Author:

Keywords:

Animals, Cerebrovascular Accident, Diffusion Magnetic Resonance Imaging, Disease Models, Animal, Fibrinolytic Agents, Infarction, Middle Cerebral Artery, Male, Neuroprotective Agents, Peptide Fragments, Plasmin, Rats, Rats, Sprague-Dawley, Science & Technology, Life Sciences & Biomedicine, Clinical Neurology, Peripheral Vascular Disease, Neurosciences & Neurology, Cardiovascular System & Cardiology, brain infarction, magnetic resonance imaging, models, animal, TISSUE-PLASMINOGEN ACTIVATOR, CEREBRAL-ARTERY OCCLUSION, INFARCTION, MICE, Fibrinolysin, Stroke, 1102 Cardiorespiratory Medicine and Haematology, 1103 Clinical Sciences, 1109 Neurosciences, Neurology & Neurosurgery, 3202 Clinical sciences, 3209 Neurosciences, 4201 Allied health and rehabilitation science

Abstract:

BACKGROUND AND PURPOSE: Microplasmin (microPli), a derivative of plasmin lacking the 5 "kringle" domains, was studied in a rat thrombotic stroke model with MRI monitoring. METHODS: 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). RESULTS: 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). CONCLUSIONS: 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.