after thrombolytic reperfusion (16,18,19,21).…”

“…These excellent activities are partly explained by the finding that, unlike tissue plasminogen activator, SMTP-7 suppresses inflammatory/oxidative responses after thrombolytic reperfusion (16,18,19,21). These beneficial properties prompted the development of SMTP-7 as an alternative stroke drug that can treat patients who do not benefit from tissue plasminogen activator-based therapy (20).…”

“…Details of this interpretation are described under "Discussion." DISCUSSION SMTP-7 has a plasminogen modulation activity that leads to a thrombolytic enhancement as observed in several animal models (14,16,20). SMTP-7 effectively treats thrombotic and embolic stroke models (17,18,20), and the involvement of an additional mechanism that leads to anti-inflammation has been suggested (16,18,19,21).…”

“…1A), one of the SMTP family compounds with profound biological activities, enhances plasminogen activation by modulating plasminogen conformation (10,(13)(14)(15). SMTP-7 thus promotes plasmin formation and clot clearance in vivo (14,16), and it has been used to treat thrombotic and embolic strokes in experimental models in rodents and nonhuman primates (17)(18)(19)(20). Unexpectedly, SMTP-7 was demonstrated to reduce hemorrhagic transformation and to have a wide therapeutic time window (17,18,20).…”

Hemorrhagic transformation of ischemic stroke

“…The rtPA directly activates the plasminogen, though SMTP-7 acts in an on-demand way. The definitive advantage of SMTP-7 against rtPA is that a therapeutic dose of SMTP-7 did just minimally affect the fibrinolytic system; however a higher dose of SMTP-7 was significantly associated with bleeding complications [229].…”