Alpha Lipoic Acid Protects Human SH-SY5Y Cells Against Quinolinic Acid-Induced Toxicity: Focusing on ROS Levels and Cell Cycle
Abstract
Objectives: An abnormal buildup of Quinolinic Acid (QuA) is usually linked to the death of nerve cells and a condition known as neuritis in various forms of neurodegenerative illness. Alpha Lipoic Acid (ALA) has substantial antioxidant properties, according to previous studies. However, the protective effects of ALA against the neurotoxicity induced by QuA are unknown. This work aimed to determine whether ALA could shield the SH-SY5Y neuroblastoma cell line from QuA induced neurotoxicity.
Methods: Cell viability was assessed using the MTT assay, while cell cycle and apoptotic effects were evaluated using flow cytometry. Cellular levels of reactive oxygen species (ROS) were also examined.
Results: The findings showed that ALA, at non-toxic concentrations, had a protective effect against QuA-induced toxicity. Moreover, pretreatment with ALA reduced the number of cells that underwent apoptosis. Also, it was found that the percentage of apoptotic cells (i.e., those in the sub-G1 phase) was considerably increased following QuA therapy. ALA also dramatically reduced the production of ROS by QuA.
Conclusion: The results suggest that ALA appears to be an effective neuroprotectant and antioxidant against QuA-induced neurotoxicity.
2. Yamamura, T., J.T. Konola, H. Wekerle, and M.B.J.J.o.n. Lees, Monoclonal antibodies against myelin proteolipid protein: identification and characterization of two major determinants. 1991. 57(5): p. 1671-1680.
3. Tilleux, S. and E.J.J.o.n.r. Hermans, Neuroinflammation and regulation of glial glutamate uptake in neurological disorders. 2007. 85(10): p. 2059-2070.
4. Mühl, H., J.J.B. Pfeilschifter, and b.r. communications, Endothelial nitric oxide synthase: a determinant of TNFα production by human monocytes/macrophages. 2003. 310(3): p. 677-680.
5. Zamani‐Garmsiri, F., S. Emamgholipour, S. Rahmani Fard, G. Ghasempour, R. Jahangard Ahvazi, and R. Meshkani, Polyphenols: potential anti‐inflammatory agents for treatment of metabolic disorders. Phytotherapy Research, 2022. 36(1): p. 415-432.
6. Maddison, D.C. and F. Giorgini. The kynurenine pathway and neurodegenerative disease. in Seminars in cell & developmental biology. 2015. Elsevier.
7. Reyes Ocampo, J., R. Lugo Huitrón, D. González-Esquivel, P. Ugalde-Muñiz, A. Jiménez-Anguiano, B. Pineda, et al., Kynurenines with neuroactive and redox properties: relevance to aging and brain diseases. 2014. 2014.
8. Schwarcz, R., J.P. Bruno, P.J. Muchowski, and H.-Q.J.N.R.N. Wu, Kynurenines in the mammalian brain: when physiology meets pathology. 2012. 13(7): p. 465-477.
9. Abbasinezhad-Moud, F., E. Azimi, M. Rostami, and E.J.R.J.o.P. Gheybi, Hesperidin Plays Neuroprotective Effects Against Quinolinic Acid in Human SH-SY5Y Cells: Focusing on ROS Levels and Cell Cycle Arrest. 2023.
10. Hestad, K., J. Alexander, H. Rootwelt, and J.O. Aaseth, The Role of Tryptophan Dysmetabolism and Quinolinic Acid in Depressive and Neurodegenerative Diseases. Biomolecules, 2022. 12(7).
11. Popoli, P., A. Pintor, M.T. Tebano, C. Frank, R. Pepponi, V. Nazzicone, et al., Neuroprotective effects of the mGlu5R antagonist MPEP towards quinolinic acid‐induced striatal toxicity: involvement of pre‐and post‐synaptic mechanisms and lack of direct NMDA blocking activity. 2004. 89(6): p. 1479-1489.
12. Rehman, M.U., A.F. Wali, A. Ahmad, S. Shakeel, S. Rasool, R. Ali, et al., Neuroprotective strategies for neurological disorders by natural products: an update. 2019. 17(3): p. 247-267.
13. Mishra, B.B. and V.K.J.E.j.o.m.c. Tiwari, Natural products: an evolving role in future drug discovery. 2011. 46(10): p. 4769-4807.
14. Khorzoughi, R.B. and R. Meshkani, Beneficial Effect of Metformin, Quercetin, and Resveratrol Combination on High Glucose-Induced lipogenesis in HepG2 Cells. Acta Biochimica Iranica, 2023. 1(2): p. 96-104.
15. Smith, A.R., S.V. Shenvi, M. Widlansky, J.H. Suh, and T.M. Hagen, Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress. Curr Med Chem, 2004. 11(9): p. 1135-46.
