Microplasmin reduces ischemic brain damage and improves neurological function in a rat stroke model monitored with MRI.

Abstract

Microplasmin (microPli), a derivative of plasmin lacking the 5 "kringle" domains, was studied in a rat thrombotic stroke model with MRI monitoring. Brain ischemia was induced by middle cerebral artery (MCA) occlusion with photochemically induced thrombosis. Brain tissue damage was assessed at 1 hour and 24 hours after MCA occlusion by MRI and 2,3,5-triphenyl tetrazolium chloride (TTC) staining. Neurological symptoms were scored at 24 hours. Animals with insufficient evidence of significant jeopardized brain tissue on perfusion-weighted imaging (PWI) at 1 hour were excluded before randomization. Included animals were randomized (blinded) to controls (solvent), 7.5 or 10 mg/kg microPli, administered as an intravenous bolus 90 minutes after MCA occlusion (n=8 per dose group). microPli treatment reduced cerebral damage measured by TTC staining at 24 hours, from 250+/-69 mm3 (mean+/-SD) in controls to 150+/-30 and 170+/-62 mm3 with 7.5 and 10 mg/kg microPli, respectively; it reduced the expansion of the PWI positive area between 1 and 24 hours, and it reduced neurological deficits from a Bederson score of 7 (6 to 9) in controls to 4.5 (3 to 8) and 4 (3 to 6), with 7.5 and 10 mg/kg microPli, respectively (median and rangeP<0.05 for each dose versus controls for all parameters). Bolus intravenous microPli given 90 minutes after thrombotic MCA occlusion in rats reduces cerebral ischemic damage and improves neurological dysfunction, suggesting that microPli could be beneficial in ischemic stroke patients.