Synergistic effects of citicoline and MK-801 in temporary experimental focal ischemia in rats.
OBJECTIVE
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 mm3 in group 1, 179.1 +/- 78.5 mm3 in group 2, 163.9 +/- 73.7 mm3 in group 3, and 84.7 +/- 56.8 mm3 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 mm3), 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.
Onal
M Z
MZ
Department of Neurology, Medical Center of Central Massachusetts Worcester 01605-2982, USA.
Li
F
F
Tatlisumak
T
T
Locke
K W
KW
Sandage
B W
BW
Fisher
M
M
D000818:Animals; D002544:Cerebral Infarction / Q000473:pathology; D003566:Cytidine Diphosphate Choline / Q000494:pharmacology*; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004357:Drug Synergism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D002546:Ischemic Attack, Transient / Q000401:mortality* / Q000473:pathology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016019:Survival Analysis
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D003566:Cytidine Diphosphate Choline; D016291:Dizocilpine Maleate