The link between membrane phospholipids and different intracellular signal transduction pathways affected by cerebral ischaemia is unclear. CDP-choline, a major neuronal membrane lipid precursor and its intracellular target proteins and transcription factors were studied to further understand its role in ischaemic stroke. Cerebral ischaemia was produced by distal, permanent occlusion of the middle cerebral artery (MCAO) in the rat. Animals receiving 500 mg/kg of CDP-choline in 0.5 ml of 0.9% saline, intraperitoneally, 24 h and 1 h before MCAO and 23 h after MCAO demonstrated a notable reduction in the phosphorylation of MAP-kinase family members, ERK1/2 and MEK1/2, as well as Elk-1 transcription factor, compared with control animals treated with 0.5 ml of 0.9% saline. Immunohistochemistry showed a particular reduction in immunoreactivity in glia. The effects of CDP-choline on intracellular mechanisms of signal transduction, suggests that this molecule may play a key role in recovery after ischaemic stroke.
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E. Runden P. Seglen F. Haug O. Ottersen T. Wieloch M. Shamloo J. H. Laake (1998) ArticleTitleRegional selective neuronal degeneration after protein phosphatase inhibition in hippocampal slice cultures: evidence for a MAP kinase-dependent mechanism J. Neurosci. 18 7296–7305 Occurrence Handle9736650
J. Yuan (1997) ArticleTitleTransducing signals of life and death Curr. Opin. Cell. Biol. 9 247–251 Occurrence Handle10.1016/S0955-0674(97)80069-5 Occurrence Handle9069264
J. Kyriakis J. Avruch (1996) ArticleTitleProtein kinase cascades activated by stress and inflammatory cytokines Bioessays 18 567–577 Occurrence Handle10.1002/bies.950180708 Occurrence Handle8757935
M. Robinson M. Cobb (1997) ArticleTitleMitogen-activated protein kinase pathways Curr. Opin. Cell. Biol. 9 180–186 Occurrence Handle10.1016/S0955-0674(97)80061-0 Occurrence Handle9069255
C. Schindler J. Darnell (1995) ArticleTitleTranscriptional responses to polypeptide ligands: the JAK-STAT pathway Ann. Rev. Biochem. 64 621–651 Occurrence Handle10.1146/annurev.bi.64.070195.003201 Occurrence Handle7574495
J. Aronowski R. Strong J. Grotta (1996) ArticleTitleCiticoline for treatment of experimental focal ischaemia: histologic and behavioral outcome Neurol. Res. 18 570–574 Occurrence Handle8985961
G. Trovarelli G. deMedio R. Dorman G. Piccinin L. Horrocks G. Porcellati (1981) ArticleTitleEffects of cytidine diphosphate choline (CDP-choline) on ischaemia-induced alteration of brain lipid in the gerbil Neurochem. Res. 6 821–833 Occurrence Handle10.1007/BF00965041 Occurrence Handle6796897
G. Weiss (1995) ArticleTitleMinireview, metabolism and action of CDP-choline as an endogenous compound and administered exogenously as citicoline Life Sci. 56 637–660 Occurrence Handle10.1016/0024-3205(94)00427-T Occurrence Handle7869846
W. M. Clark S. J. Warach L. C. Pettigrew R. E. Gammans L. A. Sabounjian (1997) ArticleTitleA randomized dose–response trial of citicoline in acute ischemic stroke patients. Citicoline stroke study group Neurology 49 1234–1235
W. M. Clark B. J. Williams K. A. Selzer R. M. Zweifler L. A. Sabounjian R. E. Gammans (1999) ArticleTitleA randomized efficiacy trial of citicoline in patients with acute ischaemic stroke Stroke 30 2592–2597 Occurrence Handle10582983
W. M. Clarke L. R. Wechsler L. A. Sabounjian U. E. Schwiderski (2001) ArticleTitleA phase III randomized trial of 2000 mg citicoline in acute ischaemic stroke patients. Citicoline stroke study group Neurology 57 1595–1602 Occurrence Handle11706098
A. Davalos J. Castillo J. Alvarez-Sabin J. J. Secades J. Mercadal S. Lopez E. Cobo S. Warach D. Sherman W. M. Clark R. Lozano (2002) ArticleTitleOral citicoline in acute ischemic stroke: an individual patient data pooling analysis of clinical trials Stroke 33 2850–2857 Occurrence Handle10.1161/01.STR.0000038691.03334.71 Occurrence Handle12468781
A. Tamura D. Graham J. McCulloch G. Teasdale (1981) ArticleTitleFocal cerebral ischaemia in the rat: description of technique and early neuropathological consequences following middle cerebral artery occlusion J. Cereb. Blood Flow Metab. 1 53–60 Occurrence Handle7328138
A. Eke K. Conger M. Anderson J. Garcia (1990) ArticleTitleHistologic assessment of neurons in rat models of cerebral ischemia Stroke 21 299–304 Occurrence Handle2305408
J. Krupinski M. Slevin E. Marti E. Catena F. Rubio J. Gaffney (2003) ArticleTitleTime-course phosphorylation of the MAP kinase group of signaling proteins and related molecules following middle cerebral artery occlusion in the rat Neuropath. App. Neurobiol. 29 144–158 Occurrence Handle10.1046/j.1365-2990.2003.00454.x
