α-Arbutin Protects Against Parkinson’s Disease-Associated Mitochondrial Dysfunction In Vitro and In Vivo

Abstract

Parkinson’s disease (PD), the most common neurodegenerative movement disorder, is characterized by the progressive loss of dopaminergic neurons in substantia nigra. The underlying mechanisms of PD pathogenesis have not been fully illustrated and currently PD remains incurable. Accumulating evidences suggest that mitochondrial dysfunction plays pivotal role in the dopaminergic neuronal death. Therefore, discovery of novel and safe agent for rescuing mitochondrial dysfunction would benefit PD treatment. Here we demonstrated for the first time that α-Arbutin (Arb), a natural polyphenol extracted from Ericaceae species, displayed significant protective effect on the rotenone (Rot)-induced mitochondrial dysfunction and apoptosis of human neuroblastoma cell (SH-SY5Y). We further found that the neuroprotective effect of Arb was associated with ameliorating oxidative stress, stabilizing of mitochondrial membrane potential, and enhancing adenosine triphosphate production. To investigate the underlying mechanism, we checked the AMP-activated protein kinase and autophagy pathway and we found that both were involved in the neuroprotection of Arb. Moreover, we explored the protective effect of Arb in drosophila PD model and found that Arb rescued parkin deficiency-induced motor function disability and mitochondrial abnormality of drosophila. Taken together, our study demonstrated that Arb got excellent neuroprotective effect on PD models both in vitro and in vivo and Arb might serve as a potent therapeutic agent for the treatment of PD.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

References

  1. Abousleiman, P. M., Muqit, M. M. K., & Wood, N. W. (2006). Expanding insights of mitochondrial dysfunction in Parkinson’s disease. Nature Reviews Neuroscience,7(3), 207–219.

    CAS  Google Scholar 

  2. Arsikin, K., Kravic-Stevovic, T., & Jovanovic, M. (2012). Autophagy-dependent and -independent involvement of AMP-activated protein kinase in 6-hydroxydopamine toxicity to SH-SY5Y neuroblastoma cells. Biochimica et Biophysica Acta,1822(11), 1826–1836.

    CAS  PubMed  Google Scholar 

  3. Auciello, F. R., Ross, F. A., Ikematsu, N., & Hardie, D. G. (2014). Oxidative stress activates AMPK in cultured cells primarily by increasing cellular AMP and/or ADP. FEBS Letters,588(18), 3361–3366.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Ball, N., Teo, W. P., Chandra, S., & Chapman, J. (2019). Parkinson’s disease and the environment. Front Neurol,10, 219.

    Google Scholar 

  5. Banerjee, R., Starkov, A. A., Beal, M. F., & Thomas, B. (2009). Mitochondrial dysfunction in the limelight of Parkinson’s disease pathogenesis. Biochimica et Biophysica Acta,1792(7), 651–663.

    CAS  PubMed  Google Scholar 

  6. Barnham, K. J., Masters, C. L., & Bush, A. I. (2004). Neurodegenerative disease and oxidative stress. Nature Reviews Drug Discovery,3(3), 205–214.

    CAS  PubMed  Google Scholar 

  7. Betarbet, R., Sherer, T. B., MacKenzie, G., Garcia-Osuna, M., Panov, A. V., & Greenamyre, J. T. (2000). Chronic systemic pesticide exposure reproduces features of Parkinson’s disease. Nature Neuroscience,3(12), 1301–1306.

    CAS  PubMed  Google Scholar 

  8. Burbulla, L. F., Song, P., Mazzulli, J. R., Zampese, E., Wong, Y. C., & Jeon, S. (2017). Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease. Science,357(6357), 1255–1261.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Dauer, W., & Przedborski, S. (2003). Parkinson’s disease: Mechanisms and models. Neuron,39(6), 889–909.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Ferretta, A., Gaballo, A., Tanzarella, P., Piccoli, C., Capitanio, N., Nico, B., et al. (2014). Effect of resveratrol on mitochondrial function: Implications in parkin-associated familiar Parkinson’s disease. Biochimica et Biophysica Acta,1842(7), 902–915.

    CAS  PubMed  Google Scholar 

  11. Fu, W., Zhuang, W., Zhou, S., & Wang, X. (2015). Plant-derived neuroprotective agents in Parkinson’s disease. American Journal of Translational Research,7(7), 1189–1202.