16. Metsla, K., S. Kirss, K. Laks, G. Sildnik, M. Palgi, T. Palumaa, et al., α-Lipoic Acid Has the Potential to Normalize Copper Metabolism, Which Is Dysregulated in Alzheimer's Disease. J Alzheimers Dis, 2022. 85(2): p. 715-728.
17. Selvakumar, E. and T.C. Hsieh, Regulation of cell cycle transition and induction of apoptosis in HL-60 leukemia cells by lipoic acid: role in cancer prevention and therapy. J Hematol Oncol, 2008. 1: p. 4.
18. Shay, K.P., R.F. Moreau, E.J. Smith, A.R. Smith, and T.M. Hagen, Alpha-lipoic acid as a dietary supplement: molecular mechanisms and therapeutic potential. Biochim Biophys Acta, 2009. 1790(10): p. 1149-60.
19. Bernini, R., F. Crisante, N. Merendino, R. Molinari, M.C. Soldatelli, and F. Velotti, Synthesis of a novel ester of hydroxytyrosol and α-lipoic acid exhibiting an antiproliferative effect on human colon cancer HT-29 cells. Eur J Med Chem, 2011. 46(1): p. 439-46.
20. Kim, D.C., D.W. Jun, E.C. Jang, S.H. Kim, E.K. Kim, S.P. Lee, et al., Lipoic Acid prevents the changes of intracellular lipid partitioning by free Fatty Acid. Gut Liver, 2013. 7(2): p. 221-7.
21. Moungjaroen, J., U. Nimmannit, P.S. Callery, L. Wang, N. Azad, V. Lipipun, et al., Reactive oxygen species mediate caspase activation and apoptosis induced by lipoic acid in human lung epithelial cancer cells through Bcl-2 down-regulation. J Pharmacol Exp Ther, 2006. 319(3): p. 1062-9.
22. Wenzel, U., A. Nickel, and H. Daniel, alpha-Lipoic acid induces apoptosis in human colon cancer cells by increasing mitochondrial respiration with a concomitant O2-*-generation. Apoptosis, 2005. 10(2): p. 359-68.
23. Dörsam, B., A. Göder, N. Seiwert, B. Kaina, and J. Fahrer, Lipoic acid induces p53-independent cell death in colorectal cancer cells and potentiates the cytotoxicity of 5-fluorouracil. Arch Toxicol, 2015. 89(10): p. 1829-46.
24. Xicoy, H., B. Wieringa, and G.J. Martens, The SH-SY5Y cell line in Parkinson's disease research: a systematic review. Mol Neurodegener, 2017. 12(1): p. 10.
25. Kovalevich, J. and D. Langford, Considerations for the use of SH-SY5Y neuroblastoma cells in neurobiology. Methods Mol Biol, 2013. 1078: p. 9-21.
26. Ebrahimi, S., F. Mirzavi, S.H. Aghaee-Bakhtiari, and S.I. Hashemy, SP/NK1R system regulates carcinogenesis in prostate cancer: Shedding light on the antitumoral function of aprepitant. Biochim Biophys Acta Mol Cell Res, 2022. 1869(5): p. 119221.
27. Wondrak, G.T., N.F. Villeneuve, S.D. Lamore, A.S. Bause, T. Jiang, and D.D. Zhang, The cinnamon-derived dietary factor cinnamic aldehyde activates the Nrf2-dependent antioxidant response in human epithelial colon cells. Molecules, 2010. 15(5): p. 3338-55.
28. Guillemin, G.J., Quinolinic acid, the inescapable neurotoxin. Febs j, 2012. 279(8): p. 1356-65.
29. Schwarcz, R., A.C. Foster, E.D. French, W.O. Whetsell, Jr., and C. Köhler, Excitotoxic models for neurodegenerative disorders. Life Sci, 1984. 35(1): p. 19-32.
30. Beal, M.F., N.W. Kowall, D.W. Ellison, M.F. Mazurek, K.J. Swartz, and J.B. Martin, Replication of the neurochemical characteristics of Huntington's disease by quinolinic acid. Nature, 1986. 321(6066): p. 168-71.
31. Chen, X., C. Guo, and J. Kong, Oxidative stress in neurodegenerative diseases. Neural Regen Res, 2012. 7(5): p. 376-85.
32. Shiri, H., A. Karimpour, M. Sattari, S. Hemmati, S. Seyyedebrahimi, and G. Panahi, Evaluation of Antioxidant Potential and Free Radical Scavenging Activity of Methanol Extract from Scrophularia striata. Acta Biochimica Iranica, 2023. 1(2): p. 71-77.
33. Pérez-De La Cruz, V., P. Carrillo-Mora, and A. Santamaría, Quinolinic Acid, an endogenous molecule combining excitotoxicity, oxidative stress and other toxic mechanisms. Int J Tryptophan Res, 2012. 5: p. 1-8.
