Effect of cytidine-5′-diphosphocholine alone, caffeine or their combination on oxidative stress and inflammatory response in an experimentally-induced Parkinson’s disease
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Soha Mohamed Hamdy
Abstract
Objectives
To investigate the effect of orally administered cytidine-5′-diphosphocholine (citicholine) (50,100,200 mg/kg), α-tocopherol (Vit E; 25 mg/kg), caffeine (10 mg/kg), L-dopa (25 mg/kg) or the combination of Vit E, caffeine with citicholine (100 mg/kg) on nigrostriatal neuronal damage induced in the mice brain by subcutaneous (s.c.) rotenone.
Methods
Swiss male mice received rotenone (1.5 mg/kg, s.c, three times per week) alone or with other drugs for 2 weeks. Mice were evaluated for brain malondialdehyde (MDA), reduced glutathione (GSH), and nitric oxide (NO), paraoxonase-1 (PON-1), acetylcholinesterase (ACHE), interlukin-1beta (IL-1β), nuclear factor kappa B (NF-κB) and monocyte chemoattractant protein (MCP-1). Histopathologic examination was also done.
Results
Cticholine co-treatment at 50, 100 or 200 mg/kg significantly decreased brain MDA and increased PON-1 activity in a dose-dependent manner. When given at 200 mg/kg, it also significantly decreased NO production, while at 100 and 200 mg/kg significantly increased GSH brain. MCP-1 significantly decreased upon treatment with 100 or 200 mg/kg of citicholine. IL-1 β and NF-κB significantly decreased and AChE significantly increased by 200 mg/kg citicholine. Oxidative stress and inflammatory biomarkers also showed favorable changes after Vit E, caffeine or L-dopa. However, the combination of Vit E and/or caffeine with 100 mg/kg citicholine was not superior to that of only citicholine at 100 or 200 mg/kg.
Conclusions
Citicholine is neuroprotective in acute rotenone nigrostriatal degeneration via antioxidant and anti-inflammatory properties. It is suggested that citicholine may have a role in treatment of Parkinson’s disease by decreasing neuro-inflammation and oxidative stress, preventing the development of neuronal damage.
Funding source: Egyptian Academy of Scientific Research and Technology
Award Identifier / Grant number: Next Generation Scholars Program
Acknowledgments
We thank all the participants.
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Research ethics: The local committee (Fayoum University) approved the design of the experiments, and the protocol conforms to its guidelines of with approval number (AEC 2339-a).
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Informed consent: Not applicable.
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Author contributions: S.H and O.A.S designed the study and supervised the research. N.A.E, H.M.R.E. and E.R.Y. conducted the experiments and analysis. N.A.E and O.A.S. wrote the manuscript. All authors revised the manuscript.
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Use of Large Language Models, AI and Machine Learning Tools: Not applicable.
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Conflict of interests: None.
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Research funding: This research was funded by the Egyptian Academy of Scientific Research and Technology.
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Data availability: All data are included in the study.
