The effects of prolonged treatment with citicoline in temporary experimental focal ischemia

Abstract

Potential therapeutic effects of cytidine 5-diphosphocholine (citicoline), a key intermediary in the biosynthesis of the membrane phospholipid, phosphatidylcholine, are presumably related to enhanced phospholipid synthesis in the ischemic brain. We evaluated prolonged citicoline treatment in a temporary focal ischemia model. Using the suture occlusion model, we induced 2 hours of temporary ischemia in 30 Sprague-Dawley rats. The rats were randomly and blindly assigned to receive intraperitoneally 500 mg/kg citicoline (HD), 100 mg/kg citicoline (LD) or physiologic saline as the control group once daily for 7 days ( n = 10 per group) beginning at the time of reperfusion. Neurological scoring (0–5 scale) was performed daily. After elective sacrifice on day 7, or earlier if death occured prematurely, the brains underwent 2,3,5-triphenyltetrazolium chloride (TTC) staining for calculation of corrected infarct and edema volume. The mean corrected infarct volume in the HD group was 125 ± 45.2 mm 3 (mean ± SD), significantly smaller than controls, 243.5 ± 88.6 mm 3 ( p < 0.01, Scheffe's-test). The LD group infarct volume was 200.2 ± 62.8 mm 3 (N.S.). The mean amount of brain edema in the HD group was 46.4 ± 45.6 mm 3 was smaller than the controls, 92.3 ± 54.4 mm 3 and the LD group, 84.9 ± 71.7 mm 3 (N.S.). Mortality before day 7 in the HD was 30% while it was 50% in the two other groups. The neurologic score on day 7 was 2.5 ± 1.8 in the HD group, 3.3 ± 1.8 in the LD group and 3.4 ± 1.7 in controls (N.S.). These results demonstrate that extended high dose citicoline treatment significantly reduced infarct volume in this temporary focal ischemia model and that there was a trend toward reducing brain edema and mortality. These effects may be related to membrane stabilization and inhibition of free fatty acid release.