Effects of citicoline combined with thrombolytic therapy in a rat embolic stroke model.
OBJECTIVE
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.
Andersen
M
M
Neurovascular Research Laboratory, Rigshospitalet Department of Neurology, Bispebjerg Hospital, Copenhagen University, Denmark.
Overgaard
K
K
Meden
P
P
Boysen
G
G
Choi
S C
SC
D000818:Animals; D002341:Carotid Artery Thrombosis / Q000150:complications*; D002533:Cerebral Angiography; D002544:Cerebral Infarction / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control; D003566:Cytidine Diphosphate Choline / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D007274:Injections, Intraperitoneal; D008297:Male; D018697:Nootropic Agents / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000627:therapeutic use; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D016896:Treatment Outcome
D005343:Fibrinolytic Agents; D018697:Nootropic Agents; D011994:Recombinant Proteins; D003566:Cytidine Diphosphate Choline; D010959:Tissue Plasminogen Activator