Journal of Ginseng Research

The Korean Society of Ginseng (고려인삼학회)
권호 표지
DOI QR코드

DOI QR Code

Ginsenosides attenuate bioenergetics and morphology of mitochondria in cultured PC12 cells under the insult of amyloid beta-peptide

  • Kwan, Kenneth Kin Leung (Shenzhen Key Laboratory of Edible and Medicinal Bioresources, Shenzhen Research Institute) ;
  • Yun, Huang (Shenzhen Key Laboratory of Edible and Medicinal Bioresources, Shenzhen Research Institute) ;
  • Dong, Tina Ting Xia (Shenzhen Key Laboratory of Edible and Medicinal Bioresources, Shenzhen Research Institute) ;
  • Tsim, Karl Wah Keung (Shenzhen Key Laboratory of Edible and Medicinal Bioresources, Shenzhen Research Institute)
  • Received : 2020.07.04
  • Accepted : 2020.09.21
  • Published : 2021.07.01
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Mitochondrial dysfunction is one of the significant reasons for Alzheimer's disease (AD). Ginsenosides, natural molecules extracted from Panax ginseng, have been demonstrated to exert essential neuroprotective functions, which can ascribe to its anti-oxidative effect, enhancing central metabolism and improving mitochondrial function. However, a comprehensive analysis of cellular mitochondrial bioenergetics after ginsenoside treatment under Aβ-oxidative stress is missing. Methods: The antioxidant activities of ginsenoside Rb1, Rd, Re, Rg1 were compared by measuring the cell survival and reactive oxygen species (ROS) formation. Next, the protective effects of ginsenosides of mitochondrial bioenergetics were examined by measuring oxygen consumption rate (OCR) in PC12 cells under Aβ-oxidative stress with an extracellular flux analyzer. Meanwhile, mitochondrial membrane potential (MMP) and mitochondrial dynamics were evaluated by confocal laser scanning microscopy. Results: Ginsenoside Rg1 possessed the strongest anti-oxidative property, and which therefore provided the best protective function to PC12 cells under the Aβ oxidative stress by increasing ATP production to 3 folds, spare capacity to 2 folds, maximal respiration to 2 folds and non-mitochondrial respiration to 1.5 folds, as compared to Aβ cell model. Furthermore, ginsenoside Rg1 enhanced MMP and mitochondrial interconnectivity, and simultaneously reduced mitochondrial circularity. Conclusion: In the present study, these results demonstrated that ginsenoside Rg1 could be the best natural compound, as compared with other ginsenosides, by modulating the OCR of cultured PC12 cells during oxidative phosphorylation, in regulating MMP and in improving mitochondria dynamics under Aβ-induced oxidative stress.

Keywords

Acknowledgement

This work is supported by GBA Institute of Collaborate Innovation (GICI-022); Special project of Foshan University of science and technology in 2019 (FSUST19-SRI10); Shenzhen Science and Technology Innovation Committee (ZDSYS201707281432317; JCYJ20170413173747440; JCYJ20180306174903174), Zhongshan Municipal Bureau of Science and Technology (ZSST20SC03); Guangzhou Science and Technology Committee Research Grant (GZSTI16SC02; GZSTI17SC02); Hong Kong RGC Theme-based Research Scheme (T13-605/18-W); Hong Kong Innovation Technology Fund (UIM/340, UIM/385, ITS/500/18FP; TUYF19SC02; PD18SC01 and HMRF18SC06).

