Effects of Citicoline Combined With Thrombolytic Therapy in a Rat Embolic Stroke Model

Abstract

Background and Purpose —We sought to evaluate the effects of the combination of cytidine-5′-diphosphocholine (citicoline) and thrombolysis on infarct size, clinical outcome, and mortality in a rat embolic stroke model. Methods —Eighty-three Sprague-Dawley rats were embolized in the carotid territory with a single fibrin embolus and randomly assigned to the following treatment groups: (1) control (saline), (2) citicoline 250 mg/kg, (3) citicoline 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 citicoline 500 mg/kg. rtPA was administered as a continuous intravenous infusion over 45 minutes starting 45 minutes after embolization; citicoline was given intraperitoneally 30 minutes and 24, 48, and 72 hours after embolization. At 96 hours, the brains were fixed and stained by hematoxylin-eosin, and infarct volumes were measured. Neurological scores were determined daily. Results —The median infarct size, measured as percentage of the affected hemisphere, in the control group was 37% (interquartile range, 26% to 69%) compared 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 combined group 5, and 19% (9% to 51%; P =NS) in group 6. The infarct size was significantly reduced in the combined citicoline+rtPA–treated groups to a median of 13% (5% to 30%; P <0.01). Citicoline 500 mg/kg and citicoline combined with rtPA also promoted functional recovery. Conclusions —These results demonstrate that the combination of low-dose citicoline and rtPA significantly reduced infarct size in this focal ischemia model.