Neuroprotective Properties of Naringenin Against 5-Fluorouracil Chemotherapy in an Adult Rat Model
DOI:
https://doi.org/10.5281/zenodo.17999088Keywords:
Naringenin, 5-fluorouracil, Brain, Neurotoxicity, NeuroprotectiveAbstract
Fluorouracil (5-FU), a widely used chemotherapeutic agent, is known to induce oxidative stress and neurotoxicity in addition to its anticancer effects. The aim of our study is to determine the protective effect of naringenin (NAR) with antioxidant capacity against the undesirable effects that 5-FU used against cancer may have on the brain. Twenty-eight adult male Sprague–Dawley rats were randomly assigned to four groups (n = 7 each): control, NAR, 5-FU, and 5-FU + NAR. 150 mg/kg 5-FU was administered intraperitoneally to the 5-FU and 5-FU + NAR groups. 100 mg/kg NAR was administered to the NAR and 5-FU + NAR groups via a gavage catheter. Biochemical analyses performed on brain tissues taken from the animals at the end of the experiment showed that 5-FU increased the levels of brain oxidative stress markers. It was found that glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels decreased and malondialdehyde (MDA) levels increased in brain tissue due to the effect of 5-FU. It was also confirmed that the situation was normalized as a result of the combined application of 5-FU and NAR. Immunohistochemical studies showed that 5-FU increased the expression of caspase 3 and TNF-α in the brain, while NAR, which has antioxidant, antiapoptotic and anti-inflammatory effects, largely inhibited their increase. These findings suggest that NAR may serve as a promising adjunct therapeutic agent to mitigate neurotoxicity associated with 5-FU chemotherapy.
References
Aebi, H., 1984. Catalase in vitro. Methods Enzymology, 105: 121-126.
Aktaş, I., Bilgiç, S., 2025a. Human health and selenium. EJONS, 9(2): 153-169.
Aktaş, I., Bilgiç, S., 2025b. Lutein’s protection against cisplatin’s pulmonary toxicity. EJONS, 9(2): 170-177.
Aktaş, I., Bilgiç, S., Gür, F.M., 2025. Protection of naringenin against 5-fluorouracil toxicity in the liver. Tissue and Cell, 96: 103023.
Aktaş, I., Gur, F.M., Martínez, J.L., Bilgiç, S., Körkoca. H., 2024b. Protective effects of silymarin against paclitaxel-induced cardiac toxicity. Bol Latinoam Caribe Plant Med Aromat, 23(5): 749-759.
Aktaş, I., Gür, F.M., Bilgiç, S., 2024a. Protective effect of misoprostol against paclitaxel- induced cardiac damage in rats. Prostaglandins & Other Lipid Mediators, 171: 106813.
Arafah, A., Rehman, M.U., Ahmad, A., AlKharfy, K.M., Alqahtani, S., Jan, B.L., Almatroudi, N.M., 2022. Myricetin (3,3′,4′,5,5′,7- Hexahydroxyflavone) prevents 5-fluorouracil-induced cardiotoxicity. ACS Omega, 7(5): 4514-4524.
Ashok, I., Sheeladevi, R., 2014. Biochemical responses and mitochondrial mediated activation of apoptosis on long-term effect of aspartame in rat brain. Redox Biol, 2: 820-831.
Azirak, S., Bilgic, S., Tastemir Korkmaz, D., Armağan, I., Ozer, M.K., 2025. Thymoquinone prevents valproic acid-induced hepatotoxicity via modulation of cytochrome P450, PPARs, and apoptotic pathways. Iranian Journal of Basic Medical Sciences, 28(7): 899-906.
Azirak, S., Bilgic, S., Tastemir Korkmaz, D., Güvenc, A.N., Kocaman, N., Ozer, M.K., 2019. The protective effect of resveratrol against risperidone-induced liver damage through an action on FAS gene expression. Gen Physiol Biophys, 38: 215-225.
Bilgic, S., Tastemir Korkmaz, D., Azirak, S., Güvenc, A.N., Kocaman, N., Ozer, M.K., 2018. Olanzapine-induced renal damages and metabolic side effects: the protective effects of thymoquinone. Journal of Turgut Ozal Medical Center, 25(1): 70-5.
Bilgiç, S., Aktaş. I., 2022. Investigation of protective effects of misoprostol against paclitaxel- induced ovarian damage in rats. Annals of Medical Research, 29(3): 233-239.
Bilgiç, S., Gür, F.M., Aktaş. I., 2022. Biochemical and histopathological investigation of the protective effect of lutein in rat kidney exposed to cisplatin. Medical Records- International Medical Journal, 4(3): 433-438.
Bilgiç, S., Özgöçmen, M., Ozer, M.K., 2023. Thymoquinone ameliorates amikacin induced oxidative damage in rat brain tissue. Biotechnic & Histochemistry, 98(1): 38-45.
Chandran, A.M.K., Christina, H., Das, S., Mumbrekar, K.D., Rao, B.S., 2019. Neuroprotective role of naringenin against methylmercury induced cognitive impairment and mitochondrial damage in a mouse model. Environmental Toxicology and Pharmacology, 71: 103224.
Chen, D., Chen, M.S., Cui, Q.C., Yang, H., Dou, Q.P., 2007. Structure-proteasome-inhibitory activity relationships of dietary flavonoids in human cancer cells. Front Biosci, 12(1): 1935-45.
Dietrich, J., Han, R., Yang, Y., Mayer-Pröschel, M., Noble, M., 2006. CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. Journal of Biology, 5: 22.
Draper, H.H., Hadley. M., 1990. Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol, 186: 421-431.
ELBeltagy, M., Mustafa, S., Umka, J., Lyons, L., Salman, A., Dormon, K., Wigmore, P., 2012. The effect of 5-fluorouracil on the long term survival and proliferation of cells in the rat hippocampus. Brain Research Bulletin, 88(5): 514-518.
ELBeltagy, M., Mustafa, S., Umka, J., Lyons, L., Salman, A., Tu, C.Y.G., Wigmore, P.M., 2010. Fluoxetine improves the memory deficits caused by the chemotherapy agent 5-fluorouracil. Behavioural Brain Research, 208(1): 112-117.
Ellman, G.L., 1959. Tissue sulfhydryl groups. Archives of Biochemistry and Biophysics, 82(1): 70-77.
Formica, V., Leary, A., Cunningham, D., Chua. Y.J., 2006. 5-fluorouracil can cross brainblood barrier and cause encephalopathy: should we expect the same from capecitabine? A case report on capecitabine-induced central neurotoxicity progressing to coma, cancer chemother. Pharmacol, 58(2): 276-278.
Ghofrani, S., Joghataei, M. T., Mohseni, S., Baluchnejadmojarad, T., Bagheri, M., Khamse, S., Roghani, M., 2015. Naringenin improves learning and memory in an Alzheimer's disease rat model: Insights into the underlying mechanisms. European Journal of Pharmacology, 764: 195-201.
Gur, F.M., 2022. Immunoexpression of androgen receptor in genital tissues of male balb/c mice. Annals of Medical Research, 29: 1049-1053.
Gur, F.M., Aktas, I., 2020. The localization of er alpha and er beta in rat testis and epididymis. Annals of Medical Research, 27: 2534-2539.
Gur, F.M., Timurkaan, S., 2012. Effects of prepubertal epididymal ligation on the androgen receptor distribution of the rat testis. Anal Quant Cytopathol Histpathol, 34(6): 317-24.
Gür, F.M., Bilgiç, S., 2022. A synthetic prostaglandin E1 analogue, misoprostol, ameliorates paclitaxel-induced oxidative damage in rat brain. Prostaglandins & Other Lipid Mediators, 162: 106663.
Gür, F.M., Bilgiç, S., Aktaş, I., 2025. Lutein, a non-provitamin a carotenoid, reduces cisplatin- induced cardiotoxicity. Prostaglandins & Other Lipid Mediators, 177: 106965.
Han, R., Yang, Y.M., Dietrich, J., Luebke, A., Mayer-Pröschel, M., Noble, M., 2008. Systemic 5-fluorouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system. Journal of Biology, 7(4): 12.
Il’yasova, D., Kennedy, K., Spasojevic, I., Wang, F., Tolun, A.A., Base, K., Dewhirst, M.W., 2011. Individual responses to chemotherapy-induced oxidative stress. Breast Cancer Research and Treatment, 125(2): 583-589.
Iraz, M., Bilgic, S., Samdanci, E., Ozerol, E., Tanbek, K., 2015. Preventive and early therapeutic effects of β-glucan on the bleomycin-induced lung fibrosis in rats. European Review for Medical & Pharmacological Sciences, 19(8).