    PubMed  PubMed Central  Google Scholar 

  12. Garcia-Jimenez, A., Teruel-Puche, J. A., Berna, J., Rodriguez-Lopez, J. N., Tudela, J., & Garcia-Canovas, F. (2017). Action of tyrosinase on alpha and beta- arbutin: A kinetic study. PLoS ONE,12(5), e0177330.

    PubMed  PubMed Central  Google Scholar 

  13. Ghosh, A., Chandran, K., Kalivendi, S. V., Joseph, J., Antholine, W. E., Hillard, C. J., et al. (2010). Neuroprotection by a mitochondria-targeted drug in a Parkinson’s disease model. Free Radical Biology and Medicine,49(11), 1674–1684.

    CAS  PubMed  Google Scholar 

  14. González-Polo, R. A., Niso-Santano, M., Ortíz-Ortíz, M. A., Gómez-Martín, A., Morán, J. M., García-Rubio, L., et al. (2007). Inhibition of paraquat-induced autophagy accelerates the apoptotic cell death in neuroblastoma SH-SY5Y cells. Toxicological Sciences,97(2), 448–458.

    PubMed  Google Scholar 

  15. Greene, J. C., Whitworth, A. J., Kuo, I., Andrews, L. A., Feany, M. B., & Pallanck, L. J. (2003). Mitochondrial pathology and apoptotic muscle degeneration in Drosophila parkin mutants. Proceedings of the National Academy of Sciences of the United States of America,100(7), 4078–4083.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Hall, A. G. (1999). Review: The role of glutathione in the regulation of apoptosis. European Journal of Clinical Investigation,29(3), 238–245.

    CAS  PubMed  Google Scholar 

  17. Hardie, D. G. (2007). AMP-activated/SNF1 protein kinases, conserved guardians of cellular energy. Nature Reviews Molecular Cell Biology,8(3), 774–785.

    CAS  PubMed  Google Scholar 

  18. Isenberg, J. S., & Klaunig, J. E. (2000). Role of the mitochondrial membrane permeability transition (MPT) in rotenone-induced apoptosis in liver cells. Toxicological Sciences,53(2), 340–351.

    CAS  PubMed  Google Scholar 

  19. Katsuragi, Y., Ichimura, Y., & Komatsu, M. (2015). p62/SQSTM1 functions as a signaling hub and an autophagy adaptor. FEBS Journal,282(24), 4672–4678.

    CAS  PubMed  Google Scholar 

  20. Kavitha, M., Manivasagam, T., Essa, M. M., Tamilselvam, K., Selvakumar, G. P., Karthikeyan, S., et al. (2014). Mangiferin antagonizes rotenone: Induced apoptosis through attenuating mitochondrial dysfunction and oxidative stress in SK-N-SH neuroblastoma cells. Neurochemical Research,39(4), 668–676.

    CAS  PubMed  Google Scholar 

  21. Koppula, S., Kumar, H., More, S. V., Lim, H. W., Hong, S. M., & Choi, D. K. (2012). Recent updates in redox regulation and free radical scavenging effects by herbal products in experimental models of Parkinson’s disease. Molecules,17(10), 11391–11420.

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Lim, K. L., & Ng, C. H. (2009). Genetic models of Parkinson disease. Biochimica et Biophysica Acta,1792(7), 604–615.

    CAS  PubMed  Google Scholar 

  23. Liu, C. S., Chen, N. H., & Zhang, J. T. (2006). Protection of PC12 cells from hydrogen peroxide-induced cytotoxicity by salvianolic acid B, a new compound isolated from Radix Salviae miltiorrhizae. Phytomedicine,14(7–8), 492–497.

    PubMed  Google Scholar 

  24. Liu, C. Q., Deng, L., & Zhang, P. (2013). Screening of high α-arbutin producing strains and production of α-arbutin by fermentation. World Journal of Microbiology and Biotechnology,29(8), 1391–1398.

    CAS  PubMed  Google Scholar 

  25. Moon, Y., Lee, K. H., Park, J. H., Geum, D., & Kim, K. (2005). Mitochondrial membrane depolarization and the selective death of dopaminergic neurons by rotenone: Protective effect of coenzyme Q (10). Journal of Neurochemistry,93(5), 1199–1208.

