Abstract 144: A Novel Multi-function Small Molecule for the Treatment of Acute Ischemic Stroke in Rodent and Non-human Primate

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Abstract

Background and rationale: DC007 is a synthetic small molecule with multiple pharmacological activities. It has been shown to have thrombolytic, anti-platelet and free radical scavenging activities in vitro. To explore its potential in treating acute ischemic stroke, we evaluated its safety and efficacy using a thromboembolic stroke model in rattus and in Cynomolgus macaque.

Methods: Effects of DC007 (10mg/kg) were compared to intravenous tPA (10mg/kg in rat; 0.9mg/kg in monkey) using a model of focal embolic cerebral ischemia in rats and monkeys. Pre-formed blood clots were introduced into middle cerebral artery through catheter cannulated into internal carotid artery of the animals. Animals (12 rats per group; 4 monkeys per group) were randomized to receive intravenous infusion of saline, tPA or DC007 at 3 hours after embolization was confirmed.

Results: DC007 reduced brain infarction and hemispheric swelling in the stroke rats more significantly than saline or tPA did, when treatments were given at 3 hours after stroke onset. At 24 hours after stroke, infraction volumes were 49.36%, 31.98%, and 40.66% for saline, DC007 and tPA group, respectively; while brain swelling rates were 17.67%, 13.20% and 22.58% for saline, DC007 and tPA group, respectively. In the thromboembolic stroke model in monkey, DC007 also showed a stronger beneficial effect on vessel patency (DC007: 46.3±10.3% vs. tPA: 22.2±12.8% in the 8 hours time period after stroke), brain infarction (DC007: 3361±354 mm3 vs. tPA: 9072±2096 mm3 measured by MRI at 24 hours after stroke) and neurobehavioral score measured at 72 hours after stroke (DC007: 46.3±10.3 vs. tPA: 60±9.8, where score 0 indicated normal, while score 77 indicated death).

Conclusions: DC007 appears to be a more potent thrombolytic compound with superior safety profile than IV rt-PA when given at 3 hours after the stroke onset in rats and monkeys. Further investigation is warranted for its potential in the treatment of AIS clinically.

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