References

  1. Eikelenboom P, Rozemuller AJ, Hoozemans JJ, Veerhuis R, Van Gool WA. Neuroinflammation and Alzheimer disease: clinical and therapeutic implications. Alzheimer Dis Assoc Disord 2000;14(Supplement):S54-61.
  2. LeBlanc A. The role of b-amyloid peptide in Alzheimer's disease. Metab Brain Dis 1994;9(1):3-31. https://doi.org/10.1007/BF01996071
  3. Brothers HM, Gosztyla ML, Robinson SR. The physiological roles of amyloid-β peptide hint at new ways to treat Alzheimer's disease. Front Aging Neurosci 2018;10.
  4. Pagani L, Eckert A. Amyloid-beta interaction with mitochondria. Int J Alzheimers Dis 2011:1-12.
  5. Sheikh-Bahaei N, Sajjadi SA, Pierce AL. Current role for biomarkers in clinical diagnosis of Alzheimer disease and frontotemporal dementia. Curr Treat Options Neurol 2017;19(12).
  6. Kim JH. Pharmacological and medical applications of Panax ginseng and ginsenosides: a review for use in cardiovascular diseases. J Ginseng Res 2018;42(3):264-9. https://doi.org/10.1016/j.jgr.2017.10.004
  7. Qi LW, Wang CZ, Yuan CS. Ginsenosides from American ginseng: chemical and pharmacological diversity. Phytochemistry 2011;72(8):689-99. https://doi.org/10.1016/j.phytochem.2011.02.012
  8. Saw CLL, Yang AYY, Cheng DC, Boyanapalli SSS, Su ZY, Khor TO, Gao S, Wang J, Jiang ZH, Kong ANT. Pharmacodynamics of ginsenosides: antioxidant activities, activation of Nrf2, and potential synergistic effects of combinations. Chem Res Toxicol 2012;25(8):1574-80. https://doi.org/10.1021/tx2005025
  9. Huang T, Fang F, Chen L, Zhu Y, Zhang J, Chen X, Shidu Yan SS. Ginsenoside Rg1 attenuates oligomeric Aβ1-42-induced mitochondrial dysfunction. Curr Alzheimer Res 2012;9(3):388-95. https://doi.org/10.2174/156720512800107636
  10. Kim J, Kim SH, Lee DS, Lee DJ, Kim SH, Chung S, Yang HO. Effects of fermented ginseng on memory impairment and b-amyloid reduction in Alzheimer's disease experimental models. J Ginseng Res 2013;37(1):100-7. https://doi.org/10.5142/jgr.2013.37.100
  11. Zhao H, Li Q, Zhang Z, Pei X, Wang J, Li Y. Long-term ginsenoside consumption prevents memory loss in aged samp8 mice by decreasing oxidative stress and up-regulating the plasticity-related proteins in hippocampus. Brain Res 2009;1256:111-22. https://doi.org/10.1016/j.brainres.2008.12.031
  12. Mohanan P, Subramaniyam S, Mathiyalagan R, Yang DC. Molecular signaling of ginsenosides Rb1, Rg1, and Rg3 and their mode of actions. J Ginseng Res 2018;42(2):123-32. https://doi.org/10.1016/j.jgr.2017.01.008
  13. Tan BL, Norhaizan ME, Liew WPP, Sulaiman Rahman HS. Antioxidant and oxidative stress: a mutual interplay in age-related diseases. Front Pharmacol 2018;9.
  14. Desler C, Hansen TL, Frederiksen JB, Marcker ML, Singh KK, Rasmussen LJ. Is there a link between mitochondrial reserve respiratory capacity and aging? J Aging Res 2012;2012:1-9.
  15. Kausar S, Wang F, Cui H. The role of mitochondria in reactive oxygen species generation and its implications for neurodegenerative diseases. Cells 2018;7(12):274. https://doi.org/10.3390/cells7120274
  16. Hu W, Mak S, Zheng Z, Xia Y, Xu M, Duan R, Dong T, Li S, Zhan C, Shang X, et al. Shexiang Baoxin Pill, a Traditional Chinese herbal formula, rescues the cognitive impairments in APP/PS1 transgenic mice. Front Pharmacol 2020;11: 1045. https://doi.org/10.3389/fphar.2020.01045
