{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T16:07:00Z","timestamp":1792685220523,"version":"4.5.0"},"reference-count":46,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2022,7,20]],"date-time":"2022-07-20T00:00:00Z","timestamp":1658275200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"OmegaPharma SRL (Cant\u00f9, Italy)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: The present study aimed to investigate the rationale and efficacy of using a citicoline, coenzyme Q10 (CAVAQ10) and vitamin B3 fixed combination in combating inflammation and oxidation in neuronal cells exposed to oxidative stress. Methods: HypoE22 cells and isolated hypothalamic specimens were selected as in vitro models to conduct the experiments. The efficacy of citicoline, CAVAQ10, and vitamin B3, with their fixed combination, were assayed after the exposure of hypothalamic cells to hydrogen peroxide (concentration range 1 nM\u201310 \u00b5M), in order to evaluate the biocompatibility of treatments. The activity of neuroprotective and pro-inflammatory factors, namely, brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), and tumor necrosis factor-\u03b1 (TNF\u03b1), involved in the neuronal cell damage in neurodegenerative diseases, were assayed in isolated hypothalamus. Results: Neither citicoline, CAVAQ10, nor vitamin B3 significantly altered hypothalamic cell viability, thus suggesting the biocompatibility of single ingredients and fixed combination in the concentration range considered for the study. In the same condition, citicoline and CAVAQ10 were also effective in reducing the gene expression of monoaminoxidase-B, involved in dopamine degradation. However, only citicoline demonstrated an ability to reduce dopamine levels. Conversely, all compounds were effective in reducing the gene expression of IL-6, and TNF\u03b1, and in inducing the gene expression of BDNF, with the co-administration of citicoline\/CAVAQ10\/vitamin B3 being generally more effective than single ingredients. Conclusions: The present findings support the beneficial and synergistic effects of citicoline, CAVAQ10, and vitamin B3 in fixed combination in reducing inflammation and oxidation, and in stimulating neurotrophin production in neuronal cells.<\/jats:p>","DOI":"10.3390\/nu14142963","type":"journal-article","created":{"date-parts":[[2022,7,21]],"date-time":"2022-07-21T03:34:40Z","timestamp":1658374480000},"page":"2963","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Citicoline\/Coenzyme Q10\/Vitamin B3 Fixed Combination Exerts Synergistic Protective Effects on Neuronal Cells Exposed to Oxidative Stress"],"prefix":"10.3390","volume":"14","author":[{"given":"Leonardo","family":"Mastropasqua","sequence":"first","affiliation":[{"name":"Ophthalmology Clinic, Department of Medicine and Aging Science, University G. d\u2019Annunzio of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1625-6305","authenticated-orcid":false,"given":"Luca","family":"Agnifili","sequence":"additional","affiliation":[{"name":"Ophthalmology Clinic, Department of Medicine and Aging Science, University G. d\u2019Annunzio of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9431-9407","authenticated-orcid":false,"given":"Claudio","family":"Ferrante","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, G. d\u2019Annunzio University, 66013 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Sacchi","sequence":"additional","affiliation":[{"name":"University Eye Clinic, San Giuseppe Hospital, IRCCS Multimedica, 20900 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2243-9033","authenticated-orcid":false,"given":"Michele","family":"Figus","sequence":"additional","affiliation":[{"name":"Ophthalmology Unit, Department of Surgery, Medicine, Molecular and Emergency, University of Pisa, 56124 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3519-2420","authenticated-orcid":false,"given":"Gemma Caterina Maria","family":"Rossi","sequence":"additional","affiliation":[{"name":"Fondazione IRCCS Policlinico San Matteo, 27100 Pavia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7874-7794","authenticated-orcid":false,"given":"Lorenza","family":"Brescia","sequence":"additional","affiliation":[{"name":"Ophthalmology Clinic, Department of Medicine and Aging Science, University G. d\u2019Annunzio of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaella","family":"Aloia","sequence":"additional","affiliation":[{"name":"Ophthalmology Clinic, Department of Medicine and Aging Science, University G. d\u2019Annunzio of Chieti-Pescara, 66100 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giustino","family":"Orlando","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, G. d\u2019Annunzio University, 66013 Chieti, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Kritsilis, M., Rizou, V.S., Koutsoudaki, P.N., Evangelou, K., Gorgoulis, V.G., and Papadopoulos, D. (2018). Ageing, Cellular Senescence and Neurodegenerative Disease. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19102937"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1054\/jocn.2001.1027","article-title":"Neuroprotection and neurodegenerative disease","volume":"9","author":"Vajda","year":"2002","journal-title":"J. Clin. Neurosci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1007\/s40263-014-0144-8","article-title":"Neuroprotective properties of citicoline: Facts, doubts and unresolved issues","volume":"28","author":"Grieb","year":"2014","journal-title":"CNS Drugs"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"858","DOI":"10.2174\/1568026615666150827095252","article-title":"Neuroprotection of Coenzyme Q10 in Neurodegenerative Diseases","volume":"16","author":"Yang","year":"2016","journal-title":"Curr. Top Med. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1016\/j.preteyeres.2019.06.003","article-title":"Cholinergic nervous system and glaucoma: From basic science to clinical applications","volume":"72","author":"Faiq","year":"2019","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"197","DOI":"10.4103\/1673-5374.244781","article-title":"Evidence on neuroprotective properties of coenzyme Q10 in the treatment of glaucoma","volume":"14","author":"Martucci","year":"2019","journal-title":"Neural Regen Res."},{"key":"ref_7","first-page":"25","article-title":"Effects of hypoxia and cytidine (5\u2032) diphosphocholine on the concentrations of dopamine, norepinephrine and metabolites in rat hypothalamus and striatum","volume":"285","author":"Saligaut","year":"1987","journal-title":"Arch. Int. Pharm. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/0306-3623(90)90598-G","article-title":"Changes in brain biogenic monoamines induced by the nootropic drugs adafenoxate and meclofenoxate and by citicholine (experiments on rats)","volume":"21","author":"Petkov","year":"1990","journal-title":"Gen. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.brainres.2010.05.073","article-title":"Effect of neurotrophic factors on neuronal apoptosis and neurite regeneration in cultured rat retinas exposed to high glucose","volume":"1346","author":"Oshitari","year":"2010","journal-title":"Brain Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/S0022-510X(03)00204-1","article-title":"Neuroprotective effect of citicoline in 6-hydroxydopamine-lesioned rats and in 6-hydroxydopamine-treated SH-SY5Y human neuroblastoma cells","volume":"215","author":"Barrachina","year":"2003","journal-title":"J. Neurol. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1080\/10623320600934341","article-title":"CDP-choline reduces dopaminergic cell loss induced by MPP(+) and glutamate in primary mesencephalic cell culture","volume":"117","author":"Radad","year":"2007","journal-title":"Int. J. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"8604723","DOI":"10.1155\/2017\/8604723","article-title":"Combination of Neuroprotective and Regenerative Agents for AGE-Induced Retinal Degeneration: In Vitro Study","volume":"2017","author":"Bikbova","year":"2017","journal-title":"Biomed. Res. Int."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3924","DOI":"10.1007\/s12325-021-01771-1","article-title":"Citicoline and Vitamin B(12) Eye Drops in Type 1 Diabetes: Results of a 36-Month Pilot Study Evaluating Macular Electrophysiological Changes","volume":"38","author":"Parisi","year":"2021","journal-title":"Adv. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"28401","DOI":"10.3390\/ijms161226099","article-title":"Cytidine 5\u2019-Diphosphocholine (Citicoline) in Glaucoma: Rationale of Its Use, Current Evidence and Future Perspectives","volume":"16","author":"Roberti","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"919","DOI":"10.2174\/1570159X15666170703111729","article-title":"Citicoline and Retinal Ganglion Cells: Effects on Morphology and Function","volume":"16","author":"Parisi","year":"2018","journal-title":"Curr. Neuropharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Cirilli, I., Damiani, E., Dludla, P.V., Hargreaves, I., Marcheggiani, F., Millichap, L.E., Orlando, P., Silvestri, S., and Tiano, L. (2021). Role of Coenzyme Q10 in Health and Disease: An Update on the Last 10 Years (2010\u20132020). Antioxidants, 10.","DOI":"10.3390\/antiox10081325"},{"key":"ref_17","first-page":"4320408","article-title":"Neuroprotection in Glaucoma: Old and New Promising Treatments","volume":"2017","author":"Rusciano","year":"2017","journal-title":"Adv. Pharmacol. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Manzar, H., Abdulhussein, D., Yap, T.E., and Cordeiro, M.F. (2020). Cellular Consequences of Coenzyme Q10 Deficiency in Neurodegeneration of the Retina and Brain. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21239299"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1017\/S1092852900020538","article-title":"Coenzyme Q10: A review of its promise as a neuroprotectant","volume":"12","author":"Young","year":"2007","journal-title":"CNS Spectr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1016\/j.brainres.2008.06.026","article-title":"Coenzyme Q10 protects retinal cells against oxidative stress in vitro and in vivo","volume":"1226","author":"Nakajima","year":"2008","journal-title":"Brain Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"45","DOI":"10.4103\/1319-4534.301299","article-title":"Coenzyme Q and its role in glaucoma","volume":"34","author":"Ahmad","year":"2020","journal-title":"Saudi J. Ophthalmol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1126\/science.aal0092","article-title":"Vitamin B3 modulates mitochondrial vulnerability and prevents glaucoma in aged mice","volume":"355","author":"Williams","year":"2017","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2509","DOI":"10.1167\/iovs.19-27099","article-title":"Nicotinamide Deficiency in Primary Open-Angle Glaucoma","volume":"60","author":"Guehlouz","year":"2019","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1111\/ceo.13818","article-title":"Improvement in inner retinal function in glaucoma with nicotinamide (vitamin B3) supplementation: A crossover randomized clinical trial","volume":"48","author":"Hui","year":"2020","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Kabir, M.T., Uddin, M.S., Mamun, A.A., Jeandet, P., Aleya, L., Mansouri, R.A., Ashraf, G.M., Mathew, B., Bin-Jumah, M.N., and Abdel-Daim, M.M. (2020). Combination Drug Therapy for the Management of Alzheimer\u2019s Disease. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21093272"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1080\/14656566.2020.1806237","article-title":"Fixed-dose combination therapy for Parkinson\u2019s disease with a spotlight on entacapone in the past 20 years: A reduced pill burden and a simplified dosing regimen","volume":"21","author":"Salamon","year":"2020","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"di Giacomo, V., Chiavaroli, A., Orlando, G., Cataldi, A., Rapino, M., Di Valerio, V., Leone, S., Brunetti, L., Menghini, L., and Recinella, L. (2020). Neuroprotective and Neuromodulatory Effects Induced by Cannabidiol and Cannabigerol in Rat Hypo-E22 cells and Isolated Hypothalamus. Antioxidants, 9.","DOI":"10.3390\/antiox9010071"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Orlando, G., Chiavaroli, A., Adorisio, S., Delfino, D.V., Brunetti, L., Recinella, L., Leone, S., Zengin, G., Acquaviva, A., and Angelini, P. (2021). Unravelling the Phytochemical Composition and the Pharmacological Properties of an Optimized Extract from the Fruit from Prunus mahaleb L.: From Traditional Liqueur Market to the Pharmacy Shelf. Molecules, 26.","DOI":"10.3390\/molecules26154422"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1513","DOI":"10.1002\/ptr.5655","article-title":"An Hydroalcoholic Chamomile Extract Modulates Inflammatory and Immune Response in HT29 Cells and Isolated Rat Colon","volume":"30","author":"Menghini","year":"2016","journal-title":"Phytother. Res."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Gandolfi, S., Marchini, G., Caporossi, A., Scuderi, G., Tomasso, L., and Brunoro, A. (2020). Cytidine 5\u2019-Diphosphocholine (Citicoline): Evidence for a Neuroprotective Role in Glaucoma. Nutrients, 12.","DOI":"10.3390\/nu12030793"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Adornetto, A., Rombol\u00e0, L., Morrone, L.A., Nucci, C., Corasaniti, M.T., Bagetta, G., and Russo, R. (2020). Natural Products: Evidence for Neuroprotection to Be Exploited in Glaucoma. Nutrient, 12.","DOI":"10.3390\/nu12103158"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Fern\u00e1ndez-Vega, B., Nicieza, J., \u00c1lvarez-Barrios, A., \u00c1lvarez, L., Garc\u00eda, M., Fern\u00e1ndez-Vega, C., Vega, J.A., and Gonz\u00e1lez-Iglesias, H. (2020). The Use of Vitamins and Coenzyme Q10 for the Treatment of Vascular Occlusion Diseases Affecting the Retina. Nutrients, 