34. Sas, K., H. Robotka, J. Toldi, and L. Vécsei, Mitochondria, metabolic disturbances, oxidative stress and the kynurenine system, with focus on neurodegenerative disorders. J Neurol Sci, 2007. 257(1-2): p. 221-39.
35. Senatorov, V.V., M. Ren, H. Kanai, H. Wei, and D.M. Chuang, Short-term lithium treatment promotes neuronal survival and proliferation in rat striatum infused with quinolinic acid, an excitotoxic model of Huntington's disease. Mol Psychiatry, 2004. 9(4): p. 371-85.
36. Rahman, A., K. Ting, K.M. Cullen, N. Braidy, B.J. Brew, and G.J. Guillemin, The excitotoxin quinolinic acid induces tau phosphorylation in human neurons. PLoS One, 2009. 4(7): p. e6344.
37. Kannan, K. and S.K. Jain, Oxidative stress and apoptosis. Pathophysiology, 2000. 7(3): p. 153-163.
38. Yang, C., Q. Yang, Y. Xiang, X.R. Zeng, J. Xiao, and W.D. Le, The neuroprotective effects of oxygen therapy in Alzheimer's disease: a narrative review. Neural Regen Res, 2023. 18(1): p. 57-63.
39. Huang, X., K. Yang, Y. Zhang, Q. Wang, and Y. Li, Quinolinic acid induces cell apoptosis in PC12 cells through HIF-1-dependent RTP801 activation. Metab Brain Dis, 2016. 31(2): p. 435-44.
40. Nakai, M., Z.H. Qin, Y. Wang, and T.N. Chase, Free radical scavenger OPC-14117 attenuates quinolinic acid-induced NF-kappaB activation and apoptosis in rat striatum. Brain Res Mol Brain Res, 1999. 64(1): p. 59-68.
41. Behan, W.M., M. McDonald, L.G. Darlington, and T.W. Stone, Oxidative stress as a mechanism for quinolinic acid-induced hippocampal damage: protection by melatonin and deprenyl. Br J Pharmacol, 1999. 128(8): p. 1754-60.
42. Nuzzo, D.J.A., Role of natural antioxidants on neuroprotection and neuroinflammation. 2021, MDPI. p. 608.
43. Della Giustina, A., M.P. Goldim, L.G. Danielski, D. Florentino, K. Mathias, L. Garbossa, et al., Alpha-lipoic acid attenuates acute neuroinflammation and long-term cognitive impairment after polymicrobial sepsis. 2017. 108: p. 436-447.
44. Carota, G., A. Distefano, M. Spampinato, C. Giallongo, G. Broggi, L. Longhitano, et al., Neuroprotective Role of α-Lipoic Acid in Iron-Overload-Mediated Toxicity and Inflammation in In Vitro and In Vivo Models. 2022. 11(8): p. 1596.
45. Taherian, S.s., R. Khayamabed, M. Tavalaee, and M.H.J.A. Nasr‐Esfahani, Alpha‐lipoic acid minimises reactive oxygen species‐induced damages during sperm processing. 2019. 51(8): p. e13314.
46. Wenzel, U., A. Nickel, and H.J.A. Daniel, α-lipoic acid induces apoptosis in human colon cancer cells by increasing mitochondrial respiration with a concomitant O 2−.-generation. 2005. 10: p. 359-368.
47. Lv, C., S. Maharjan, Q. Wang, Y. Sun, X. Han, S. Wang, et al., α-Lipoic acid promotes neurological recovery after ischemic stroke by activating the Nrf2/HO-1 pathway to attenuate oxidative damage. 2017. 43(3): p. 1273-1287.
48. Erdinest, N., O. Shmueli, Y. Grossman, H. Ovadia, A.J.I.o. Solomon, and v. science, Anti-inflammatory effects of alpha linolenic acid on human corneal epithelial cells. 2012. 53(8): p. 4396-4406.
49. Mark, K.v.d., J.S. Chen, K. Steliou, S.P. Perrine, and D.V.J.J.o.c.p. Faller, α‐Lipoic acid induces p27Kip‐dependent cell cycle arrest in non‐transformed cell lines and apoptosis in tumor cell lines. 2003. 194(3): p. 325-340.
50. Sadi, G., Ö. Yılmaz, T.J.M. Güray, and C. Biochemistry, Effect of vitamin C and lipoic acid on streptozotocin-induced diabetes gene expression: mRNA and protein expressions of Cu–Zn SOD and catalase. 2008. 309: p. 109-116.
Files | ||
Issue | Vol 1 No 4 (2023) | |
Section | Original Articles | |
DOI | https://doi.org/10.18502/abi.v1i4.14723 | |
Keywords | ||
Alpha Lipoic Acid Quinolinic Acid SH-SY5Y neuroblastoma cell line Oxidative stress |
Rights and permissions | |
![]() |
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |