Home Medicine 6-OHDA mediated neurotoxicity in SH-SY5Y cellular model of Parkinson disease suppressed by pretreatment with hesperidin through activating L-type calcium channels
Article
Licensed
Unlicensed Requires Authentication

6-OHDA mediated neurotoxicity in SH-SY5Y cellular model of Parkinson disease suppressed by pretreatment with hesperidin through activating L-type calcium channels

  • Leila Elyasi EMAIL logo , Mehrdad Jahanshahi , S. B. Jameie , Hatef Ghasemi Hamid Abadi , Emsehgol Nikmahzar , Masoumeh Khalili , Melika Jameie and Mana Jameie
Published/Copyright: September 14, 2020

Abstract

Objectives

Parkinson’s disease (PD) is a neurological condition with selective progressive degeneration of dopaminergic neurons. Routine therapies are symptomatic and palliative. Although, hesperidin (Hsd) is known for its neuroprotective effects, its exact cellular mechanism is still a mystery. Considering the important role of calcium (Ca2+) in cellular mechanisms of neurodegenerative diseases, the present study aimed to investigate the possible effects of Hsd on Ca2+ channels in cellular model of PD and the possible association between the selective vulnerability of neurons in cellular models of PD and expression of the physiological phenotype that changes Ca2+ homeostasis.

Methods

SH-SY5Y cell line was used in this study; cell damage was induced by 150 µM 6-OHDA and the cells’ viability was examined using MTT assay. Intracellular calcium, reactive oxygen species (ROS) and mitochondrial membrane potential were determined by the fluorescence spectrophotometry method. The expressions of calcium channel receptors were determined by gel electrophoresis and immunoblotting.

Results

Loss of cell viability and mitochondrial membrane potential were confirmed in 6-OHDA treated cells. In addition, intracellular ROS and calcium levels, calcium channel receptors significantly increased in 6-OHDA-treated cells. Incubation of SH-SY5Y cells with hesperidin showed a protective effect, reduced the biochemical markers of cell damage/death, and balanced calcium hemostasis.

Conclusions

Based on our findings, it seems that hesperidin could suppress the progression of the cellular model of PD via acting on intracellular calcium homeostasis. Further studies are needed to confirm the potential benefits of preventive and therapeutic effects of stabilizing cellular calcium homeostasis in neurodegenerative disease.


Corresponding author: Dr. Leila Elyasi, Neuroscience Research Center, Department of Anatomy, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran. Phone: +98 9113932235, E-mail:

Funding source: Golestan University of Medical Sciences (Gorgan, Iran)

Award Identifier / Grant number: 96122308

Acknowledgments

We would like to express our gratitude to the Neuroscience Research Center, Golestan University of Medical Sciences, Gorgan, Iran.

  1. Research funding: This work was supported by the Deputy of Research and Technology, Golestan University of Medical Sciences (Gorgan, Iran) under Grant number 96122308. In addition, all procedures were in accordance with the ethical principles accepted in the Golestan University of Medical Sciences. (IR. goums.REC.1396314).

  2. Author contributions: Study concept and design: L. Elyasi; M .Jahanshahi data acquisition: L. Elyasi; H.Ghasemi; data analysis and interpretation: L. Elyasi; khalili Masoumeh drafting of the manuscript: L. Elyasi; E.G. Nikmahzar and study supervision: L. Elyasi. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: This work was approved by Ethical committee of the Deputy of Research and Technology, Golestan University of Medical Sciences (Gorgan, Iran).

References

1. Tysnes, O-B, Storstein, A. Epidemiology of Parkinson’s disease. J Neural Transm 2017;124:901–5. https://doi.org/10.1007/s00702-017-1686-y.10.1007/s00702-017-1686-ySearch in Google Scholar PubMed

2. Mhyre, TR, Boyd, JT, Hamill, RW, Maguire-Zeiss, KA. Parkinson’s disease. Subcell Biochem 2012;65:389–455. https://doi.org/10.1007/978-94-007-5416-4_16.10.1007/978-94-007-5416-4_16Search in Google Scholar PubMed PubMed Central

3. Sulzer, D, Surmeier, DJ. Neuronal vulnerability, pathogenesis, and Parkinson’s disease. Mov Disord 2013;28:715–24. https://doi.org/10.1002/mds.25187.10.1002/mds.25187Search in Google Scholar PubMed

4. Yacoubian, TA, Standaert, DG. Targets for neuroprotection in Parkinson’s disease. Biochim Biophys Acta (BBA) – Mol Basis Dis 2009;1792:676–87. https://doi.org/10.1016/j.bbadis.2008.09.009.10.1016/j.bbadis.2008.09.009Search in Google Scholar PubMed PubMed Central

5. Magalingam, KB, Radhakrishnan, AK, Haleagrahara, N. Protective mechanisms of flavonoids in Parkinson’s disease. Oxid Med Cell Longev 2015;2015. https://doi.org/10.1155/2015/314560.10.1155/2015/314560Search in Google Scholar PubMed PubMed Central

6. Corona, JC. Natural compounds for the management of Parkinson’s disease and attention-deficit/hyperactivity disorder. BioMed Res Int 2018;2018. https://doi.org/10.1155/2018/4067597.10.1155/2018/4067597Search in Google Scholar PubMed PubMed Central

7. Parhiz, H, , Roohbakhsh, A, Soltani, F, Rezaee, R, Iranshahi, M. Antioxidant and anti‐inflammatory properties of the citrus flavonoids hesperidin and hesperetin: an updated review of their molecular mechanisms and experimental models. Phytother Res 2015;29:323–31. https://doi.org/10.1002/ptr.5256.10.1002/ptr.5256Search in Google Scholar PubMed

8. Li, C, Schluesener, H. Health-promoting effects of the citrus flavanone hesperidin. Crit Rev Food Sci Nutr 2017;57:613–31. https://doi.org/10.1080/10408398.2014.906382.10.1080/10408398.2014.906382Search in Google Scholar PubMed

9. Antunes, MS, Goes, AT, Boeira, SP, Prigol, M, Jesse, CR, et al. Protective effect of hesperidin in a model of Parkinson’s disease induced by 6-hydroxydopamine in aged mice. Nutrition 2014;30:1415–22. https://doi.org/10.1016/j.nut.2014.03.024.10.1016/j.nut.2014.03.024Search in Google Scholar PubMed

10. Poetini, MR, Araujo, SM, Trindade de Paula, M, Bortolotto, VC, Meichtry, LB, Polet de Almeida, F, et al. Hesperidin attenuates iron-induced oxidative damage and dopamine depletion in Drosophila melanogaster model of Parkinson’s disease. Chem Biol Interact 2018;279:177–86. https://doi.org/10.1016/j.cbi.2017.11.018.10.1016/j.cbi.2017.11.018Search in Google Scholar PubMed

11. Hajialyani, M, Hosein Farzaei, M, Echeverría, J, Nabavi, SM, Uriarte, E, Sobarzo-Sánchez, E. Hesperidin as a neuroprotective agent: a review of animal and clinical evidence. Molecules 2019;24. https://doi.org/10.3390/molecules24030648.10.3390/molecules24030648Search in Google Scholar PubMed PubMed Central

12. Zaichick, SV, McGrath, KM, Caraveo, G. The role of Ca2+ signaling in Parkinson’s disease. Dis Models Mech 2017;10:519–35. https://doi.org/10.1242/dmm.028738.10.1242/dmm.028738Search in Google Scholar PubMed PubMed Central

13. Surmeier, DJ, Guzman, JN, Sanchez-Padilla, J. Calcium, cellular aging, and selective neuronal vulnerability in Parkinson’s disease. Cell Calcium 2010;47:175–82. https://doi.org/10.1016/j.ceca.2009.12.003.10.1016/j.ceca.2009.12.003Search in Google Scholar PubMed PubMed Central

14. Pasternak, B, Svanström, H, Nielsen, NM, Fugger, L, Melbye, M, Hviid, A. Use of calcium channel blockers and Parkinson’s disease. Am J Epidemiol 2012;175:627–35. https://doi.org/10.1093/aje/kwr362.10.1093/aje/kwr362Search in Google Scholar PubMed

15. Ritz, B, Rhodes, SL, Qian, L, Schernhammer, E, Olsen, JH, Friis, S. L-type calcium channel blockers and Parkinson disease in Denmark. Ann Neurol 2010;67:600–6.10.1002/ana.21937Search in Google Scholar

16. Betzer, C, Lassen, LB, Olsen, A, Kofoed, RH, Reimer, L, Gregersen, E, et al. Alpha-synuclein aggregates activate calcium pump SERCA leading to calcium dysregulation. EMBO Rep 2018;19. https://doi.org/10.15252/embr.201744617.10.15252/embr.201744617Search in Google Scholar PubMed PubMed Central

17. Elyasi, L, Jahanshahi, M, Ghazvini, H, Nikmahzar, E. The protective effects of citrus aurantium flower extract against 6-hydroxydopamine-mediated cell damage in human neuroblastoma SH-SY5Y cells. Int J Morphol 2018;36. https://doi.org/10.4067/s0717-95022018000200435.10.4067/S0717-95022018000200435Search in Google Scholar

18. Boix, J, Padel, T, Paul, G. A partial lesion model of Parkinson’s disease in mice–Characterization of a 6-OHDA-induced medial forebrain bundle lesion. Behav Brain Res 2015;284:196–206. https://doi.org/10.1016/j.bbr.2015.01.053.10.1016/j.bbr.2015.01.053Search in Google Scholar PubMed

