Citrulline – The Powerhouse Nutrient for Cardiometabolic and Brain Health
DOI:
https://doi.org/10.12775/QS.2025.38.58197Keywords
Citrulline, Watermelon juice, Cognitive function, Vascular health, Neuroprotection, Neurodegenerative diseases, Oxidative stressAbstract
Citrulline, a non-essential amino acid and precursor to L-arginine, plays a pivotal role in nitric oxide (NO) synthesis, with profound implications for vascular health and neuroprotection. By enhancing NO production, citrulline supports endothelial function, vasodilation, and cerebral circulation, thereby mitigating cognitive decline associated with aging and neurodegenerative diseases. Unlike direct arginine supplementation, citrulline offers superior bioavailability, bypassing first-pass metabolism and achieving sustained plasma levels of arginine. Furthermore, citrulline's antioxidant properties counteract oxidative stress by modulating reactive oxygen species (ROS), reducing lipid peroxidation, and protecting neuronal integrity. Emerging evidence suggests its potential in delaying endothelial senescence and preventing ferroptosis, establishing its role in vascular and neuroprotective strategies. Dietary sources, such as watermelon juice, further enhance citrulline’s accessibility, combining its bioactivity with additional antioxidants like lycopene. While existing studies underscore its promise, targeted research is needed to confirm its direct impact on cognitive function and explore its application in neurodegenerative populations. This review synthesizes current knowledge on citrulline's mechanisms, therapeutic potential, and broader implications for aging and vascular health.
References
1. Papadia, C., Osowska, S., Cynober, L., & Forbes, A. (2017). Citrulline in health and disease. Review on human studies. Clinical Nutrition, 37(6), 1823–1828. https://doi.org/10.1016/j.clnu.2017.10.009
2. Bahri, S., Zerrouk, N., Aussel, C., Moinard, C., Crenn, P., Curis, E., Chaumeil, J., Cynober, L., & Sfar, S. (2012). Citrulline: From metabolism to therapeutic use. Nutrition, 29(3), 479–484. https://doi.org/10.1016/j.nut.2012.07.002
3. Tsuboi, T., Maeda, M., & Hayashi, T. (2018). Administration of L-arginine plus L-citrulline or L-citrulline alone successfully retarded endothelial senescence. PLoS ONE, 13(2), e0192252. https://doi.org/10.1371/journal.pone.0192252
4. Allerton, T. D., Proctor, D. N., Stephens, J. M., Dugas, T. R., Spielmann, G., & Irving, B. A. (2018). L-Citrulline supplementation: Impact on cardiometabolic health. Nutrients, 10(7), 921. https://doi.org/10.3390/nu10070921
5. Khalaf, D., Krüger, M., Wehland, M., Infanger, M., & Grimm, D. (2019). The effects of oral L-arginine and L-citrulline supplementation on blood pressure. Nutrients, 11(7), 1679. https://doi.org/10.3390/nu11071679
6. Barkhidarian, B., Khorshidi, M., Shab-Bidar, S., & Hashemi, B. (2019). Effects of L-citrulline supplementation on blood pressure: A systematic review and meta-analysis. Avicenna Journal of Phytomedicine, 9(1), 10-20. Retrieved from https://doi.org/10.22038/AJP.2018.11590
7. Gautam, S., Latif, S., & Kang, Y. S. (2024). Effect of various pathological conditions on nitric oxide level and l-citrulline uptake in motor neuron-like (NSC-34) cell lines. Biomolecules & Therapeutics, 32(1), 154-161. https://doi.org/10.4062/biomolther.2023.110
8. Lee, K. E., & Kang, Y. S. (2017). Characteristics of l-citrulline transport through blood-brain barrier in the brain capillary endothelial cell line (TR-BBB cells). Journal of Biomedicine & Biotechnology, 24(1), 28. https://doi.org/10.1186/s12929-017-0336-x
9. Azizi, S., Ebrahimi-Mameghani, M., Mobasseri, M., Karamzad, N., & Mahdavi, R. (2021). Oxidative stress and nitrate/nitrite (NOx) status following citrulline supplementation in type 2 diabetes: A randomised, double-blind, placebo-controlled trial. Journal of Human Nutrition and Dietetics, 34(1), 64-72. https://doi.org/10.1111/jhn.12792
10. Yabuki, Y., Shioda, N., Yamamoto, Y., Shigano, M., Kumagai, K., Morita, M., & Fukunaga, K. (2013). Oral l-citrulline administration improves memory deficits following transient brain ischemia through cerebrovascular protection. Brain Research, 1520, 157-167. https://doi.org/10.1016/j.brainres.2013.04.030
11. Pérez-Neri, I., Ramírez-Bermúdez, J., Ojeda-López, C., Montes, S., Soto-Hernández, J. L., & Ríos, C. (2020). Glutamine and citrulline concentrations reflect nitric oxide synthesis in the human nervous system. Neurologia (Engl Ed), 35(2), 96-104. https://doi.org/10.1016/j.nrl.2017.07.013
12. Matsuo, K., Yabuki, Y., & Fukunaga, K. (2017). Combined l-citrulline and glutathione administration prevents neuronal cell death following transient brain ischemia. Brain Research, 1663, 123-131. https://doi.org/10.1016/j.brainres.2017.03.014
13. Habib, M. R., Tokutake, Y., & Yonekura, S. (2024). Palmitic acid-induced cell death: Impact of endoplasmic reticulum and oxidative stress, mitigated by l-citrulline. Animal Bioscience. https://doi.org/10.5713/ab.24.0249
14. Lee, K. E., & Kang, Y. S. (2018). l-Citrulline restores nitric oxide level and cellular uptake at the brain capillary endothelial cell line (TR-BBB cells) with glutamate cytotoxicity. Microvascular Research, 120, 29-35. https://doi.org/10.1016/j.mvr.2018.05.010
15. Yabuki, Y., Shioda, N., Yamamoto, Y., Shigano, M., Kumagai, K., Morita, M., & Fukunaga, K. (2013). Oral l-citrulline administration improves memory deficits following transient brain ischemia through cerebrovascular protection. Brain Research, 1520, 157-167. https://doi.org/10.1016/j.brainres.2013.04.030
16. Gautam, S., Latif, S., & Kang, Y. S. (2024). Effect of various pathological conditions on nitric oxide level and l-citrulline uptake in motor neuron-like (NSC-34) cell lines. Biomolecules & Therapeutics, 32(1), 154-161. https://doi.org/10.4062/biomolther.2023.110
17. Figueroa, A., Maharaj, A., Kang, Y., Dillon, K. N., Martinez, M. A., Morita, M., Nogimura, D., & Fischer, S. M. (2023). Combined citrulline and glutathione supplementation improves endothelial function and blood pressure reactivity in postmenopausal women. Nutrients, 15(7), 1557. https://doi.org/10.3390/nu15071557
18. Ba, T., Zhao, D., Chen, Y., Zeng, C., Zhang, C., Niu, S., & Dai, H. (2022). L-citrulline supplementation restrains ferritinophagy-mediated ferroptosis to alleviate iron overload-induced thymus oxidative damage and immune dysfunction. Nutrients, 14(21), 4549. https://doi.org/10.3390/nu14214549
19. Barakat, W., Fahmy, A., Askar, M., & El-Kannishy, S. (2018). Effectiveness of arginase inhibitors against experimentally induced stroke. Naunyn-Schmiedeberg's Archives of Pharmacology, 391(6), 603-612. https://doi.org/10.1007/s00210-018-1489-1
20. Rashid, J., Kumar, S. S., Job, K. M., Liu, X., Fike, C. D., & Sherwin, C. M. T. (2020). Therapeutic potential of citrulline as an arginine supplement: A Clinical Pharmacology review. Pediatric Drugs, 22(3), 279–293. https://doi.org/10.1007/s40272-020-00384-5
21. Romero, M. J., Platt, D. H., Caldwell, R. B., & Caldwell, R. W. (2006). Therapeutic use of citrulline in cardiovascular disease. Cardiovascular Drug Reviews, 24(3–4), 275–290. https://doi.org/10.1111/j.1527-3466.2006.00275.x
22. Volino-Souza, M., De Oliveira, G. V., Conte-Junior, C. A., Figueroa, A., & Alvares, T. S. (2022). Current Evidence of Watermelon (Citrullus lanatus) Ingestion on Vascular Health: A Food Science and Technology Perspective. Nutrients, 14(14), 2913. https://doi.org/10.3390/nu14142913
23. Bailey, S. J., Blackwell, J. R., Williams, E., Vanhatalo, A., Wylie, L. J., Winyard, P. G., & Jones, A. M. (2016). Two weeks of watermelon juice supplementation improves nitric oxide bioavailability but not endurance exercise performance in humans. Nitric Oxide, 59, 10–20. https://doi.org/10.1016/j.niox.2016.06.008
24. Ellis, A. C., Mehta, T., Nagabooshanam, V. A., Dudenbostel, T., Locher, J. L., & Crowe-White, K. M. (2021). Daily 100% watermelon juice consumption and vascular function among postmenopausal women: A randomized controlled trial. Nutrition Metabolism and Cardiovascular Diseases, 31(10), 2959–2968. https://doi.org/10.1016/j.numecd.2021.06.022
25. Crowe-White, K. M., Nagabooshanam, V. A., Dudenbostel, T., Locher, J. L., Chavers, T. P., & Ellis, A. C. (2021). 100% Watermelon Juice as a Food-First Intervention to Improve Cognitive Function: Ancillary Findings from a Randomized Controlled Trial. Journal of Nutrition in Gerontology and Geriatrics, 40(4), 304–312. https://doi.org/10.1080/21551197.2021.1988028
26. Burton-Freeman, B., Freeman, M., Zhang, X., Sandhu, A., & Edirisinghe, I. (2021). Watermelon and L-Citrulline in Cardio-Metabolic Health: Review of the Evidence 2000–2020. Current Atherosclerosis Reports, 23(12). https://doi.org/10.1007/s11883-021-00978-5
27. Hrelia, P., Sita, G., Ziche, M., Ristori, E., Marino, A., Cordaro, M., Molteni, R., Spero, V., Malaguti, M., Morroni, F., & Hrelia, S. (2020). Common protective strategies in neurodegenerative disease: Focusing on risk factors to target the cellular redox system. Oxidative Medicine and Cellular Longevity, 2020, 1–18. https://doi.org/10.1155/2020/8363245
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2025 Daria Pedrycz, Mateusz Drabczyk, Emilia Pedrycz, Karolina Karoń, Grzegorz Drapała, Wojciech Grabowski, Łukasz Karoń, Anna Zygmunt, Sławomir Karoń
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
Stats
Number of views and downloads: 156
Number of citations: 0