Lowry, O.H., Rosebrough, N.J., Farr, A.L., Randall, R.J., 1951. Protein measurement with the folin phenol reagent. Journal of Biological Chemistry, 193(1): 265-275.
Mansour, L.A., Elshopakey, G.E., Abdelhamid, F.M., Albukhari, T.A., Almehmadi, S.J., Refaat, B., Risha, E.F., 2023. Hepatoprotective and neuroprotective effects of naringenin against lead-induced oxidative stress, inflammation, and apoptosis in rats. Biomedicines, 11(4): 1080.
Marklund, S., Marklund, G., 1974. Involvement of the superoxide anion radical in the autoxidation of pyrogallol and a convenient assay for superoxide dismutase. Journal of Cellular Physiology, 47(3): 469-474.
Mihlon, F., Ray, C.E.J., Messersmith, W., 2010. Chemotherapy agents: a primer for the interventional radiologist. Semin Intervent Radiol, 27(4): 384-90.
Mir, I.A., Tiku, A.B., 2015. Chemopreventive and therapeutic potential of “naringenin,” a favanone present in citrus fruits. Nutrition and Cancer, 67: 27-42.
Mustafa, S., Walker, A., Bennett, G., Wigmore, P.M., 2008. 5-fluorouracil chemotherapy affects spatial working memory and newborn neurons in the adult rat hippocampus. European Journal of Neuroscience, 28(2): 323-330.
Raafat, R.S., Habib, M.Z., AbdElfattah, A.A., Olama, N.K., Abdelraouf, S.M., Hendawy, N., Aboul-Fotouh, S., 2023. Amisulpride attenuates 5-fluorouracil-induced cognitive deficits via modulating hippocampal Wnt/GSK-3β/β-catenin signaling in Wistar rats. International Immunopharmacology, 124: 110945.
Sadek, K.M., Lebda, M.A., Abouzed, T.K., Nasr, S.M., El-Sayed, Y., 2018. The molecular and biochemical insight view of lycopene in ameliorating tramadol-induced liver toxicity in a rat model: Implication of oxidative stress, apoptosis, and MAPK signaling pathways. Environmental Science and Pollution Research International, 25(33): 33119-30.
Spencer, J.P., 2008. Food for thought: The role of dietary flavonoids in enhancing human memory, learning and neuro-cognitive performance: Symposium on ‘diet and mental health’. Proceedings of the Nutrition Society, 67: 238-52.
Uzkeser, H., Sener, E., Bakan, E., Hacimuftuoglu, A., 2012. Preventive role of mirtazapine in methotrexate induced nephrotoxicity in rats. Scienceasia, 38: 129-135.
Wali, A.F., Rashid, S., Rashid, S.M., Ansari, M.A., Khan, M.R., Haq, N., Rehman, M.U., 2020. Naringenin regulates doxorubicin-induced liver dysfunction: impact on oxidative stress and inflammation. Plants, 9(4): 550.
Welbat, J.U., Chaisawang, P., Pannangrong, W., Wigmore, P., 2018. Neuroprotective properties of asiatic acid against 5-fluorouracil chemotherapy in the hippocampus in an adult rat model. Nutrients, 10: 1053.
Youdim, K.A., Dobbie, M.S., Kuhnle, G., Proteggente, A.R., Abbott, N.J., Rice‐Evans, C., 2003. Interaction between flavonoids and the blood–brain barrier: in vitro studies. Journal of neurochemistry, 85(1): 180-192.
Zeweil, M.M., Sadek, K.M., Elsadek, M.F., Mahmoud, S.F., Ahmed, B.M., Khafaga, A.F., 2020. Sidr honey abrogates the oxidative stress and downregulates the hyaluronic acid concentration and gene expression of TGF‐β1 and COL1a1 in rat model of thioacetamide‐induced hepatic fibrosis. Animal Science Journal, 91(1): e13434.
Zhang, Y., Yin, N., Liang, S., Shen, S., Li, D., Faiola, F., 2019. 5-fluorouracil-induced neurotoxicity in rat cerebellum granule cells involves oxidative stress and activation of caspase-3 pathway. International Journal of Clinical and Experimental Medicine, 12(3): 2334-2343.
Zhou, P., Wang, Z., Chen, C., Famurewa, A.C., Olatunji, O.J., 2023. Naringin ameliorates 5- fluorouracil elicited neurotoxicity by curtailing oxidative stress and iNOS/NF- ĸB/caspase-3 pathway. Open Chemistry, 21(1): 20230126.
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