    CAS  PubMed  Google Scholar 

  26. Narendra, D., Tanaka, A., Suen, D. F., & Youle, R. J. (2008). Parkin is recruited selectively to impaired mitochondria and promotes their autophagy. Journal of Cell Biology,183(5), 795–803.

    CAS  PubMed  Google Scholar 

  27. Ng, C. H., Guan, M. S., Koh, C., Ouyang, X., Yu, F., Tan, E. K., et al. (2012). AMP kinase activation mitigates dopaminergic dysfunction and mitochondrial abnormalities in Drosophila models of Parkinson’s disease. Journal of Neuroscience,32(41), 14311–14317.

    CAS  PubMed  Google Scholar 

  28. Park, J. S., Davis, R. L., & Sue, C. M. (2018). Mitochondrial dysfunction in Parkinson’s disease: New mechanistic insights and therapeutic perspectives. Current Neurology and Neuroscience Reports,18(5), 21.

    PubMed  PubMed Central  Google Scholar 

  29. Park, J., Lee, S. B., Lee, S., Kim, Y., Song, S., Kim, S., et al. (2006). Mitochondrial dysfunction in Drosophila PINK1 mutants is complemented by parkin. Nature,44(7097), 1157–1161.

    Google Scholar 

  30. Poels, J., Spasić, M. R., & Callaerts, P. (2009). Expanding roles for AMP-activated protein kinase in neuronal survival and autophagy. BioEssays,31(9), 944–952.

    CAS  PubMed  Google Scholar 

  31. Reed, D. J., & Savage, M. K. (1995). Influence of metabolic inhibitors on mitochondrial permeability transition and glutathione status. Biochimica et Biophysica Acta,1271(1), 43–50.

    PubMed  Google Scholar 

  32. Reinhardt, P., Schmid, B., Burbulla, L. F., Schondorf, D. C., Wagner, L., Glatza, M., et al. (2013). Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression. Cell Stem Cell,12(3), 354–367.

    CAS  PubMed  Google Scholar 

  33. Ryan, B. J., Hoek, S., Fon, E. A., & Wade-Martins, R. (2015). Mitochondrial dysfunction and mitophagy in Parkinson’s: From familial to sporadic disease. Trends in Biochemical Sciences,40(4), 200–210.

    CAS  PubMed  Google Scholar 

  34. Schapira, A. H. V. (2008). Mitochondria in the etiology and pathogenesis of Parkinson’s disease. The Lancet Neurology,7(3), 97–109.

    CAS  PubMed  Google Scholar 

  35. Solesio, M., Prime, T., Logan, A., Murphy, M. P., Del Mar Arroyo-Jimenez, M., Jordán, J., et al. (2013). The mitochondria-targeted anti-oxidant MitoQ reduces aspects of mitochondrial fission in the 6-OHDA cell model of Parkinson’s disease. Biochimica et Biophysica Acta,1832(1), 174–182.

    CAS  PubMed  Google Scholar 

  36. Sugimoto, K., Nishimura, T., Nomura, K., Sugimoto, K., & Kuriki, T. (2003). Syntheses of arbutin-alpha-glycosides and a comparison of their inhibitory effects with those of alpha-arbutin and arbutin on human tyrosinase. Chemical & Pharmaceutical Bulletin,51(7), 798–801.

    CAS  Google Scholar 

  37. Sundararaman, A., Amirtham, U., & Rangarajan, A. (2016). Calcium-oxidant signaling network regulates AMP-activated protein kinase (AMPK) activation upon matrix deprivation. Journal of Biological Chemistry,291(28), 14410–14429.

    CAS  PubMed  Google Scholar 

  38. Surmeier, D. J., Obeso, J. A., & Halliday, G. M. (2017). Selective neuronal vulnerability in Parkinson disease. Nature Reviews Neuroscience,18(2), 101–113.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Talpade, D. J., Greene, J. G., Higgins, D. S., & Greenamyre, J. T. (2000). In vivo labeling of mitochondrial complex I (NADH:ubiquinone oxidoreductase) in rat brain using [(3)H]dihydrorotenone. Journal of Neurochemistry,75(6), 2611–2621.