References
1. Van Den Eeden, SK, Tanner, CM, Bernstein, AL, Fross, RD, Leimpeter, A, Bloch, DA, et al.. Incidence of Parkinson’s disease: variation by age, gender, and race/ethnicity. Am J Epidemiol 2003;157:1015–22. https://doi.org/10.1093/aje/kwg068.Search in Google Scholar PubMed
2. Jellinger, KA. Recent developments in the pathology of Parkinson’s disease. J Neural Transm Suppl 2002:347–76. https://doi.org/10.1007/978-3-7091-6139-5_33.Search in Google Scholar PubMed
3. Ramesh, S, Arachchige, ASPM. Depletion of dopamine in Parkinson’s disease and relevant therapeutic options: a review of the literature. AIMS Neurosci 2023;10:200–31. https://doi.org/10.3934/Neuroscience.2023017.Search in Google Scholar PubMed PubMed Central
4. Groenewegen, HJ. The basal ganglia and motor control. Neural Plast 2003;10:107–20. https://doi.org/10.1155/NP.2003.107.Search in Google Scholar PubMed PubMed Central
5. Munhoz, RP, Tumas, V, Pedroso, JL, Silveira-Moriyama, L. The clinical diagnosis of Parkinson’s disease. Arq Neuropsiquiatr 2024;82:1–10. https://doi.org/10.1055/s-0043-1777775.Search in Google Scholar PubMed PubMed Central
6. Wirdefeldt, K, Adami, HO, Cole, P, Trichopoulos, D, Mandel, J. Epidemiology and etiology of Parkinson’s disease: a review of the evidence. Eur J Epidemiol 2011;26:S1–58. https://doi.org/10.1007/s10654-011-9581-6.Search in Google Scholar PubMed
7. Drechsel, DA, Patel, M. Role of reactive oxygen species in the neurotoxicity of environmental agents implicated in Parkinson’s disease. Free Radic Biol Med 2008;44:1873–86. https://doi.org/10.1016/j.freeradbiomed.2008.02.008.Search in Google Scholar PubMed PubMed Central
8. Priyadarshi, A, Khuder, SA, Schaub, EA, Priyadarshi, SS. Environmental risk factors and Parkinson’s disease: a metaanalysis. Environ Res 2001;86:122–7. https://doi.org/10.1006/enrs.2001.4264.Search in Google Scholar PubMed
9. Nagatsu, T, Sawada, M. Inflammatory process in Parkinson’s disease: role for cytokines. Curr Pharmaceut Des 2005;11:999–1016. https://doi.org/10.2174/1381612053381620.Search in Google Scholar PubMed
10. Greenamyre, JT, Cannon, JR, Drolet, R, Mastroberardino, PG. Lessons from the rotenone model of Parkinson’s disease. Trends Pharmacol Sci 2010;31:141–2. author reply 142-3. https://doi.org/10.1016/j.tips.2009.12.006.Search in Google Scholar PubMed PubMed Central
11. Liu, HQ, Zhu, XZ, Weng, EQ. Intracellular dopamine oxidation mediates rotenone-induced apoptosis in PC12 cells. Acta Pharmacol Sin 2005;26:17–26. https://doi.org/10.1111/j.1745-7254.2005.00003.x.Search in Google Scholar PubMed
12. Poewe, W, Antonini, A, Zijlmans, JC, Burkhard, PR, Vingerhoets, F. Levodopa in the treatment of Parkinson’s disease: an old drug still going strong. Clin Interv Aging 2010;5:229–38. https://doi.org/10.2147/cia.s6456.Search in Google Scholar PubMed PubMed Central
13. Connolly, BS, Lang, AE. Pharmacological treatment of Parkinson disease: a review. JAMA 2014;311:1670–83. https://doi.org/10.1001/jama.2014.3654.Search in Google Scholar PubMed
14. Perez-Lloret, S, Negre-Pages, L, Damier, P, Delval, A, Derkinderen, P, Destée, A, et al., Of the COPARK Study Group. L-DOPA-induced dyskinesias, motor fluctuations and health-related quality of life: the COPARK survey. Eur J Neurol 2017;24:1532–8. https://doi.org/10.1111/ene.13466.Search in Google Scholar PubMed
15. Abdel-Salam, OME. Drug therapy for Parkinson’s disease: an update. World J Pharmacol 2015;4:117–43. https://doi.org/10.5497/wjp.v4.i1.117.Search in Google Scholar
