Idebenone protects against ethanol toxicity in HT-22 cells through strengthening neuroimmune response

Year 2023, , 121 - 128, 30.08.2023

Betul Cicek

https://doi.org/10.31797/vetbio.1305675

Abstract

Idebenone, an analogue of coenzyme Q10, may function as a neuroprotective agent with its antioxidant and anti-inflammatory properties. The current report was designed to examine the beneficial effects of idebenone on ethanol-related neurotoxicity in hippocampal neuronal HT-22 cells in vitro and annotate the neuroprotective mechanism of idebenone. 75 mM ethanol was applied to the cells for 24h to develop ethanol toxicity. Then, different concentrations of idebenone (final concentration in the well to be 1, 2.5, and 5 μM) were applied to HT-22 cells for 24 h to explore the protective impact against ethanol-induced hippocampal damage. Cell viability was evaluated with MTT test. MDA, SOD, and GSH concentrations were examined to interpret oxidative damage. Moreover, the effects of idebenone on IL-1β, IL-6, and IL-23 neuroimmune-related genes expression levels were assigned by the RT-PCR analysis. In our study, 75 mM ethanol decreased neuronal cell viability by approximately 61%. All concentrations of idebenone were not toxic to neurons. In addition, idebenone increased cell viability by reducing the damage caused by alcohol. Idebenone reversed the reduction in antioxidant capacity caused by ethanol through decreasing MDA and increasing SOD and GSH levels. In addition, idebenone attenuated ethanol-induced impairment in neuroimmune and neuroinflammatory responses by reducing IL-1β, IL-6, and IL-23 mRNA expression levels. Treatment with idebenone increased antioxidant capacity and a significant improvement was achieved in neuroimmune and neuroinflammatory parameters. Possible mechanisms underlying these beneficial effects cover the down-regulation of IL-1β, IL-6, and IL-23 receptors, and antioxidant restoration of idebenone.

Keywords

Ethanol toxicity, HT-22, Idebenone, Neuroimmunity, Oxidative damage

Supporting Institution

The authors disclosed that they did not receive any grant during conduction or writing of this study

Project Number

Not applicable.

Thanks

Not applicable.