19. Elyasi, L, Eftekhar-Vaghefi, SH, Esmaeili-Mahani, S. Morphine protects SH-SY5Y human neuroblastoma cells against 6-hydroxydopamine-induced cell damage: involvement of anti-oxidant, calcium blocking, and anti-apoptotic properties. Rejuvenation Res 2014;17:255–63. https://doi.org/10.1089/rej.2013.1473.10.1089/rej.2013.1473Search in Google Scholar PubMed

20. Li, Y, Shi, W, Li, Y, Zhou, Y, Hu, X, Song, C, et al. Neuroprotective effects of chlorogenic acid against apoptosis of PC12 cells induced by methylmercury. Environ Toxicol Pharmacol 2008;26:13–21. https://doi.org/10.1016/j.etap.2007.12.008.10.1016/j.etap.2007.12.008Search in Google Scholar PubMed

21. Sadeghnia, HR, Jamshidi, R, Afshari, AR, Mollazadeh, H, Forouzanfar, F, Rakhshandeh, H. Terminalia chebula attenuates quinolinate-induced oxidative PC12 and OLN-93 cell death. Mult Scler Relat Disord 2017;14:60–7. https://doi.org/10.1016/j.msard.2017.03.012.10.1016/j.msard.2017.03.012Search in Google Scholar PubMed

22. Elyasi, L, Eftekhar-Vaghefi, SH, Asadi-Shekaari, M, Esmaeili-Mahani, S. Induction of cross-tolerance between protective effect of morphine and nicotine in 6-hydroxydopamine-induce neurotoxicity in SH-SY5Y human dopaminergic neuroblastoma cells. Int J Neurosci 2019;129:129–38. https://doi.org/10.1080/00207454.2018.1494169.10.1080/00207454.2018.1494169Search in Google Scholar PubMed

23. Faivre, F, Sánchez-Catalán, MJ, Dovero, S, Bido, S, Joshi, A, Bezard, E, et al. Ablation of the tail of the ventral tegmental area compensates symptoms in an experimental model of Parkinson’s disease. Neurobiol Dis 2020;139:104818. https://doi.org/10.1016/j.nbd.2020.104818.10.1016/j.nbd.2020.104818Search in Google Scholar PubMed

24. Duchen, MR. Mitochondria, calcium-dependent neuronal death and neurodegenerative disease. Pflueg Arch Eur J Physiol 2012;464:111–21. https://doi.org/10.1007/s00424-012-1112-0.10.1007/s00424-012-1112-0Search in Google Scholar PubMed PubMed Central

25. Lin, G, Sun, Y, Long, J, Sui, X, Yang, J, Wang, Q, et al. Involvement of the Nrf2-Keap1 signaling pathway in protection against thallium-induced oxidative stress and mitochondrial dysfunction in primary hippocampal neurons. Toxicol Lett 2020;319:66–73. https://doi.org/10.1016/j.toxlet.2019.11.008.10.1016/j.toxlet.2019.11.008Search in Google Scholar PubMed

26. Dong, X-X., Wang, Y, Qin, Z-H. Molecular mechanisms of excitotoxicity and their relevance to pathogenesis of neurodegenerative diseases. Acta Pharmacol Sin 2009;30:379. https://doi.org/10.1038/aps.2009.24.10.1038/aps.2009.24Search in Google Scholar PubMed PubMed Central

27. Hurley, MJ, Brandon, B, Gentleman, SM, Dexter, DT. Parkinson’s disease is associated with altered expression of CaV1 channels and calcium-binding proteins. Brain 2013;136:2077–97. https://doi.org/10.1093/brain/awt134.10.1093/brain/awt134Search in Google Scholar PubMed

28. Sandebring, A, Dehvari, N, Perez-Manso, M, Thomas, KJ, Karpilovski, E, Cookson, MR, et al. Parkin deficiency disrupts calcium homeostasis by modulating phospholipase C signalling. FEBS J 2009;276:5041–52. https://doi.org/10.1111/j.1742-4658.2009.07201.x.10.1111/j.1742-4658.2009.07201.xSearch in Google Scholar PubMed PubMed Central

29. Mosharov, EV, Larsen, KE, Kanter, E, Phillips, KA, Wilson, K, Schmitz, Y, et al. Interplay between cytosolic dopamine, calcium, and alpha-synuclein causes selective death of substantia nigra neurons. Neuron 2009;62:218–29. https://doi.org/10.1016/j.neuron.2009.01.033.10.1016/j.neuron.2009.01.033Search in Google Scholar PubMed PubMed Central

30. Surmeier, DJ, Guzman, JN, Sanchez-Padilla, J, Schumacker, PT. The role of calcium and mitochondrial oxidant stress in the loss of substantia nigra pars compacta dopaminergic neurons in Parkinson’s disease. Neuroscience 2011;198:221–31. https://doi.org/10.1016/j.neuroscience.2011.08.045.10.1016/j.neuroscience.2011.08.045Search in Google Scholar PubMed PubMed Central

31. Giorgi, C, Baldassari, F, Bononi, A, Bonora, M, De Marchi, E, Marchi, S, Missiroli, S, et al. Mitochondrial Ca2+ and apoptosis. Cell Calcium 2012;52:36–43.10.1016/j.ceca.2012.02.008Search in Google Scholar PubMed PubMed Central

32. Smaili, S, Hirata, H, Ureshino, R, Monteforte, PT, Morales, AP, Muler, ML, et al. Calcium and cell death signaling in neurodegeneration and aging. An Acad Bras Cienc 2009;81:467–75. https://doi.org/10.1590/s0001-37652009000300011.10.1590/S0001-37652009000300011Search in Google Scholar

33. Karn, A, Zhao, C, Yang, F, Cui, J, Gao, Z, Wang, M, et al. In-vivo biotransformation of citrus functional components and their effects on health. Crit Rev Food Sci Nutr 2020:1–21. https://doi.org/10.1080/10408398.2020.1746234.10.1080/10408398.2020.1746234Search in Google Scholar PubMed

34. Yu, X, Li, X, Jiang, G, Wang, X, Chang, HC, Hsu, WH, et al. Isradipine prevents rotenone-induced intracellular calcium rise that accelerates senescence in human neuroblastoma SH-SY5Y cells. Neuroscience 2013;246:243–53. https://doi.org/10.1016/j.neuroscience.2013.04.062.10.1016/j.neuroscience.2013.04.062Search in Google Scholar PubMed

35. Wickenden, AD, Krajewski, JL, London, B, Wagoner, PK, Wilson, WA, Clark, S, et al. N-(6-chloro-pyridin-3-yl)-3,4-difluoro-benzamide (ICA-27243): a novel, selective KCNQ2/Q3 potassium channel activator. Mol Pharmacol 2008;73:977–86. https://doi.org/10.1124/mol.107.043216.10.1124/mol.107.043216Search in Google Scholar PubMed

Received: 2019-12-03
Accepted: 2020-06-11
Published Online: 2020-09-14

© 2020 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Review
  3. Update of hypothyroidism and its management in Unani medicine
  4. Original Articles
  5. 6-OHDA mediated neurotoxicity in SH-SY5Y cellular model of Parkinson disease suppressed by pretreatment with hesperidin through activating L-type calcium channels
  6. Modulation of sleep using electrical vestibular nerve stimulation prior to sleep onset: a pilot study
  7. Nitric oxide mediates the antidepressant-like effect of modafinil in mouse forced swimming and tail suspension tests
  8. Effect of mobile phone usage on cognitive functions, sleep pattern, visuospatial ability in Parkinsons patients; a possible correlation with onset of clinical symptoms
  9. Food-added azodicarbonamide alters haematogical parameters, antioxidant status and biochemical/histomorphological indices of liver and kidney injury in rats
  10. Conditioned medium from the human umbilical cord-mesenchymal stem cells stimulate the proliferation of human keratinocytes
  11. p53 upregulated mediator of apoptosis (Puma) deficiency increases survival of adult neural stem cells generated physiologically in the hippocampus, but does not protect stem cells generated in surplus after an excitotoxic lesion
  12. In vitro antioxidants and hepatoprotective effects of Pleurotus tuber-regium on carbon tetrachloride–treated rats
  13. Mitigative effect of Momordica cymbalaria fruit extract against sodium fluoride induced hepatotoxicity in Wistar male albino rats
  14. Amine-modified kaolinite clay preserved thyroid function and renal oxidative balance after sub-acute exposure in rats
  15. Aqueous extract of dry powder blend of seeds and leaves of Picralima nitida (Stapf) T. & H. Durand reduce pain and inflammation in animal models
  16. Methanol extract of Caesalpinia benthamiana normalizes blood pressure and attenuates oxidative stress in uninephrectomized hypertensive rats
  17. Evaluation of antidiabetic effect of Cistus salviifolius L. (Cistaceae) in streptozotocin-nicotinamide induced diabetic mice
  18. Correlation between biofilm formation and antimicrobial susceptibility pattern toward extended spectrum β-lactamase (ESBL)- and non-ESBL-producing uropathogenic bacteria
Downloaded on 20.1.2026 from https://www.degruyterbrill.com/document/doi/10.1515/jbcpp-2019-0270/html
Scroll to top button