SYNERGISTIC EFFECTS OF CITICOLINE AND MK-801 IN TEMPORARY EXPERIMENTAL FOCAL ISCHEMIA IN RATS

Background and Purpose Citicoline, a naturally occurring precursor of phosphatidylcholine, is neuroprotective and is currently being assesse d in clinical trials. To evaluate potential synergistic neuroprotectiv e effects of prolonged citicoline treatment and early N-methyl-D-aspar tate (NMDA) antagonist therapy, suboptimal treatment regimens of citic oline and MK-801 were tested alone and in combination in a rat model o f temporary focal ischemia. Methods Four groups of Sprague-Dawley rats (n=12 per group) underwent 90 minutes of temporary middle cerebral ar tery occlusion (MCAO) with the suture model. Animals were randomly and blindly assigned to one of four treatment groups: (1) saline, vehicle ; (2) MK-801, 0.5 mg/kg IV bolus at 60 minutes after MCAO followed by saline 1 mL/kg IP daily for 7 days; (3) saline IV at 60 minutes after MCAO followed by citicoline 250 mg/kg IP daily for 7 days; or (4) both MK-801 and citicoline (daily for 7 days) active treatment. Triphenylt etrazolium chloride staining was used to assess postmortem infarct vol ume. Neurological scores were determined daily. Results Premature mort ality between days 2 and 4 was 33.3% in group 1, 41.7% in groups 2 and 3, and 25.0% in group 4. Mean corrected infarct volume was significan tly reduced in group 4 compared with the others (175.2+/-89.3 mm(3) in group 1, 179.1+/-78.5 mm(3) in group 2, 163.9+/-73.7 mm(3) in group 3 , and 84.7+/-56.8 mm(3) in group 4 [P<.02, ANOVA and P<.05, Scheffe's test for group 1 versus group 4]). Mean infarct volume in animals dyin g prematurely was significantly (P<.05, Student's t test) larger in gr oup 1 than those surviving for 7 days (247.2+/-89.5 versus 139.2+/-68. 2 mm(3)), but there was no significant difference in infarct volume in groups 2, 3, and 4 between animals dying prematurely and those surviv ing for 7 days. Conclusions These results demonstrate synergistic neur oprotective effects of citicoline and an NMDA antagonist in temporary experimental focal ischemia.