Effects of citicoline combined with thrombolytic therapy in a rat embolic stroke model

Background and Purpose-We sought to evaluate the effects of the combination of cytidine-5'-diphosphocholine (citicoline) and thrombolysis on infarct s ize, clinical outcome, and mortality in a rat embolic stroke model. Methods-Eighty-three Sprague-Dawley rats were embolized in the carotid terr itory with a single fibrin embolus and randomly assigned to the following t reatment groups: (1) control (saline), (2) citicoline 250 mg/kg, (3) citico line 500 mg/kg, (4) recombinant tissue plasminogen activator (rtPA) 5 mg/kg , (5) rtPA 5 mg/kg plus citicoline 250 mg/kg? and (6) rtPA 5 mg/kg plus cit icoline 500 mg/kg. rtPA was administered as a continuous intravenous infusi on over 45 minutes starting 45 minutes after embolization; citicoline was g iven intraperitoneally 30 minutes and 24, 48, and 72 hours after embolizati on. At 96 hours, the brains were fixed and stained by hematoxylin-eosin, an d infarct volumes were measured. Neurological scores were determined daily. Results-The median infarct size, measured as percentage of the affected hem isphere, in the control group was 37% (interquartile range, 26% to 69%) com pared with 22% (5% to 52%; P=NS) in group 2, 11% (5% to 34%; P=NS) in group 3, 24% (12% to 31%; P=NS) in group 4, 11% (3% to 22%; P=0.02) in the combi ned group 5, and 19% (9% to 51%; P=NS) in group 6. The infarct size was sig nificantly reduced in the combined citicoline +rtPA-treated groups to a med ian of 13% (5% to 30%; P<0.01). Citicoline 500 mg/kg and citicoline combine d with rtPA also promoted functional recovery. Conclusions-These results demonstrate that the combination of low-dose citi coline and rtPA significantly reduced infarct size in this focal ischemia m odel.