Effects of CDP-choline on neurologic deficits and cerebral glucose metabolism in a rat model of cerebral ischemia.

Kakihana, Mitsuru; Fukuda, Naohisa; Suno, Masahiro; Nagaoka, Akinobu

doi:10.1161/01.str.19.2.217

Cited by 75 publications

(42 citation statements)

References 27 publications

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“…The relevance of this mechanism was challenged, however, because acetylcholine concentrations were not significantly increased by citicoline treatment. 130 In addition, citicoline was shown to reduce oxidative stress.…”

Section: Citicolinementioning

confidence: 99%

Multifunctional Actions of Approved and Candidate Stroke Drugs

Minnerup

Schäbitz

2009

Neurotherapeutics

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Summary: Ischemic stroke causes brain damage by multiple pathways. Previous stroke trials have demonstrated that drugs targeting one or only a few of these pathways fail to improve clinical outcome after stroke. Drugs with multimodal actions have been suggested to overcome this challenge. In this review, we describe the mechanisms of action of agents approved for secondary prevention of ischemic stroke, such as antiplatelet, antihypertensive, and lipid-lowering drugs. These drugs exhibit considerable properties beyond their classical mechanisms, including neuroprotective and neuroregenerative properties. In addition, candidate stroke drugs currently studied in clinical phase III trials are described. Among these, albumin, hematopoietic growth factors, and citicoline have been identified as promising agents with multiple mechanisms. These drugs offer hope that additional treatment options for the acute phase after a stroke will become available in the near future.

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Section: Citicolinementioning

confidence: 99%

Multifunctional Actions of Approved and Candidate Stroke Drugs

Minnerup

Schäbitz

2009

Neurotherapeutics

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“…3 In models of transient global ischemia, CIT reduced production of free fatty acids, a tissue-toxic byproduct of membrane breakdown secondary to an ischemic insult. 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.…”

mentioning

confidence: 97%

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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“…Regarding neurological function, however, data are uncertain. Several studies assessing global (Kakihana et al 1988) and focal (Aronowski et al 1996;Hurtado et al 2007) cerebral ischemia models have reported an improvement on neurological outcome, while other studies could not found differences after citicoline treatment (Schabitz et al 1996(Schabitz et al , 1999. However, no systematic review has explored the adherence of citicoline experimental research on stroke models to the Stroke Therapy Academic Industry Roundtable (STAIR) recommendations (STAIR 1999).…”

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confidence: 99%

Citicoline in pre‐clinical animal models of stroke: a meta‐analysis shows the optimal neuroprotective profile and the missing steps for jumping into a stroke clinical trial

Bustamante

Giralt

García-Bonilla

et al. 2012

Journal of Neurochemistry

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The neuroprotective actions of citicoline have been documented for experimental stroke therapy. We used a systematic review and meta-analysis to assess this evidence. From 64 identified studies using citicoline in stroke animal models, only those describing ischemic occlusive stroke and reporting data on infarct volume and/or neurological outcome were included (14 studies, 522 animals). Overall, the quality of the studies was modest (5, 4-6), while the absence of studies involving animals with co-morbidities, females, old animals or strain differences indicated that studies did not fulfill the STAIR recommendations. Weighted mean difference meta-analysis showed citicoline to reduce infarct volume by 27.8% [(19.9%, 35.6%); p < 0.001]. In the stratified analysis, citicoline effect on reducing infarct volume was higher in proximal occlusive models of middle cerebral artery (MCA) compared with distal occlusion. Moreover, the efficacy was superior using multiple doses than single dose and when a co-treatment was administered compared with citicoline monotherapy, the only independent factor identified in the meta-regression. Citicoline improved neurological deficit by 20.2% [(6.8%, 33.7%); p = 0.015], but only four studies including 176 animals reported these data. In conclusion, this meta-analysis provides evidence of citicoline efficacy in stroke animal models and shows the optimal neuroprotective profile and the missing experimental requirements before jumping into clinical trials. Keywords: animal models, citicoline, ischemic stroke, metaanalysis, meta-regression, systematic review. J. Neurochem. (2012) 123, 217-225. Stroke remains one of the leading causes of mortality and disability in western countries. Nevertheless, no neuroprotective agent has demonstrated clear efficacy in phase III clinical trials that can be translated into clinical recommendations or guidelines (Gladstone et al. 2002). Regarding citicoline and based on the evidence shown by animal models, several studies have been conducted in human stroke. Although some of those studies have shown overall benefits (Clark et al. 1999(Clark et al. , 2001, their results are broadly inconclusive.Cytidine diphosphocholine (CDP choline or citicoline) is an essential intermediate in the synthesis of structural phospholipids of cell membranes. Moreover, the formation of this compound from phosphorylcholine is the rate-limiting step of this biosynthetic pathway Hatcher 2007, 2010 | 2012 | 123 | 217-225 doi: 10.1111/j.1471-4159.2012.07891.x cerebral ischemia (Goto et al. 1988). In vitro studies using nerve tissues have shown that hypoxia induces a timedependent decrease in the synthesis of structural phospholipids (Cohen 1973), suggesting the relevance of the new phospholipid synthesis after stroke. As a result of these physiological and pathological effects, the administration of citicoline has been proposed as a neuroprotective therapy for human stroke (Secades 2002). With this background, the potential neuroprotective role of citicoline has ...

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Effects of CDP-choline on neurologic deficits and cerebral glucose metabolism in a rat model of cerebral ischemia.

Cited by 75 publications

References 27 publications

Multifunctional Actions of Approved and Candidate Stroke Drugs

Multifunctional Actions of Approved and Candidate Stroke Drugs

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

Citicoline in pre‐clinical animal models of stroke: a meta‐analysis shows the optimal neuroprotective profile and the missing steps for jumping into a stroke clinical trial

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