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Neuroprotective Role of Quercetin on Rotenone-Induced Toxicity in SH-SY5Y Cell Line Through Modulation of Apoptotic and Autophagic Pathways

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Abstract

The detrimental impact on the food chain due to the overuse of rotenone is partly responsible for alpha-synuclein (α-syn) mediated neurotoxicity. It is hypothesized that rotenone overdose leads to cytosolic proteopathy resulting in modulation of apoptosis and autophagic pathways. The aim of our study is to explore the neuroprotective role of quercetin, a beneficial polyphenol against rotenone-induced neurotoxicity in dopaminergic human SH-SY5Y cell lines. In our study we demonstrated the correlation of rotenone-induced neurotoxicity through elevation of intracellular reactive oxygen species (ROS) and imbalance in the mitochondrial membrane potential (MMP). Moreover, the morphological distortion of cell, condensation of nuclei, externalization of the inner phosphatidylserine, cleavage of caspase 3, and Poly ADP Ribose Polymerase (PARP) confirmed apoptosis. However, all these lethal effects were ameliorated by treatment of quercetin to the cells. On the other hand rotenone has a strong effect on autophagy which is a regulated degrading and recycling cellular process to remove dysfunctional proteins. Indeed, rotenone-mediated autophagy resulted in the enhancement of autophagosome-bound microtubule-associated protein light chain-3 (LC3-II) expression. Furthermore, excess accumulation of acidic vesicles was detected in presence of rotenone. Lysosome associated membrane protein (LAMP-2A) is yet another crucial protein that recruits overexpressed or misfolded proteins into the lumen of lysosome to trigger autophagy. In all cases the impact of rotenone on the cells acquired significant protection through quercetin treatment. In the present work we therefore opine the prospects of quercetin as a therapeutic candidate against neurotoxicity.

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References

  1. Tysnes O, Storstein A (2017) Epidemiology of Parkinson’s disease. J Neural Trans 124(8):901–905. https://doi.org/10.1007/s00702-017-1686-y

    Article  Google Scholar 

  2. Goedert M, Eisenberg D, Crowther R (2017) Propagation of tau aggregates and neurodegeneration. Annu Rev Neurosci 40:189–210. https://doi.org/10.1146/annurev-neuro-072116-031153

    Article  CAS  PubMed  Google Scholar 

  3. Elbaz A, Dufouil C, Alpérovitch A (2007) Interaction between genes and environment in neurodegenerative diseases. C R Biol 330(4):318–328. https://doi.org/10.1016/j.crvi.2007.02.018

    Article  CAS  PubMed  Google Scholar 

  4. Yuan Y, Yan W, Sun J, Huang J, Mu Z, Chen N (2015) The molecular mechanism of rotenone-induced α-synuclein aggregation: emphasizing the role of the calcium/GSK3β pathway. TOXLET 8958:1–9. https://doi.org/10.1016/j.toxlet.2014.11.029

    Article  CAS  Google Scholar 

  5. Samantaray S, Knaryan V, Guyton M, Matzelle D, Ray S, Banik N (2007) The parkinsonian neurotoxin rotenone activates calpain and caspase-3 leading to motoneuron degeneration in spinal cord of Lewis rats. Neuroscience 146(2):741–755

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Sarkar S, Raymick J, Imam S (2016) Neuroprotective and therapeutic strategies against Parkinson’s disease: recent perspectives. Int J Mol Sci 17:904–935. https://doi.org/10.3390/ijms17060907

    Article  CAS  PubMed Central  Google Scholar 

  7. Moors T, Hoozemans J, Ingrassia A, Beccari T, Parnetti L, Chartier-Harlin M, van de Berg W (2017) Therapeutic potential of autophagy-enhancing agents in Parkinson’s disease. Mol Neurodegener 12(1):11

    Article  PubMed  PubMed Central  Google Scholar 

  8. Martinez-Vicente M, Talloczy Z, Kaushik S, Massey A, Mazzulli J, Mosharov E, Hodara R, Fredenburg R, Wu D, Follenzi A, Dauer W, Przedborski S, Ischiropoulos H, Lansbury P, Sulzer D, Cuervo A (2008) Dopamine-modified α-synuclein blocks chaperone-mediated autophagy. J Clin Invest 118:777–788

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Massi A, Bortolini O, Ragno D, Bernardi T, Tacchini S, Risi CD (2017) Research progress in the modification of quercetin leading to anticancer agents. Molecules 22:1270–1296

    Article  PubMed Central  Google Scholar 

  10. Mlcek J, Jurikova T, Skrovankova S, Sochor J (2016) Quercetin and its anti-allergic immune response. Molecules 21:622–636

    Article  Google Scholar 

  11. Wang S, Yao J, Zhou B, Yang J, Chaudry MT, Wang MI, Xiao F, Yao L, Yin W (2018) Bacteriostatic effect of quercetin as an antibiotic alternative in vivo and its antibacterial mechanism in vitro. J Food Prot 81:68–78

    Article  CAS  PubMed  Google Scholar 

  12. Lee S, Lee HH, Shin YS, Kang H, Cho H (2017) The anti-HSV-1 effect of quercetin is dependent on the suppression of TLR-3 in Raw 264.7 cells. Arch Pharm Res 40(5):623–630. https://doi.org/10.1007/s12272-017-0898-x

    Article  CAS  PubMed  Google Scholar 

  13. Yao C, Xi C, Hu K, Gao W, Cai X, Qin J, Shiyun L, Canghao D, Wei Y (2018) Inhibition of enterovirus 71 replication and viral 3C protease by quercetin. Virol J 15:116–128. https://doi.org/10.1186/s12985-018-1023-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sadabady RR, Eidi A, Zarghami N, Barzegar A (2016) Intracellular ROS protection efficiency and free radical-scavenging activity of quercetin and quercetin-encapsulated liposomes. Artif Cells Nanomed Biotechnol 44:128–134

    Article  Google Scholar 

  15. Yang T, Kong B, Gu JW, Kuang YQ, Cheng L, Yang WT, Xia X, Shu HF (2014) Anti-apoptotic and anti-oxidative roles of quercetin after traumatic brain Injury. Cell Mol Neurobiol 34(6):797–806

    Article  CAS  PubMed  Google Scholar 

  16. Yao L, Yao J, Han C, Yang J, Chaudhry MT, Wang S, Liu H, Yin Y (2016) Quercetin, inflammation and immunity. Nutrients 8(4):166–180

    Article  Google Scholar 

  17. Chatterjee J, Langhnoja J, Pillai PP, Mustak MS (2019) Neuroprotective effect of quercetin against radiationinduced endoplasmic reticulum stress in neurons. J Biochem Mol Toxicol 33(2):1–8

    Article  Google Scholar 

  18. Rakshit J, Mallick A, Roy S, Sarbajna A, Dutta M, Bandyopadhyay J (2020) Iron-induced apoptotic cell death and autophagy dysfunction in human neuroblastoma cell line SH-SY5Y. Biol Trace Elem Res 193(1):138–151. https://doi.org/10.1007/s12011-019-01679-6

    Article  CAS  PubMed  Google Scholar 

  19. Li N, Ragheb K, Lawler G, Sturgis J, Rajwa B, Melendez JA, Robinson JP (2003) Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J Biol Chem 278(10):8516–8525. https://doi.org/10.1074/jbc.M210432200

    Article  CAS  PubMed  Google Scholar 

  20. Sun H, He X, Liu C, Li L, Zhou R, Jin T, Yue S, Feng D, Gong J, Sun J, Ji J, Xiang L (2017) Effect of oleracein E, a neuroprotective tetrahydroisoquinoline, on rotenone induced Parkinson’s Disease cell and animal models. ACS Chem Neurosci 8(1):155–164

