Synergistic Effects of Citicoline and MK-801 in Temporary Experimental Focal Ischemia in Rats

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Abstract
Background and Purpose Citicoline, a naturally occurring precursor of phosphatidylcholine, is neuroprotective and is currently being assessed in clinical trials. To evaluate potential synergistic neuroprotective effects of prolonged citicoline treatment and early N -methyl- d -aspartate (NMDA) antagonist therapy, suboptimal treatment regimens of citicoline and MK-801 were tested alone and in combination in a rat model of temporary focal ischemia. Methods Four groups of Sprague-Dawley rats (n=12 per group) underwent 90 minutes of temporary middle cerebral artery 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. Triphenyltetrazolium chloride staining was used to assess postmortem infarct volume. Neurological scores were determined daily. Results Premature mortality 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 significantly 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, Scheffé’s test for group 1 versus group 4]). Mean infarct volume in animals dying prematurely was significantly ( P <.05, Student’s t test) larger in group 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 surviving for 7 days. Conclusions These results demonstrate synergistic neuroprotective effects of citicoline and an NMDA antagonist in temporary experimental focal ischemia.