    CAS  PubMed  Google Scholar 

  40. Tessari, I., Bisaglia, M., Valle, F., et al. (2008). The reaction of alpha-synuclein with tyrosinase: Possible implications for Parkinson disease. Journal of Biological Chemistry,283(24), 16808–16817.

    CAS  PubMed  Google Scholar 

  41. Thomas, B., & Beal, M. F. (2007). Parkinson’s disease. Human Molecular Genetics,16(2), 183–194.

    Google Scholar 

  42. Uribe, P., Villegas, J. V., Boguen, R., Treulen, F., Sánchez, R., Mallmann, P., et al. (2017). Use of the fluorescent dye tetramethylrhodamine methyl ester perchlorate for mitochondrial membrane potential assessment in human spermatozoa. Andrologia. https://doi.org/10.1111/and.12753.

    Article  PubMed  Google Scholar 

  43. Uttara, B., Singh, A. V., Zamboni, P., & Mahajan, R. T. (2009). Oxidative stress and neurodegenerative diseases: A review of upstream and downstream antioxidant therapeutic options”. Current Neuropharmacology,7(1), 65–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Wang, X., & Hai, C. (2016). Novel insights into redox system and the mechanism of redox regulation. Molecular Biology Reports,43(7), 607–628.

    CAS  PubMed  Google Scholar 

  45. Wang, C., Lu, R., Ouyang, X., Ho, M. W., Chia, W., Yu, F., et al. (2007). Drosophila overexpressing parkin R275W mutant exhibits dopaminergic neuron degeneration and mitochondrial abnormalities. Journal of Neuroscience,27(32), 8563–8570.

    CAS  PubMed  Google Scholar 

  46. Weisova, P., Davila, D., Tuffy, L. P., Ward, M. W., Concannon, C. G., & Prehn, J. H. (2011). Role of 5′-adenosine monophosphate-activated protein kinase in cell survival and death responses in neurons. Antioxidants & Redox Signaling,14(2011), 1863–1876.

    CAS  Google Scholar 

  47. Whitworth, A. J., Wes, P. D., & Pallanck, L. J. (2006). Drosophila models pioneer a new approach to drug discovery for Parkinson’s disease. Drug Discovery Today,11(3/4), 119–126.

    CAS  PubMed  Google Scholar 

  48. Xiong, N., Huang, J., Zhang, Z., Zhang, Z., Xiong, J., Liu, X., et al. (2009). Stereotaxical infusion of rotenone: A reliable rodent model for Parkinson’s disease. PLoS ONE,4(11), e7878.

    PubMed  PubMed Central  Google Scholar 

  49. Xiong, N., Long, X., Xiong, J., Jia, M., Chen, C., Huang, J., et al. (2012). Mitochondrial complex I inhibitor rotenone-induced toxicity and its potential mechanisms in Parkinson’s disease models. Critical Reviews in Toxicology,42(7), 613–632.

    CAS  PubMed  Google Scholar 

  50. Zhang, H. A., Gao, M., Zhang, L., Zhao, Y., Shi, L. L., Chen, B. N., et al. (2012). Salvianolic acid A protects human SH-SY5Y neuroblastoma cells against H2O2-induced injury by increasing stress tolerance ability. Biochemical and Biophysical Research Communications,421(3), 479–483.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported from the National Science Foundation of China (Grant Nos. 81672508, 81773802), and Jiangsu Provincial Foundation for Distinguished Young Scholars (BK20170041), Key University Science Research Project of Jiangsu Province (No. 16KJA180004), Natural Science Foundation of Shaanxi Province (2019JM-016), Fundamental Research Funds for the Central Universities and China-Sweden Joint Mobility Project (51811530018).

Author information

Affiliations

Authors

Corresponding authors

Correspondence to Chengwu Zhang or Lin Li.

Ethics declarations

Conflict of interests

The authors declare no conflict of interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Ding, Y., Kong, D., Zhou, T. et al. α-Arbutin Protects Against Parkinson’s Disease-Associated Mitochondrial Dysfunction In Vitro and In Vivo. Neuromol Med 22, 56–67 (2020). https://doi.org/10.1007/s12017-019-08562-6

Download citation

Keywords

  • α-Arbutin
  • Parkinson’s disease
  • Mitochondria
  • Oxidative stress
  • Autophagy