Effects of Citicoline Combined With Thrombolytic Therapy in a Rat Embolic Stroke Model

Abstract

Background and Purpose-We sought to evaluate the effects of the combination of cytidine-5Ј-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%; PϭNS) in group 2, 11% (5% to 34%; PϭNS) in group 3, 24% (12% to 31%; PϭNS) in group 4, 11% (3% to 22%; Pϭ0.02) in the combined group 5, and 19% (9% to 51%; PϭNS) in group 6. The infarct size was significantly reduced in the combined citicolineϩrtPA-treated groups to a median of 13% (5% to 30%; PϽ0.01). 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.

Neuroprotection for ischemic stroke: Past, present and future

“…In another MCA occlusion study, treatment was begun at 15 min after onset of ischemia; citicoline improved behavioral and morphological indices chiefly in rats with submaximal insults (ischemia of 30-75 min) (Aronowski et al, 1996a). When ischemia was produced by clot embolus, one study showed that citicoline begun at 45 min failed to affect infarct size unless tPA was co-administered (Andersen et al, 1999); and another showed that citicoline administered prior to tPA failed to confer additional benefit but, if administered 10 min after tPA, led to less ischemic injury than with tPA alone (Alonso de Lecinana M. et al, 2006). An interesting recent report (Hurtado et al, 2007) provides evidence that citicoline treatment begun 24 hours after MCA occlusion and maintained for 28 days improves functional outcome and enhances dendritic complexity and spine density in layer V pyramidal cells of the undamaged motor cortex, suggesting that chronic treatment may increase neuronal plasticity within noninjured, functionally connected brain regions.…”

Inhibitors of Brain Phospholipase A2Activity: Their Neuropharmacological Effects and Therapeutic Importance for the Treatment of Neurologic Disorders

“…CDP-choline (citicoline) inhibits cPLA 2 activity and lowers the concentration of free fatty acids in a dose-and time-dependent manner (Adibhatla et al, 2002). This compound is an intermediate in PtdCho biosynthesis that has been used for the treatment of ischemic and head injuries (Andersen et al, 1999;Dempsey and Rao, 2003). It not only restores the concentration of PtdCho after ischemic injury by increasing PtdCho synthesis from diacylglycerol but also blocks the activation of cPLA 2 activity (Adibhatla et al, 2002).…”

Tissue Plasminogen Activator (tPA) and Matrix Metalloproteinases in the Pathogenesis of Stroke: Therapeutic Strategies

“…tPA + neuroserpin (an endogenous tPA inhibitor) [25,89,90]. tPA + CDP-choline showed benefit in an animal model of stroke [91]. A high dose of CDP-choline (1000 mg/kg) was better than tPA alone and equally as good as the combination with tPA [92].…”