12.","DOI":"10.3390\/nu12030723"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Recinella, L., Chiavaroli, A., di Giacomo, V., Antolini, M.D., Acquaviva, A., Leone, S., Brunetti, L., Menghini, L., Ak, G., and Zengin, G. (2021). Anti-Inflammatory and Neuromodulatory Effects Induced by Tanacetum parthenium Water Extract: Results from In Silico, In Vitro and Ex Vivo Studies. Molecules, 26.","DOI":"10.3390\/molecules26010022"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"30301","DOI":"10.1038\/srep30301","article-title":"Oral CoQ10 attenuates high salt-induced hypertension by restoring neurotransmitters and cytokines in the hypothalamic paraventricular nucleus","volume":"6","author":"Gao","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_35","first-page":"966","article-title":"BDNF enhances retinal ganglion cell survival in cats with optic nerve damage","volume":"42","author":"Chen","year":"2001","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/bs.pbr.2015.05.007","article-title":"Advance in the pathogenesis and treatment of normal-tension glaucoma","volume":"221","author":"Mastropasqua","year":"2015","journal-title":"Prog. Brain Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1272\/jnms.JNMS.2021_88-305","article-title":"Brain-derived Neurotrophic Factor in the Aqueous Humor of Glaucoma Patients","volume":"88","author":"Igarashi","year":"2021","journal-title":"J. Nippon Med. Sch."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"324","DOI":"10.29271\/jcpsp.2019.04.324","article-title":"Comparative Effects of Monosialoganglioside versus Citicoline on Apoptotic Factor, Neurological Function and Oxidative Stress in Newborns with Hypoxic-Ischemic Encephalopathy","volume":"29","author":"Liang","year":"2019","journal-title":"J. Coll Physicians Surg. Pak."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1007\/s12640-018-9971-6","article-title":"Ameliorative Effects of \u03b1-Tocopherol and\/or Coenzyme Q10 on Phenytoin-Induced Cognitive Impairment in Rats: Role of VEGF and BDNF-TrkB-CREB Pathway","volume":"35","author":"Nagib","year":"2019","journal-title":"Neurotox Res."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Zengin, G., Ak, G., Ceylan, R., Uysal, S., Llorent-Mart\u00ednez, E., Di Simone, S.C., Rapino, M., Acquaviva, A., Libero, M.L., and Chiavaroli, A. (2022). Novel Perceptions on Chemical Profile and Biopharmaceutical Properties of Mentha spicata Extracts: Adding Missing Pieces to the Scientific Puzzle. Plants, 11.","DOI":"10.3390\/plants11020233"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1124\/jpet.121.000826","article-title":"Differential Susceptibilities of Catecholamines to Metabolism by Mono-443 amine Oxidases","volume":"379","author":"Goldstein","year":"2021","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"455","DOI":"10.3727\/096504012X13285365944256","article-title":"Coenzyme Q10 decreases basic fibroblast growth factor (bFGF)-induced 445 angiogenesis by blocking ERK activation","volume":"19","author":"Choi","year":"2011","journal-title":"Oncol. Res."},{"key":"ref_43","first-page":"440","article-title":"Combined Use of Nicotinamide and Pyruvate for Neuroenhancement in Open-Angle Glau- 447 coma-Reply","volume":"140","author":"Liebmann","year":"2022","journal-title":"JAMA Ophthalmol."},{"key":"ref_44","first-page":"440","article-title":"Combined Use of Nicotinamide and Pyruvate for Neuroenhancement in Open-Angle Glau- 449 coma","volume":"140","author":"Wong","year":"2022","journal-title":"JAMA Ophthalmol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2959","DOI":"10.1007\/s12035-020-01926-1","article-title":"The Role of Mitochondria in Neurodegenerative Diseases: The Lesson from Alzheimer\u2019s Disease and Parkinson\u2019s Disease","volume":"57","author":"Corti","year":"2020","journal-title":"Mol. Neurobiol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.mito.2019.07.003","article-title":"Mitochondrial dysfunction in neurodegenerative diseases and drug targets via apoptotic signaling","volume":"49","author":"Wu","year":"2019","journal-title":"Mitochondrion"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/14\/2963\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:54:13Z","timestamp":1760140453000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/14\/14\/2963"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,7,20]]},"references-count":46,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2022,7]]}},"alternative-id":["nu14142963"],"URL":"https:\/\/doi.org\/10.3390\/nu14142963","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,20]]}}}