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Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport.

Abstract

BACKGROUND AND PURPOSE

Cytidine-5'-diphosphocholine (citicoline or CDP-choline), an intermediate in the biosynthesis of phosphatidylcholine, has shown beneficial effects in a number of CNS injury models including cerebral ischemia. Citicoline is the only neuroprotectant that has proved efficacy in patients with moderate to severe stroke. However, the precise mechanism by which citicoline is neuroprotective is not fully known. The present study was designed to search for mechanisms of citicoline neuroprotective properties using in vivo and in vitro models of brain ischemia.

METHODS

Focal brain ischemia was produced in male adult Fischer rats by occluding both the common carotid and middle cerebral arteries. Brain glutamate levels were determined at fixed intervals after occlusion. Animals were then sacrificed, and infarct volume and brain ATP levels were measured. As in vitro model of ischemia, rat cultured cortical neurones or astrocytes, isolated or in co-culture, were exposed to oxygen-glucose deprivation (OGD) either in the absence or in the presence of citicoline (1-100 microM). Viability was studied by measuring LDH release. Glutamate release and uptake, and ATP levels were also determined.

RESULTS

Citicoline (0.5, 1 and 2 g/kg i.p. administered 1 h before the occlusion) produced a reduction of the infarct size measured at striatum (18, 27 and 42% inhibition, respectively, n = 8, P < 0.05 vs. ischemia), effect that correlated with the inhibition caused by citicoline on ischemia-induced increase in glutamate concentrations after the onset of the ischemia. Citicoline also inhibited ischemia-induced decrease in cortical and striatal ATP levels. Incubation of cultured rat cortical neurones with citicoline (10 and 100 microM) prevented OGD-induced LDH and glutamate release and caused a recovery in ATP levels after OGD, confirming our previous results. In addition, citicoline (100 microM) caused an increase in glutamate uptake and in EAAT2 glutamate transporter membrane expression in cultured rat astrocytes.

CONCLUSIONS

Our present findings show novel mechanisms for the neuroprotective effects of citicoline, which cooperate to decrease brain glutamate release after ischemia.

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  • Authors+Show Affiliations

    ,

    Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain.

    , , , , , , , , , ,

    Source

    Neurobiology of disease 18:2 2005 Mar pg 336-45

    MeSH

    Adenosine Triphosphate
    Amino Acid Transport System X-AG
    Animals
    Animals, Newborn
    Astrocytes
    Biological Transport
    Brain
    Brain Ischemia
    Cell Survival
    Cells, Cultured
    Cerebral Infarction
    Coculture Techniques
    Cytidine Diphosphate Choline
    Cytoprotection
    Disease Models, Animal
    Excitatory Amino Acid Transporter 2
    Glutamate Plasma Membrane Transport Proteins
    Glutamic Acid
    L-Lactate Dehydrogenase
    Male
    Nerve Degeneration
    Neurons
    Neuroprotective Agents
    Rats
    Rats, Inbred F344
    Rats, Wistar
    Symporters

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    15686962

    Citation

    Hurtado, Olivia, et al. "Neuroprotection Afforded By Prior Citicoline Administration in Experimental Brain Ischemia: Effects On Glutamate Transport." Neurobiology of Disease, vol. 18, no. 2, 2005, pp. 336-45.
    Hurtado O, Moro MA, Cárdenas A, et al. Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport. Neurobiol Dis. 2005;18(2):336-45.
    Hurtado, O., Moro, M. A., Cárdenas, A., Sánchez, V., Fernández-Tomé, P., Leza, J. C., ... Lizasoain, I. (2005). Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport. Neurobiology of Disease, 18(2), pp. 336-45.
    Hurtado O, et al. Neuroprotection Afforded By Prior Citicoline Administration in Experimental Brain Ischemia: Effects On Glutamate Transport. Neurobiol Dis. 2005;18(2):336-45. PubMed PMID: 15686962.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport. AU - Hurtado,Olivia, AU - Moro,María A, AU - Cárdenas,Antonio, AU - Sánchez,Verónica, AU - Fernández-Tomé,Paz, AU - Leza,Juan C, AU - Lorenzo,Pedro, AU - Secades,Julio J, AU - Lozano,Rafael, AU - Dávalos,Antoni, AU - Castillo,José, AU - Lizasoain,Ignacio, PY - 2004/03/29/received PY - 2004/07/23/revised PY - 2004/10/13/accepted PY - 2005/2/3/pubmed PY - 2005/5/13/medline PY - 2005/2/3/entrez SP - 336 EP - 45 JF - Neurobiology of disease JO - Neurobiol. Dis. VL - 18 IS - 2 N2 - BACKGROUND AND PURPOSE: Cytidine-5'-diphosphocholine (citicoline or CDP-choline), an intermediate in the biosynthesis of phosphatidylcholine, has shown beneficial effects in a number of CNS injury models including cerebral ischemia. Citicoline is the only neuroprotectant that has proved efficacy in patients with moderate to severe stroke. However, the precise mechanism by which citicoline is neuroprotective is not fully known. The present study was designed to search for mechanisms of citicoline neuroprotective properties using in vivo and in vitro models of brain ischemia. METHODS: Focal brain ischemia was produced in male adult Fischer rats by occluding both the common carotid and middle cerebral arteries. Brain glutamate levels were determined at fixed intervals after occlusion. Animals were then sacrificed, and infarct volume and brain ATP levels were measured. As in vitro model of ischemia, rat cultured cortical neurones or astrocytes, isolated or in co-culture, were exposed to oxygen-glucose deprivation (OGD) either in the absence or in the presence of citicoline (1-100 microM). Viability was studied by measuring LDH release. Glutamate release and uptake, and ATP levels were also determined. RESULTS: Citicoline (0.5, 1 and 2 g/kg i.p. administered 1 h before the occlusion) produced a reduction of the infarct size measured at striatum (18, 27 and 42% inhibition, respectively, n = 8, P < 0.05 vs. ischemia), effect that correlated with the inhibition caused by citicoline on ischemia-induced increase in glutamate concentrations after the onset of the ischemia. Citicoline also inhibited ischemia-induced decrease in cortical and striatal ATP levels. Incubation of cultured rat cortical neurones with citicoline (10 and 100 microM) prevented OGD-induced LDH and glutamate release and caused a recovery in ATP levels after OGD, confirming our previous results. In addition, citicoline (100 microM) caused an increase in glutamate uptake and in EAAT2 glutamate transporter membrane expression in cultured rat astrocytes. CONCLUSIONS: Our present findings show novel mechanisms for the neuroprotective effects of citicoline, which cooperate to decrease brain glutamate release after ischemia. SN - 0969-9961 UR - https://www.unboundmedicine.com/medline/citation/15686962/Neuroprotection_afforded_by_prior_citicoline_administration_in_experimental_brain_ischemia:_effects_on_glutamate_transport_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(04)00242-6 DB - PRIME DP - Unbound Medicine ER -