    Article  CAS  PubMed  Google Scholar 

  21. Pouchieu C, Piel C, Carles C, Gruber A, Helmer C, Tual S, Marcotullio E, Lebailly P, Baldi I (2018) Pesticide use in agriculture and Parkinson’s disease in the AGRICAN cohort study. Int J Epidemiol 47(1):299–310

    Article  PubMed  Google Scholar 

  22. Chiaradia E, Renzone G, Scaloni A, Caputo M, Costanzi E, Gambelunghe A, Muzi G, Avellini L, Emiliani C, Buratta S (2019) Protein carbonylation in dopaminergic cells exposed to rotenone. Toxicol Lett 309:20–32

    Article  CAS  PubMed  Google Scholar 

  23. Datla KP, Zbarsky V, Rai D, Parkar S, Osakabe N, Aruoma OI, Dexter DT (2007) Short term supplementation with plant extracts rich in flavonoids protect nigrostriatal dopaminergic neurons in a rat model of Parkinson’s disease. J Am Coll Nutr 26(4):341–349. https://doi.org/10.1080/07315724.2007.10719621

    Article  CAS  PubMed  Google Scholar 

  24. Filomeni G, Graziani I, Zio DD, Dini L, Centonze D, Rotilio G, Ciriolo MR (2012) Neuroprotection of kaempferol by autophagy in models of rotenone-mediated acute toxicity: possible implications for Parkinson’s disease. Neurobiol Aging 33(4):765–785

    Article  Google Scholar 

  25. Curro M, Bellocco E, Lentile R et al (2017) Neuroprotective effects of phloretin and its glycosylated derivative on rotenone-induced toxicity in human SH-SY5Y neuronal-like cells. Biofactors 43(4):549–557

    Article  PubMed  Google Scholar 

  26. Deng YN, Shi J, Liu J, Qu QM (2013) Celastrol protects human neuroblastoma SH-SY5Y cells from rotenone-induced injury through induction of autophagy. Neurochem Int 63(1):1–9

    Article  CAS  PubMed  Google Scholar 

  27. Kuang L, Cao X, Lu Z (2017) Baicalein protects against rotenone induced neurotoxicity through induction of autophagy. Biol Pharm Bull 40(9):1537–1543

    Article  CAS  PubMed  Google Scholar 

  28. Jang W, Kim HJ, Li H, Jo KD, Lee MK, Song SH, Yang HO (2014) 1,25-Dyhydroxyvitamin D3 attenuates rotenone-induced neurotoxicity in SH-SY5Y cells through induction of autophagy. Biochem Biophys Res Commun 451(1):142–148. https://doi.org/10.1016/j.bbrc.2014.07.081

    Article  CAS  PubMed  Google Scholar 

  29. Kang SY, Lee SB, Kim HJ, Kim HT, Yang HO, Jang W (2017) Autophagic modulation by rosuvastatin prevents rotenone-induced neurotoxicity in an in vitro model of Parkinson’s disease. Neurosci Lett 642:20–26

    Article  CAS  PubMed  Google Scholar 

  30. Kale A, Piskin Ö, Bas Y, Aydin BG, Can M, Elmas Ö, Büyükuysal Ç (2018) Neuroprotective effects of quercetin on radiation-induced brain injury in rats. J Radiat Res 59(4):404–410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Moreno L, Puerta E, Suárez S, Santos M, Ramirez MJ, Irache JM (2017) Effect of the oral the oral administration of nanoencapsulated quercetin on a mouse model of Alzheimer’s disease. Int J Pharm 517:50–57

    Article  CAS  PubMed  Google Scholar 

  32. Nieoczym D, Socała K, Raszewski G, Wlaź P (2014) Effect of quercetin and rutin in some acute seizure models in mice. Prog Neuropsychopharmacol Biol Psychiatry 54:50–57

