Protective Effect Of Citicoline Research Articles

Protective effect of citicoline on random flap survival in a rat mode

BackgroundMedical therapy for flap survival has been extensively investigated. In this study, we explored the effect of citicoline (CDP-choline, CDPC), used for clinical treatment of cerebral trauma, on random skin flap survival in rats. Materials and methodsSixty rats were divided into three groups: low-dose (CDPC-L), high-dose (CDPC-H), and control. The CDPC-L and CDPC-H groups were intraperitoneally injected with 100 mg/kg and 300 mg/kg CDPC every day, respectively; the control group was injected with an equivalent volume of normal saline. The survival region was assessed on the 7th day after the flap operation. The microvascular density and neutrophil density were measured by hematoxylin and eosin staining. Lead angiography was used to detect angiogenesis, and laser Doppler was used to detect blood perfusion. Expression levels of vascular endothelial growth factor (VEGF), interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, Toll-like receptor (TLR) 4, and nuclear factor kappa B (NF-κB) were detected by immunohistochemistry. Malondialdehyde and superoxide dismutase were used to determine the lipid peroxidation level. ResultsThe average survival region of the flap was significantly larger in the CDPC-H group than in CDPC-L and control groups, with less ischemic necrosis. VEGF expression, microvascular density, angiogenesis, blood perfusion, and superoxide dismutase in the flap were higher in the CDPC-H group than in the CDPC-L and control groups. In addition, levels of neutrophil density, IL-1β, IL-6, TNF-α, TLR4, NF-κB, and malondialdehyde decreased significantly in the CDPC-H group. ConclusionHigh-dose CDPC injection after a random flap operation is beneficial for flap survival.

Protective Effects of Citicoline and Benfotiamine Each Alone and in Combination on Streptozotocin-induced Memory Impairment in Mice.

ObjectiveDiabetes mellitus is associated with cognitive disorders such as Alzheimer’s disease. Studies have shown that citicoline and benfotiamine can improve memory and learning through different mechanism of actions. The aim of this study was to compare the individual effects of benfotiamine (100, 200, 300 mg/kg) and citicoline (50, 100, 250, 500 mg/kg, gavage) and their co-administration on memory impairments in diabetic mice.MethodsDiabetes was induced by a single dose of streptozotocin (STZ, 140 mg/kg, intraperitoneal) and benfotiamine and/or citicoline were administered for three weeks. Memory was evaluated using the object recognition task (ORT) and passive avoidance test (PAT).ResultsResults from ORT shows that citicoline at 50, 100, 250, and 500 mg/kg and benfotiamine at 100, 200, and 300 mg/kg and their combination (benfotiamine at 100 mg/kg added to citicoline at 50, 100, and 250 mg/kg) are equally effective in reversing the memory loss induced by STZ (p < 0.001). PAT results demonstrate that citicoline at 100, 250, and 500 mg/kg and benfotiamine at above doses did not improve the latency time when administered separately, but benfotiamine at a fixed dose of 100 mg/kg in the presence of citicoline at 50, 100, and 250 mg/kg increased the latency time and improved memory significantly.ConclusionIn conclusion, in PAT, co-administration of benfotiamine and citicoline was more effective than either alone in improving memory. Regarding ORT, although benfotiamine added to citicoline improved memory notably, the difference between combination therapy and single-drug therapy was not considerable.

Protective effects of citicoline in neonatal rats with necrotizing enterocolitis

Protective effects of citicoline in neonatal rats with necrotizing enterocolitis

Abstract 2330: Citicoline Is A Strong Pro-angiogenic Molecule And Protects Brain Endothelial Cells From Apoptosis After Stroke

Background and purposes - Citicoline is neuroprotective agent used in stroke patients. Citicoline induces angiogenesis i n vitro ; however, the molecular mechanisms induced by citicoline have not been fully investigated. The present study was designed to investigate the key signalling mechanisms through which citicoline modulates angiogenesis-associated with stroke recovery. Methods - In vitro angiogenesis assays: migration (Bodyen chamber, a chemotaxis assay and wound recovery), proliferation and differentiation into tube-like structures in Matrigel TM as well as spheroid development assays were carried out using human brain microvessel endothelial cells (HBMECs). Western blotting was performed on the protein extraction from HBMEC stimulated with citicoline. Citicoline signalling pathway was studied using a phospho-protein screening array performed by Kinexus. A Staurosporin/calcium ionophore-induced apoptosis assay was performed by seeding HBMEC on the glass coverslips. Cells were pre-incubated with citicoline and the apoptosis was induced by addition of the ionophore or staurosporin. Cells were examined by microscoy and/or stained using propidium iodide and Hoechst stain solution and then counted under fluorescence microscope. Transient MCAO was carried out on Sprague Dawley rats (n=4 per group) with and without citicoline treatment (1000mg/Kg) applied at the time of occlusion and subsequently every 3 days until euthanasia (21 days). Vascularity of the stroke-affected regions was examined with antibodies recognising the microvessels (CD34) and active cells (CD105). Results - Citicoline presented no mitogenic and chemotactic effects on HBMEC; however, it significantly increased wound recovery, the formation of tube-like structures in Matrigel TM -with a stronger effect than FGF-2, and enhanced spheroid development and sprouting. Citicoline induced the expression of ERK-1/2, known to be involved in last step of signalling pathways of angiogenesis. Kinexus results showed an over-expression of ASK-1, HER2, IRS-1 and Jun and inhibition of Hsp27, Integrin alpha4, MEK1 (MAP2K1) and Histone H2B proteins. Knock-down of IRS-1 with targeted siRNA inhibited the pro-angiogenic effects (sprouting and tube-formation) of citicoline in HBMECs. The percentage of surviving cells was higher in the presence of citicoline after inducing apoptosis. Histology of infarcted regions showed that citicoline significantly increased the numbers of new active (CD105-positive) microvessels. Conclusion - The findings demonstrate both a pro-angiogenic and protective effect of citicoline on HBMECs in vitro and following MCAO in vitro. Additionally, this molecule may play a key role in the modulation of angiogenesis thereby and ultimately, improving tissue function, revascularisation and neuronal survival after ischaemic stroke.

Citicoline induces angiogenesis improving survival of vascular/human brain microvessel endothelial cells through pathways involving ERK1/2 and insulin receptor substrate-1

BackgroundCiticoline is one of the neuroprotective agents that have been used as a therapy in stroke patients. There is limited published data describing the mechanisms through which it acts.MethodsWe used in vitro angiogenesis assays: migration, proliferation, differentiation into tube-like structures in Matrigel™ and spheroid development assays in human brain microvessel endothelial cells (hCMEC/D3). Western blotting was performed on protein extraction from hCMEC/D3 stimulated with citicoline. An analysis of citicoline signalling pathways was previously studied using a Kinexus phospho-protein screening array. A staurosporin/calcium ionophore-induced apoptosis assay was performed by seeding hCMEC/D3 on to glass coverslips in serum poor medium. In a pilot in vivo study, transient MCAO in rats was carried out with and without citicoline treatment (1000 mg/Kg) applied at the time of occlusion and subsequently every 3 days until euthanasia (21 days). Vascularity of the stroke-affected regions was examined by immunohistochemistry.ResultsCiticoline presented no mitogenic and chemotactic effects on hCMEC/D3; however, it significantly increased wound recovery, the formation of tube-like structures in Matrigel™ and enhanced spheroid development and sprouting. Citicoline induced the expression of phospho-extracellular-signal regulated kinase (ERK)-1/2. Kinexus assays showed an over-expression of insulin receptor substrate-1 (IRS-1). Knock-down of IRS-1 with targeted siRNA in our hCMEC/D3 inhibited the pro-angiogenic effects of citicoline. The percentage of surviving cells was higher in the presence of citicoline. Citicoline treatment significantly increased the numbers of new, active CD105-positive microvessels following MCAO.ConclusionsThe findings demonstrate both a pro-angiogenic and protective effect of citicoline on hCMEC/D3 in vitro and following middle cerebral artery occlusion (MCAO) in vivo.

The protective effect of citicoline on the progression of the perimetric defects in glaucomatous patients (perimetric study with a 10-year follow-up).

Acta Ophthalmologica ScandinavicaVolume 78, Issue S232 p. 56-57 Free Access The protective effect of citicoline on the progression of the perimetric defects in glaucomatous patients (perimetric study with a 10-year follow-up) M. Virno, M. Virno Institute of Ophthalmology, La Sapienza University, RomeSearch for more papers by this authorJ. Pecori-Giraldi, J. Pecori-Giraldi Institute of Ophthalmology, La Sapienza University, RomeSearch for more papers by this authorA. Liguori, A. Liguori Institute of Ophthalmology, La Sapienza University, RomeSearch for more papers by this authorF. de Gregorio, F. de Gregorio Institute of Ophthalmology, La Sapienza University, RomeSearch for more papers by this author M. Virno, M. Virno Institute of Ophthalmology, La Sapienza University, RomeSearch for more papers by this authorJ. Pecori-Giraldi, J. Pecori-Giraldi Institute of Ophthalmology, La Sapienza University, RomeSearch for more papers by this authorA. Liguori, A. Liguori Institute of Ophthalmology, La Sapienza University, RomeSearch for more papers by this authorF. de Gregorio, F. de Gregorio Institute of Ophthalmology, La Sapienza University, RomeSearch for more papers by this author First published: 25 August 2010 https://doi.org/10.1111/j.1600-0420.2000.tb01107.xCitations: 27AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL No abstract is available for this article. References Virno M., Giraldi Pecori J., Grechi G., Covelli GP & De Gregorio F. (1989): Valore terapeutico della citicolina nel paziente glaucomatoso (indagine perimetrica computerizzata). Boll Ocul 68 (suppl. 2): 251– 258. Giraldi Pecori J., Virno M., Covelli GP, Grechi G. & De Gregorio F. (1989): Therapeutic value of citicoline in the treatment of glaucoma. Int Ophthalmol 13: 109– 115. Brogliatti B., Rolle T., Cantatore A. & Bianco M. (1991): Citicolina vs Gangliosidi vs GM1 effetti sulla sensibilità centrale in pazienti glaucomatosi. Boll Ocul 70 (suppl. 1): 263– 269. Porciatti V., Schiavi C., Benedetti P., Baldi A. & Campos E. (1998): Cytidine-5′-diphosphocholine improves visual acuity, contrast sensitivity and visually-evoked potentials of amblyopic subjects. Curr Eye Res 141– 148. Campos EC (1997): Future directions in the treatment of amblyopia. Lancet 26, 349 (9060): 1190. Parisi V., Manni G., Colacino G. & Bucci M G: (1999): Cytidine-5′-diphosphocoline (citicoline) improves retinal and cortical responses in patients with glaucoma. Ophthalmology 106(6): 1126– 1134. Accornero N., Berardelli A., Cruccu G. & Manfredi M. (1984): Computerized video-screen perimetry. Arch Ophthalmol 102: 40. Clark WM, Warach SJ, Pettigrew LC, Gammans RE & Sabounjian LA. (1997): A randomized dose-response trial of citicoline in acute ischemic stroke patients. Citicoline Stroke Study Group. Neurology 49(3): 671– 678. Caamano J., Gomez MJ, Franco A. & Cacabelos R. (1994): Effects of CDP-choline on cognition and cerebral hemodynamica in patients with Alzheimer's disease. Methods Find Exp Clin Pharmacol 16(3): 211– 218. Eberhardt R., Birbamer G., Gerstenbrand F., Rainer E. & Traegner H. (1990): Citicoline in the treatment of Parkinson's disease. Clin Ther 12(6): 489– 495. Virno M., Giraldi Pecori J., Pellegrino N., Taverniti L., De Gregorio F. & Sedran L. (1993): Farmaci attivi sull'emodinamica oculare. Boll Ocul 72 (suppl. 2): 1– 20. Citing Literature Volume78, IssueS232December 2000Pages 56-57 ReferencesRelatedInformation