R. M. Adibhatla J. F. Hatcher (2002) ArticleTitleCiticoline mechanisms and clinical efficacy in cerebral ischemia Neurosci. Res. 70 133–139 Occurrence Handle10.1002/jnr.10403
O. Hurtado M. A. Moro A. Cardenas V. Sanchez P. Fernandez-Tome J. C. Leza P. Lorenzo J. J. Secades R. Lozano A. Davalos J. Castillo I. Lizasoain (2005) ArticleTitleNeuroprotection afforded by prior citicoline administration in experimental brain ischaemia: effects on glutamate transport Nerobiol. Dis. 18 336–345 Occurrence Handle10.1016/j.nbd.2004.10.006
M. Sobrado M. G. Lopez F. Carcellar A. G. Garcia J. M. Roda (2003) ArticleTitleCombined nimodipine and citicoline reduce infarct size, attenuate apoptosis and increase bcl−2 expression after focal cerebral ischaemia Neuroscience 118 107–113 Occurrence Handle10.1016/S0306-4522(02)00912-0 Occurrence Handle12676142
A. M. Rao J. F. Hatcher R. J. Dempsey (2001) ArticleTitleDoes CDP-choline modulate phospholipase activities after transient forebrain ischaemia? Brain Res. 893 268–272 Occurrence Handle10.1016/S0006-8993(00)03280-7 Occurrence Handle11223016
M. Asahi M. Hoshimaru Y. Uemura T. Tokime M. Kojima T. Ohtsuka N. Matsuura T. Aoki K. Shibahara H. Kikuchi (1997) ArticleTitleExpression of interleukin−1β converting enzyme gene family and bcl−2 gene family in the rat brain following permanent occlusion of the middle cerebral artery J.Cereb. Blood Flow. Metab 17 11–18 Occurrence Handle10.1097/00004647-199701000-00003 Occurrence Handle8978382
R. Mallampalli A. Ryan R. Salome S. Jackowski (2000) ArticleTitleTumor necrosis factor-alpha inhibits expression of CTP-phosphocholine cytidylyltransferase J. Biol. Chem. 31 9699–9708 Occurrence Handle10.1074/jbc.275.13.9699
P. Antony J. N. Kanfer L. Freysz (2000) ArticleTitlePhosphatidylcholine metabolism in nuclei of phorbol ester-activated LA-N−1 neuroblastoma cells Neurochem. Res. 25 1073–1082 Occurrence Handle10.1023/A:1007613827552 Occurrence Handle11055744
A. Meister B. Kleuser M. Ollert G. Gercken (1996) ArticleTitleBetaine generation in cardiac myocytes after adrenergic activation of phosphatidylcholine hydrolysis J. Mol.Cell Cardiol. 28 1109–1118 Occurrence Handle10.1006/jmcc.1996.0102 Occurrence Handle8762047
M. Slevin J. Krupinski A. Slowik J. Gaffney A. Szczudlik (2000) ArticleTitleActivation of MAP kinase (ERK−1/ERK−2), tyrosine kinase and VEGF in the human brain following acute ischaemic stroke Neuroreport 11 2759–2764 Occurrence Handle10976958
E. Irving F. Barone A. Reith S. Hadingham A. Parsons (2000) ArticleTitleDifferential activation of MAPK/ERK and p38/SAPK in neurones and glia following focal cerebral ischaemia in the rat Brain Res. Mol. Brain Res. 77 65–75 Occurrence Handle10.1016/S0169-328X(00)00043-7 Occurrence Handle10814833
K. Walton R. DiRocco B. Bartlett E. Koury V. Marcy B. Jarvis E. M. Schaefer R. V. Bhat (1998) ArticleTitleActivation of p38MAPK in microglia after ischemia J. Neurochem. 70 1764–1767 Occurrence Handle9523596
S. Skaper L. Facci P. Strijbos (2001) ArticleTitleNeuronal protein kinase signalling cascades and excitotoxic cell death Ann. NY Acad. Sci. 939 11–22 Occurrence Handle11462762
G. Zhau Z. Bao J. Dixon (1995) ArticleTitleComponents of new human protein kiase signal transduction pathway J. Biol. Chem. 270 12665–12669 Occurrence Handle7759517
A. Simi M. Ingelman-Sundberg N. Tindberg (2000) ArticleTitleNeuroprotective agent clomethizole attenuates c-fos, c-jun, and AP−1 activation through inhibition of p38 MAP kinase J. Cereb. Blood Flow Metab. 20 1077–1088 Occurrence Handle10908041
W. Clark S. Warach L. Pettigrew R. Gammans L. A. Sabounjian (1997) ArticleTitleRandomized dose–response trial of citicoline in acute ischaemic stroke patients Neurology 49 671–678 Occurrence Handle9305321
W. Schabitz J. Weber K. Takano B. Sandage K. Locke M. Fisher (1996) ArticleTitleThe effects of prolonged treatment with citicoline in temporary experimental focal ischaemia J. Neurol. Sci. 138 21–25 Occurrence Handle10.1016/0022-510X(95)00341-X Occurrence Handle8791234
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Krupinski, J., Slevin, M. & Badimon, L. Citicoline Inhibits MAP Kinase Signalling Pathways after Focal Cerebral Ischaemia. Neurochem Res 30, 1067–1073 (2005). https://doi.org/10.1007/s11064-005-7201-0
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DOI: https://doi.org/10.1007/s11064-005-7201-0