    Article  CAS  PubMed  Google Scholar 

  33. Priyanga K, Vijayalakshmi K (2018) Effect of quercetin and hesperidin on rotenone induced SH-SY5Y cells. J Pharm Chem Biol Sci 5(4):429–436

    Google Scholar 

  34. Bournival J, Quessy P, Martinoli MG (2009) Protective effects of resveratrol and quercetin against MPP+ induced oxidative stress act by modulating markers of apoptotic death in dopaminergic neuron. Cell Mol Neurobiol 29:1169–1180

    Article  CAS  PubMed  Google Scholar 

  35. Bournival J, Plouffe M, Renaud J, Provencher C, Martinoli MG (2012) Quercetin and sesamin protect dopaminergic cells from MPP+-induced neuroinflammation in a microglial (N9)-neuronal (PC12) coculture system. Oxid Med Cell Longev 2012:921941

    Article  PubMed  PubMed Central  Google Scholar 

  36. Ly JD, Grubb DR, Lawen A (2003) The mitochondrial membrane potential (∆Ψm) in apoptosis; an update. Apoptosis 8:115–128

    Article  CAS  PubMed  Google Scholar 

  37. Nemani VM, Lu W, Berge V, Nakamura K, Onoa B, Lee MK, Chaudhry FA, Nicoll RA, Edwards RH (2010) Increased expression of alpha synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65(1):66–79

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Senior SL, Ninkina N, Deacon R, Bannerman D, Buchman VL, Cragg SJ, Wade-Martins R (2008) Increased striatal dopamine release and hyperdopaminergic like behavior in mice lacking both alpha-synuclein and gamma-synuclein. Eur J Neurosci 27(4):947–957

    Article  PubMed  PubMed Central  Google Scholar 

  39. Emamzadeh FN (2017) Role of apolipoproteins and α-synuclein in Parkinson’s disease. J Mol Neurosci 62(3–4):344–355. https://doi.org/10.1007/s12031-017-0942-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Antonioli M, Rienzo D, Piacentini M, Fimia GM (2017) Emerging mechanism in initiating and terminating autophagy. Trends Biochem Sci 42(1):28–41

    Article  CAS  PubMed  Google Scholar 

  41. Cuervo AM, Wong E (2014) Chaperone-mediated autophagy: roles in disease and aging. Cell Res 24(1):92–104

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

JB sincerely acknowledges Maulana Abul Kalam Azad University of Technology, West Bengal (MAKAUT, WB) for laboratory and infrastructure facilities. SP gratefully thanks UGC (Grant No. F/17-164/2013/SA-1) and ICMR JRF (Grant No. 3/1/3/JRF-2013/HRD-10-40901) for providing fellowship. JC is further thankful to MAKAUT TEQIP program for providing fellowship. Furthermore the authors are grateful to Jyotirmoy Rakshit and Dr. Susmita Roy, Dept. of Biotechnology, MAKAUT,WB for their critical reviewing and valuable suggestions during the manuscript preparation. Thanks are also due to Aleepta Guha Ray and Dr. Arun Bandyopadhyay, Indian Institute of Chemical Biology (CSIR), Kolkata for extending their experimental support whenever required. The authors are also thankful to CRNN, University of Calcutta for flow cytometry facilities.

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  1. Department of Biotechnology, Maulana Abul Kalam Azad University of Technology, West Bengal, Haringhata, West Bengal, India

    Sourav Pakrashi, Joyeeta Chakraborty & Jaya Bandyopadhyay

  2. Department of Microbiology, Bidhannagar College, Kolkata, West Bengal, India

    Sourav Pakrashi

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Pakrashi, S., Chakraborty, J. & Bandyopadhyay, J. Neuroprotective Role of Quercetin on Rotenone-Induced Toxicity in SH-SY5Y Cell Line Through Modulation of Apoptotic and Autophagic Pathways. Neurochem Res 45, 1962–1973 (2020). https://doi.org/10.1007/s11064-020-03061-8

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