Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport
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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2005-03-01
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| Series: | Neurobiology of Disease |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0969996104002426 |
| _version_ | 1818414516433584128 |
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| author | Olivia Hurtado María A. Moro Antonio Cárdenas Verónica Sánchez Paz Fernández-Tomé Juan C. Leza Pedro Lorenzo Julio J. Secades Rafael Lozano Antoni Dávalos José Castillo Ignacio Lizasoain |
| author_facet | Olivia Hurtado María A. Moro Antonio Cárdenas Verónica Sánchez Paz Fernández-Tomé Juan C. Leza Pedro Lorenzo Julio J. Secades Rafael Lozano Antoni Dávalos José Castillo Ignacio Lizasoain |
| author_sort | Olivia Hurtado |
| collection | DOAJ |
| description | 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 μM). 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 μM) prevented OGD-induced LDH and glutamate release and caused a recovery in ATP levels after OGD, confirming our previous results. In addition, citicoline (100 μM) 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. |
| first_indexed | 2024-12-14T11:20:20Z |
| format | Article |
| id | doaj.art-a935beda8aba49cb8f2d500ef6365b32 |
| institution | Directory Open Access Journal |
| issn | 1095-953X |
| language | English |
| last_indexed | 2024-12-14T11:20:20Z |
| publishDate | 2005-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Neurobiology of Disease |
| spelling | doaj.art-a935beda8aba49cb8f2d500ef6365b322022-12-21T23:03:47ZengElsevierNeurobiology of Disease1095-953X2005-03-01182336345Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transportOlivia Hurtado0María A. Moro1Antonio Cárdenas2Verónica Sánchez3Paz Fernández-Tomé4Juan C. Leza5Pedro Lorenzo6Julio J. Secades7Rafael Lozano8Antoni Dávalos9José Castillo10Ignacio Lizasoain11Departamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), 28040 Madrid, SpainDepartamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), 28040 Madrid, SpainInstituto de Farmacología y Toxicología, UCM-CSIC, Madrid, SpainDepartamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), 28040 Madrid, SpainInstituto de Farmacología y Toxicología, UCM-CSIC, Madrid, SpainDepartamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), 28040 Madrid, SpainDepartamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), 28040 Madrid, SpainDepartamento Médico, Grupo Ferrer SA, Barcelona, SpainDepartamento Médico, Grupo Ferrer SA, Barcelona, SpainServicio de Neurología, Hospital Doctor Josep Trueta, Girona, SpainServicio de Neurología, Hospital Clínico Universitario de Santiago, Santiago de Compostela, SpainDepartamento de Farmacología, Facultad de Medicina, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; Corresponding author. Fax: +34 91 3941478.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 μM). 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 μM) prevented OGD-induced LDH and glutamate release and caused a recovery in ATP levels after OGD, confirming our previous results. In addition, citicoline (100 μM) 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.http://www.sciencedirect.com/science/article/pii/S0969996104002426AstrocytesATPCerebral infarctionMiddle cerebral artery occlusionNeuronesOGD |
| spellingShingle | Olivia Hurtado María A. Moro Antonio Cárdenas Verónica Sánchez Paz Fernández-Tomé Juan C. Leza Pedro Lorenzo Julio J. Secades Rafael Lozano Antoni Dávalos José Castillo Ignacio Lizasoain Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport Neurobiology of Disease Astrocytes ATP Cerebral infarction Middle cerebral artery occlusion Neurones OGD |
| title | Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport |
| title_full | Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport |
| title_fullStr | Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport |
| title_full_unstemmed | Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport |
| title_short | Neuroprotection afforded by prior citicoline administration in experimental brain ischemia: effects on glutamate transport |
| title_sort | neuroprotection afforded by prior citicoline administration in experimental brain ischemia effects on glutamate transport |
| topic | Astrocytes ATP Cerebral infarction Middle cerebral artery occlusion Neurones OGD |
| url | http://www.sciencedirect.com/science/article/pii/S0969996104002426 |
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