References

• Alfonso-Loeches, S., Urena-Peralta, J., Morillo-Bargues, M. J., Gómez-Pinedo, U., & Guerri, C. (2016). Ethanol-induced TLR4/NLRP3 neuroinflammatory response in microglial cells promotes leukocyte infiltration across the BBB. Neurochemical Research, 41, 193-209. https://doi. org/10.1007/s11064-015-1760-5
• AshaRani, P. V., Karuvetil, M. Z., Brian, T. Y. W., Satghare, P., Roystonn, K., Peizhi, W., Cetty, L., Zainuldin, N. A., & Subramaniam, M. (2022). Prevalence and correlates of physical comorbidities in alcohol use disorder (AUD): A pilot study in treatment-seeking population. International Journal of Mental Health and Addiction, 23, 1-18. https://doi. org/10.1007/ s11469-021-00734-5
• Bailey, C. S., Jagielo-Miller, J. E., Keller, P. S., Glaser, E. P., Wilcox, A. L., & Prendergast, M. A. (2022). Ethanol sustains phosphorylated tau protein in the cultured neonatal rat hippocampus: Implications for fetal alcohol spectrum disorders. Alcohol, 103, 45-54. https://doi.org/10.1016/j.alcohol.2022.07.007
• Belhorma, K., Darwish, N., Benn-Hirsch, E., Duenas, A., Gates, H., Sanghera, N., Wu, J., & French, R. L. (2021). Developmental ethanol exposure causes central nervous system dysfunction and may slow the aging process in a Drosophila model of fetal alcohol spectrum disorder. Alcohol, 94, 65-73. https://doi. org/10.1016/j.alcohol.2021.03.006
• Bhowmick, S., Alikunju, S., & Abdul-Muneer, P. M. (2022). NADPH oxidase-induced activation of transforming growth factor-beta-1 causes neuropathy by suppressing antioxidant signaling pathways in alcohol use disorder. Neuropharmacology, 213, 1-13. https://doi.org/10.1016/j.neuropharm.2022.109136
• Cicek, B., Hacimuftuoglu, A., Yeni, Y., Danisman, B., Ozkaraca, M., Mokhtare, B., Kantarci, M., Spanakis, M., Nikitovic,D., Lazopoulos, G., Tsarouhas, K., Tsatsakis A., & Taghizadehghalehjoughi, A. (2023). Chlorogenic acid attenuates doxorubicin-induced oxidative stress and markers of apoptosis in cardiomyocytes via Nrf2/HO-1 and dityrosine signaling. Journal of Personalized Medicine, 13(4), 649-675. https://doi.org/10.3390/jmp13040649 Coleman Jr, L. G., Zou, J., Qin, L., & Crews, F. T. (2018). HMGB1/IL-1β complexes regulate neuroimmune responses in alcoholism. Brain, Behavior, and Immunity, 72, 61-77. https://doi.org/10. 1016/j.bbi.2017.10.027
• Crews, F. T., Sarkar, D. K., Qin, L., Zou, J., Boyadjieva, N., & Vetreno, R. P. (2015). Neuroimmune function and the consequences of alcohol exposure. Alcohol Research: Current Reviews, 37(2): 331–351.
• Dukay, B., Walter, F. R., Vigh, J. P., Barabási, B., Hajdu, P., Balassa, T., Migh, E., Kincses, A., Hoyk, Z., Szögi, T., Borbély, E., Csoboz, B., Horváth, P., Fülöp, L., Penke, B., Vígh, L., Deli, A.M., Sántha, M., & Tóth, M. E. (2021). Neuroinflammatory processes are augmented in mice overexpressing human heat-shock protein B1 following ethanol-induced brain injury, Journal of Neuroinflammation, 18(1), 22-46. https://doi. org/1-24.0.1186/s12974-020-02070-2
• Erickson, E. K., Grantham, E. K., Warden, A. S., & Harris, R. A. (2019). Neuroimmune signaling in alcohol use disorder. Pharmacology Biochemistry and Behavior, 177, 34-60. https://doi.org/10.1016/j.pbb. 2018.12.007
• Ferah Okkay, I., Okkay, U., Cicek, B., Yilmaz, A., Yesilyurt, F., Mendil, A. S., & Hacimuftuoglu, A. (2021). Neuroprotective effect of bromelain in 6-hydroxydopamine induced in vitro model of Parkinson’s disease. Molecular Biology Reports, 48, 7711-7717. https://doi.org/10.1007/s11033-021-06779-y Gano, A., Pautassi, R. M., Doremus-Fitzwater, T. L., & Deak, T. (2017). Conditioned effects of ethanol on the immune system. Experimental Biology and Medicine, 242(7), 718-730. https://doi.org/10.1177/1535370217694097
• Gano, A., Pautassi, R. M., Doremus-Fitzwater, T. L., Barney, T. M., Vore, A. S., & Deak, T. (2019). Conditioning the neuroimmune response to ethanol using taste and environmental cues in adolescent and adult rats. Experimental Biology and Medicine, 244(5), 362-371. https://doi.org/10.1177/1535370219831709
• Gorky, J., & Schwaber, J. (2016). The role of the gut–brain axis in alcohol use disorders. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 65, 234-241. https://doi.org/10.1016/j.pnpbp.2015.06.013
• Gueven, N., Woolley, K., & Smith, J. (2015). Border between natural product and drug: Comparison of the related benzoquinones idebenone and coenzyme Q10. Redox Biology, 4, 289-295. https://doi.org/10.1016/j.redox .2015.01.009
• Jaber, S. M., Shealinna, X. G., Milstein, J. L., VanRyzin, J. W., Waddell, J., & Polster, B. M. (2020). Idebenone has distinct effects on mitochondrial respiration in cortical astrocytes compared to cortical neurons due to differential NQO1 activity. Journal of Neuroscience, 40(23), 4609-4619. https://doi.org/ 10.1523/JNEUROSCI.1632-17.2020
• Kelley, K. W., & Dantzer, R. (2011). Alcoholism and inflammation: Neuroimmunology of behavioral and mood disorders. Brain, Behavior, and Immunity, 25(1), 13-20. https://doi.org/10.1016/j.bbi.2010.12.013