16. García-Cobos, R, Frank-García, A, Gutiérrez-Fernández, M, Díez-Tejedor, E. Citicoline, use in cognitive decline: vascular and degenerative. J Neurol Sci 2010;299:188–92. https://doi.org/10.1016/j.jns.2010.08.027.Search in Google Scholar PubMed
17. Ribeiro, JA, Sebastião, AM. Caffeine and adenosine. J Alzheimers Dis 2010;20:S3–15. https://doi.org/10.3233/JAD-2010-1379.Search in Google Scholar PubMed
18. Schepici, G, Silvestro, S, Bramanti, P, Mazzon, E. Caffeine: an overview of its beneficial effects in experimental models and clinical trials of Parkinson’s disease. Int J Mol Sci 2020;21:4766. https://doi.org/10.3390/ijms21134766.Search in Google Scholar PubMed PubMed Central
19. Ruiz-Larrea, MB, Leal, AM, Liza, M, Lacort, M, de Groot, H. Antioxidant effects of estradiol and 2-hydroxyestradiol on iron-induced lipid peroxidation of rat liver microsomes. Steroids 1994;59:383–8. https://doi.org/10.1016/0039-128x(94)90006-x.Search in Google Scholar PubMed
20. Eckerson, HW, Wyte, CM, La Du, BN. The human serum paraoxonase/arylesterase polymorphism. Am J Hum Genet 1983;35:1126–38.Search in Google Scholar
21. Abdel-Salam, OME, Omara, EA, El-Shamarka, MES, Hussein, J. Nigrostriatal damage after systemic rotenone and/or lipopolysaccharide and the effect of cannabis. Comp Clin Pathol 2014;23:1343–58. https://doi.org/10.1007/s00580-013-1788-3.Search in Google Scholar
22. Radad, K, Rausch, WD, Gille, G. Rotenone induces cell death in primary dopaminergic culture by increasing ROS production and inhibiting mitochondrial respiration. Neurochem Int 2006;49:379–86. https://doi.org/10.1016/j.neuint.2006.02.003.Search in Google Scholar PubMed
23. Xiong, ZK, Lang, J, Xu, G, Li, HY, Zhang, Y, Wang, L, et al.. Excessive levels of nitric oxide in rat model of Parkinson’s disease induced by rotenone. Exp Ther Med 2015;9:553–8. https://doi.org/10.3892/etm.2014.2099.Search in Google Scholar PubMed PubMed Central
24. Abdel-Salam, OME, Youness, ER, Ahmed, NA, El-Toumy, SA, Souleman, AMA, Shaffie, N, et al.. Bougainvillea spectabilis flowers extract protects against the rotenone-induced toxicity. Asian Pac J Tropical Med 2017;10:478–90. https://doi.org/10.1016/j.apjtm.2017.05.013.Search in Google Scholar PubMed
25. Turrens, JF. Mitochondrial formation of reactive oxygen species. J Physiol 2003;552:335–44. https://doi.org/10.1113/jphysiol.2003.049478.Search in Google Scholar PubMed PubMed Central
26. Grivennikova, VG, Vinogradov, AD. Generation of superoxide by the mitochondrial Complex I. Biochim Biophys Acta 2006;1757:553–61. https://doi.org/10.1016/j.bbabio.2006.03.013.Search in Google Scholar PubMed
27. Li, N, Ragheb, K, Lawler, G, Sturgis, J, Rajwa, B, Melendez, JA, et al.. Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J Biol Chem 2003;278:8516–25. https://doi.org/10.1074/jbc.M210432200.Search in Google Scholar PubMed
28. Brown, GC. Nitric oxide and neuronal death. Nitric Oxide 2010;23:153–65. https://doi.org/10.1016/j.niox.2010.06.001.Search in Google Scholar PubMed
29. Wink, DA, Feelisch, M, Vodovotz, Y, Fukuto, J, Grisham, MB. The chemical biology of nitric oxide. In: Reactive oxygen species in biological systems (G Colton). New York, NY, USA: Kluwer Academic/Plenum Publishers; 1999:245–91 pp.10.1007/0-306-46806-9_10Search in Google Scholar
30. Badawi, HM, Abdelsalam, RM, Abdel-Salam, OM, Youness, ER, Shaffie, NM, Eldenshary, EDS. Bee venom attenuates neurodegeneration and motor impairment and modulates the response to L-dopa or rasagiline in a mice model of Parkinson’s disease. Iran J Basic Med Sci 2020;23:1628–38. https://doi.org/10.22038/ijbms.2020.46469.10731.Search in Google Scholar PubMed PubMed Central
