The effects of prolonged treatment with citicoline in temporary experimental focal ischemia

Schäbitz, Wolf Rüdiger; Weber, W.; Takano, Kentaro; Sandage, Bobby W.; Locke, Kenneth W.; Fisher, Marc

doi:10.1016/0022-510x(95)00341-x

Cited by 100 publications

(72 citation statements)

References 18 publications

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“…At the same time, a parallel series of experiments was conducted to evaluate the effect of a fully effective dose of CIT on infarct size, given alone and in combination with rtPA. In previous studies using a temporary focal occlusion model in rats, CIT significantly reduced infarct size at a dose of 500 mg/kg IP 6 but not at a dose of 250 mg/kg IP. 7 The findings with these doses of CIT in the present study are consistent with those in the temporary focal occlusion model.…”

Section: Discussionmentioning

confidence: 76%

“…3 Additionally, CIT improved neurological outcome 4 and increased survival time in global chronic hypoxia. 5 In models of temporary focal ischemia, CIT reduced the size of cerebral infarcts 6,7 and extended the duration of ischemia required to produce a given behavioral deficit or infarct size. 8 A neuroprotective effect of CIT was reported in clinical studies of CIT-treated older (aged 50 to 85 years) subjects in which cognitive 9 -11 and behavioral parameters improved.…”

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confidence: 99%

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

Andersen

Overgaard

Meden

et al. 1999

Stroke

100

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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.

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Section: Discussionmentioning

confidence: 76%

mentioning

confidence: 99%

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

Andersen

Overgaard

Meden

et al. 1999

Stroke

100

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“…In a rat model of transient MCA occlusion, high-dose citicoline treatment begun at the time of reperfusion (2 h) reduced infarct volume by one-half, but the study was flawed by failure to control brain temperature and substantial premature mortality (Schabitz et al, 1996). 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).…”

Section: Phospholipid Precursor: Citicolinementioning

confidence: 99%

Neuroprotection for ischemic stroke: Past, present and future

2008

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Neuroprotection for ischemic stroke refers to strategies, applied singly or in combination, that antagonize the injurious biochemical and molecular events that eventuate in irreversible ischemic injury. There has been a recent explosion of interest in this field, with over 1000 experimental papers and over 400 clinical articles appearing within the past 6 years. These studies, in turn, are the outgrowth of three decades of investigative work to define the multiple mechanisms and mediators of ischemic brain injury, which constitute potential targets of neuroprotection. Rigorously conducted experimental studies in animal models of brain ischemia provide incontrovertible proof-of-principle that high-grade protection of the ischemic brain is an achievable goal. Nonetheless, many agents have been brought to clinical trial without a sufficiently compelling evidence-based pre-clinical foundation. At this writing, around 160 clinical trials of neuroprotection for ischemic stroke have been initiated. Of the approximately 120 completed trials, two-thirds were smaller early-phase safetyfeasibility studies. The remaining one-third were typically larger (>200 subjects) phase II or III trials, but, disappointingly, only fewer than one-half of these administered neuroprotective therapy within the 4-6 hour therapeutic window within which efficacious neuroprotection is considered to be achievable. This fact alone helps to account for the abundance of "failed" trials.This review presents a close survey of the most extensively evaluated neuroprotective agents and classes and considers both the strengths and weakness of the pre-clinical evidence as well as the results and shortcomings of the clinical trials themselves. Among the agent-classes considered are calcium channel blockers; glutamate antagonists; GABA agonists; antioxidants/radical scavengers; phospholipid precursor; nitric oxide signal-transduction down-regulator; leukocyte inhibitors; hemodilution; and a miscellany of other agents. Among promising ongoing efforts, therapeutic hypothermia, high-dose human albumin therapy, and hyperacute magnesium therapy are considered in detail. The potential of combination therapies is highlighted. Issues of clinical-trial funding, the need for improved translational strategies and clinical-trial design, and "thinking outside the box" are emphasized. Part I: Neuroprotection -from Past to the PresentNeuroprotection for ischemic brain injury has emerged only recently as a topic of serious biomedical inquiry. A MEDLINE survey (PubMed, 2007) reveals virtually no publications on this topic until the early 1990's but a remarkable surge in publications over the past 10 years Correspondence and reprint requests to:

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“…9 For a 60-g gerbil, each citicoline dose (200 mg/mL saline) was given in a volume of 150 L. Treatment with citicoline did not affect the brain temperature, mean arterial blood pressure, or arterial PO 2 and PCO 2 for the sham-operated and ischemic groups during 3-hour postischemic reperfusion. 9,11,18,25 A total of 84 gerbils were used for lipid analyses in the present study and divided into the following groups: sham-operated group (shams)ϩvehicle (saline), nϭ12; shamsϩciticoline, nϭ8; ischemiaϩvehicle (saline), nϭ8 for each time point (1, 2, 3, and 6 days); and ischemiaϩciticoline, nϭ8 for each time point (1, 2, 3, and 6 days). For glutathione studies, 96 gerbils were assigned to the following 12 groups (nϭ8 each): shamsϩvehicle (saline), shamsϩciticoline, ischemiaϩvehicle (saline) (30 minutes, 2 hours, 6 hours, 1 day, and 3 days), and ischemiaϩciticoline (30 minutes, 2 hours, 6 hours, 1 day, and 3 days).…”

Section: Transient Forebrain Ischemiamentioning

confidence: 99%

Effects of Citicoline on Phospholipid and Glutathione Levels in Transient Cerebral Ischemia

Adibhatla

Hatcher

Dempsey

2001

Stroke

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Background and Purpose-Cytidine-5Ј-diphosphocholine (citicoline or CDP-choline) is an essential intermediate in the biosynthesis of phosphatidylcholine, an important component of the neural cell membrane. Citicoline provided significant neuroprotection after transient forebrain ischemia in gerbils. This study was undertaken to examine changes and effects of citicoline on phospholipids and glutathione synthesis after transient cerebral ischemia and reperfusion. Methods-Ten-minute transient forebrain ischemia was induced by bilateral carotid artery occlusion in male Mongolian gerbils with reperfusion up to 6 days. Citicoline (500 mg/kg IP in saline) was given to gerbils just after the end of ischemia, at 3-hour reperfusion, and daily thereafter until 1 day before euthanasia. Hippocampal lipids were extracted and analyzed by thin-layer and gas chromatography. Glutathione was measured by using an enzymatic recycling assay. Glutathione reductase activity was determined by measuring NADPH oxidation. Results-Significant decreases in phospholipids occurred at 1-day reperfusion. Citicoline significantly restored the phosphatidylcholine, sphingomyelin, and cardiolipin levels but did not affect phosphatidylinositol and phosphatidylserine at 1 day. The phospholipids returned to sham levels over days 2 to 6 and were unaffected by citicoline. Ceramide levels significantly increased by 3 and 6 days of reperfusion and were unaltered by citicoline. Ischemia resulted in significant decreases in glutathione and glutathione reductase activity over 3 days of reperfusion. Citicoline significantly increased total glutathione and glutathione reductase activity and decreased the glutathione oxidation ratio, an indicator of glutathione redox status. Conclusions-Our data indicated that the effects of citicoline on phospholipids occurred primarily during the first day of reperfusion, with effects on glutathione being important over the 3-day reperfusion period.

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The effects of prolonged treatment with citicoline in temporary experimental focal ischemia

Cited by 100 publications

References 18 publications

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

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

Neuroprotection for ischemic stroke: Past, present and future

Effects of Citicoline on Phospholipid and Glutathione Levels in Transient Cerebral Ischemia

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