• Lee, H. J., Park, J. H., & Hoe, H. S. (2022). Idebenone regulates Aβ and LPS-induced neurogliosis and cognitive function through inhibition of NLRP3 inflammasome/IL-1β axis activation. Frontiers in Immunology, 13, 87-111. https://doi.org/10.3389/fimmu.2022.749336
• Lowe, P. P., Gyongyosi, B., Satishchandran, A., Iracheta-Vellve, A., Cho, Y., Ambade, A., & Szabo, G. (2018). Reduced gut microbiome protects from alcohol-induced neuroinflammation and alters intestinal and brain inflammasome expression. Journal of Neuroinflammation, 15, 298. https://doi.org/10.1186/s12974-018-1328-9
• Meier, M. H., Caspi, A., R. Knodt, A., Hall, W., Ambler, A., Harrington, H., Hogan, S., Houts, R.M., Poulton, R., Ramrakha, S., Hariri, A.R, & Moffitt, T. E. (2022). Long-term cannabis use and cognitive reserves and hippocampal volume in midlife. American Journal of Psychiatry, 179(5), 362-374. https://doi.org/10.1176/appi.ajp.2021.21060664
• Mira, R. G., Lira, M., Tapia-Rojas, C., Rebolledo, D. L., Quintanilla, R. A., & Cerpa, W. (2020). Effect of alcohol on hippocampal-dependent plasticity and behavior: Role of glutamatergic synaptic transmission. Frontiers in Behavioral Neuroscience, 13, 288-303. https://doi.org/10.3389/fnbeh.2019.00288
• Muscoli, C., Fresta, M., Cardile, V., Palumbo, M., Renis, M., Puglisi, G., Paolino, D., Nisticò, S., Rotiroti, D., & Mollace, V. (2002). Ethanol-induced injury in rat primary cortical astrocytes involves oxidative stress: effect of idebenone. Neuroscience Letters, 329(1), 21-24. https://doi.org/10.1016/s0304-3940(02)00567-0 Nitsch, L., Schneider, L., Zimmermann, J., & Müller, M. (2021). Microglia-Derived Interleukin 23: A crucial cytokine in Alzheimer’s. Frontiers in Neurology. 12, 508-511. https://doi.org/10.3389/fneur.2021.639353
• Patel, R. R., Khom, S., Steinman, M. Q., Varodayan, F. P., Kiosses, W. B., Hedges, D. M., Vlkolinsky, R., Nadav, T., Polis, I., Bajo, M., Roberts., A., & Roberto, M. (2019). IL-1β expression is increased and regulates GABA transmission following chronic ethanol in mouse central amygdala. Brain, Behavior, and Immunity, 75, 208-219. https://doi.org/10.1016/j.bbi.2018.10.009
• Peana, A. T., Sánchez-Catalán, M. J., Hipólito, L., Rosas, M., Porru, S., Bennardini, F., Romualdi, P., Caputi, F.F., Candeletti, S., Polache, A., Granero, L., & Acquas, E. (2017). Mystic acetaldehyde: The never-ending story on alcoholism. Frontiers in Behavioral Neuroscience, 11, 81-100. https://doi.org/10.3389/fnbeh.2017.00081
• Quintanilla, R. A., Pérez, M. J., Aranguiz, A., Tapia-Monsalves, C., & Mendez, G. (2020). Activation of the melanocortin-4 receptor prevents oxidative damage and mitochondrial dysfunction in cultured hippocampal neurons exposed to ethanol. Neurotoxicity Research, 38, 421-433. https://doi.org/10.1007/s12640-020-00204-1 Shastri, S., Shinde, T., Perera, A. P., Gueven, N., & Eri, R. (2020). Idebenone protects against spontaneous chronic murine colitis by alleviating endoplasmic reticulum stress and inflammatoryresponse. Biomedicines, 8(10), 384-404. https://doi.org/10.3390/biomedicines8100384
• Simpson, D. S., & Oliver, P. L. (2020). ROS generation in microglia: understanding oxidative stress and inflammation in neurodegenerative disease. Antioxidants, 9(8), 743-771. https://doi.org/10.3390/antiox9080743
• Song, K., Na, J. Y., Kim, S., & Kwon, J. (2015). Rutin upregulates neurotrophic factors resulting in attenuation of ethanol‐induced oxidative stress in HT22 hippocampal neuronal cells. Journal of the Science of Food and Agriculture, 95(10), 2117-2123. https://doi.org/10.1002/jsfa.6927 Suárez-Rivero, J. M., Pastor-Maldonado, C. J., Povea-Cabello, S., Álvarez-Córdoba, M., Villalón-García, I., Munuera-Cabeza, M., Suárez-Carrillo, A., Talaverón-Rey, M., & Sánchez-Alcázar, J. A. (2021). Coenzyme q10 analogues: Benefits and challenges for therapeutics. Antioxidants, 10(2), 236-256. https://doi.org/10.3390/antiox10020236
• Szelényi, J. (2001). Cytokines and the central nervous system. Brain Research Bulletin, 54(4), 329-338. https://doi.org/10.1016/S0361-9230(01)00428-2
• Tsermpini, E. E., Plemenitaš Ilješ, A., & Dolžan, V. (2022). Alcohol-Induced Oxidative Stress and the Role of Antioxidants in Alcohol Use Disorder: A Systematic Review. Antioxidants, 11(7), 1374-1398. https://doi.org/10.3390/antiox11071374
• Varodayan, F. P., Pahng, A. R., Davis, T. D., Gandhi, P., Bajo, M., Steinman, M. Q., Kiosses, W. B., Blednov, Y. A., Burkart, M.D., Edwards, S., Roberts, A. J., & Roberto, M. (2023). Chronic ethanol induces a pro-inflammatory switch in interleukin-1β regulation of GABAergic signaling in the medial prefrontal cortex of male mice. Brain, Behavior, and Immunity, 110, 125-139. https://doi.org/10.1016/j.bbi.2023.02.020
• Wang, P., Luo, Q., Qiao, H., Ding, H., Cao, Y., Yu, J., Liu, R., Zhang, Q., Zhu, H., & Qu, L. (2017). The neuroprotective effects of carvacrol on ethanol-induced hippocampal neurons impairment via the antioxidative and antiapoptotic pathways. Oxidative Medicine and Cellular Longevity, 17, 1-18. https://doi.org/10.1155/2017/4079425