31. La Du, BN. Human serum paraoxonase/arylesterase. In: Kalow, W, editors. Pharmacogenetics of Drug Metabolism, New York: Pergamon; 1992:51–91 pp.Search in Google Scholar
32. Li, WF, Costa, LG, Richter, RJ, Hagen, T, Shih, DM, Tward, A, et al.. Catalytic efficiency determines the in-vivo efficacy of PON1 for detoxifying organophosphorus compounds. Pharmacogenetics 2000;10:767–79. https://doi.org/10.1097/00008571-200012000-00002.Search in Google Scholar PubMed
33. Narayan, S, Liew, Z, Paul, K, Lee, PC, Sinsheimer, JS, Bronstein, JM, et al.. Household organophosphorus pesticide use and Parkinson’s disease. Int J Epidemiol 2013;42:1476–85. https://doi.org/10.1093/ije/dyt170.Search in Google Scholar PubMed PubMed Central
34. Ng, DS, Chu, T, Esposito, B, Hui, P, Connelly, PW, Gross, PL. Paraoxonase-1 deficiency in mice predisposes to vascular inflammation, oxidative stress, and thrombogenicity in the absence of hyperlipidemia. Cardiovasc Pathol 2008;17:226–32. https://doi.org/10.1016/j.carpath.2007.10.001.Search in Google Scholar PubMed
35. Nguyen, SD, Sok, DE. Preferential inhibition of paraoxonase activity of human paraoxonase 1 by negatively charged lipids. J Lipid Res 2004;45:2211–20. https://doi.org/10.1194/jlr.M400144-JLR200.Search in Google Scholar PubMed
36. Aosaki, T, Miura, M, Suzuki, T, Nishimura, K, Masuda, M. Acetylcholine-dopamine balance hypothesis in the striatum: an update. Geriatr Gerontol Int 2010;10:S148–57. https://doi.org/10.1111/j.1447-0594.2010.00588.x.Search in Google Scholar PubMed
37. Fox, SH. Non-dopaminergic treatments for motor control in Parkinson’s disease. Drugs 2013;73:1405–15. https://doi.org/10.1007/s40265-013-0105-4. Erratum in: Drugs. 2014;74(11):1305.Search in Google Scholar PubMed
38. Secades, JJ. Citicoline: pharmacological and clinical review, 2010 update. Rev Neurol 2011;52:S1–62.Search in Google Scholar
39. Alvarez-Sabín, J, Román, GC. Citicoline in vascular cognitive impairment and vascular dementia after stroke. Stroke 2011;42:S40–3. https://doi.org/10.1161/STROKEAHA.110.606509.Search in Google Scholar PubMed
40. Gutiérrez-Fernández, M, Rodríguez-Frutos, B, Fuentes, B, Vallejo-Cremades, MT, Alvarez-Grech, J, Expósito-Alcaide, M, et al.. CDP-choline treatment induces brain plasticity markers expression in experimental animal stroke. Neurochem Int 2012;60:310–7. https://doi.org/10.1016/j.neuint.2011.12.015.Search in Google Scholar PubMed
41. Gareri, P, Castagna, A, Cotroneo, AM, Putignano, S, De Sarro, G, Bruni, AC. The role of citicoline in cognitive impairment: pharmacological characteristics, possible advantages, and doubts for an old drug with new perspectives. Clin Interv Aging 2015;10:1421–9. https://doi.org/10.2147/CIA.S87886.Search in Google Scholar PubMed PubMed Central
42. Devasagayam, TP, Kamat, JP, Mohan, H, Kesavan, PC. Caffeine as an antioxidant: inhibition of lipid peroxidation induced by reactive oxygen species. Biochim Biophys Acta 1996;1282:63–70. https://doi.org/10.1016/0005-2736(96)00040-5.Search in Google Scholar PubMed
43. Sonsalla, PK, Wong, LY, Harris, SL, Richardson, JR, Khobahy, I, Li, W, et al.. Delayed caffeine treatment prevents nigral dopamine neuron loss in a progressive rat model of Parkinson’s disease. Exp Neurol 2012;234:482–7. https://doi.org/10.1016/j.expneurol.2012.01.022.Search in Google Scholar PubMed PubMed Central
44. Metro, D, Cernaro, V, Santoro, D, Papa, M, Buemi, M, Benvenga, S, et al.. Beneficial effects of oral pure caffeine on oxidative stress. J Clin Transl Endocrinol 2017;10:22–7. https://doi.org/10.1016/j.jcte.2017.10.001.Search in Google Scholar PubMed PubMed Central
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