  17. Yu X, Li Y, Mu X. Effect of quercetin on PC12 Alzheimer's disease cell model induced by Aβ25-35 and its mechanism based on Sirtuin1/Nrf2/HO-1 pathway. Biomed Res Int 2020;2020:1-10.
  18. Zhou B, Li L, Qiu X, Wu J, Xu L, Shao W. Long non-coding RNA ANRIL knockdown suppresses apoptosis and pro-inflammatory cytokines while enhancing neurite outgrowth via binding microRNA-125a in a cellular model of Alzheimer's disease. Mol Med Rep 2020;22:1489-97. https://doi.org/10.3892/mmr.2020.11203
  19. Wang J, Sun P, Bao Y, Liu J, An L. Cytotoxicity of single-walled carbon nanotubes on PC12 cells. Toxicol In Vitro 2011;25:242-50. https://doi.org/10.1016/j.tiv.2010.11.010
  20. Gao J, Liu S, Xu F, Liu Y, Lv C, Deng Y, Shi J, Gong Q. Trilobatin protects against oxidative injury in neuronal PC12 cells through regulating mitochondrial ROS homeostasis mediated by AMPK/Nrf2/Sirt3 signaling pathway. Front Mol Neurosci 2018;11:267. https://doi.org/10.3389/fnmol.2018.00267
  21. Ferrick D, Neilson A, Beeson C. Advances in measuring cellular bioenergetics using extracellular flux. Drug Discov Today 2008;13:268-74. https://doi.org/10.1016/j.drudis.2007.12.008
  22. Liu X, Zhu X, Chen M, Ge Q, Shen Y, Pan S. Resveratrol protects PC12 cells against OGD/R-induced apoptosis via the mitochondrial-mediated signaling pathway. Acta Biochim Biophys Sin 2016;48:342-53. https://doi.org/10.1093/abbs/gmw011
  23. Kwan KKL, Huang Y, Leung KW, Dong TTX, Tsim KWK. Danggui Buxue Tang, A Chinese herbal decoction containing Astragali Radix and Angelicae Sinensis Radix, modulates mitochondrial bioenergetics in cultured cardiomyoblasts. Front Pharmacol 2019;10.
  24. Dagda RK, Cherra SJ, Kulich SM, Tandon A, Park D, Chu CT. Loss of pink1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission. J Biol Chem 2009;284(20):13843-55. https://doi.org/10.1074/jbc.M808515200
  25. Tong Y, Bai L, Gong R, Chuan JL, Duan XM, Zhu YX. Shikonin protects PC12 cells against b-amyloid peptide-induced cell injury through antioxidant and antiapoptotic activities. Sci Rep 2018;8(1).
  26. Liu Q, Kou JP, Yu BY. Ginsenoside Rg1 protects against hydrogen peroxide-induced cell death in PC12 cells via inhibiting Nf-kB activation. Neurochem Int 2011;58(1):119-25. https://doi.org/10.1016/j.neuint.2010.11.004
  27. Li J, Liu D, Wu JF, Zhang D, Cheng BB, Zhang YN, Yin ZF, Wang Y, Du J, Ling C. Ginsenoside Rg1 attenuates ultraviolet b-induced glucocortisides resistance in keratinocytes via Nrf2/hdac2 signaling. Sci Rep 2016;6(1).
  28. Wang Y, Liu Q, Xu YQ, Zhang YY, Lv YN, Tan Y, Jiang N, Cao GS, Ma XN, Wang JR, et al. Ginsenoside Rg1 protects against oxidative stress-induced neuronal apoptosis through myosin IIA-actin related cytoskeletal reorganization. Int J Biol Sci 2016;12(11):1341-56. https://doi.org/10.7150/ijbs.15992
  29. Liu M, Bai XY, Yu ST, Zhao WX, Qiao JH, Liu Y, Zhao DQ, Wang JW, Wang S. Ginsenoside Re Inhibits ROS/ASK-1 dependent mitochondrial apoptosis pathway and activation of Nrf2-antioxidant response in beta-amyloid-challenged SH-SY5Y Cells. Molecules 2019;24(15):2687. https://doi.org/10.3390/molecules24152687
  30. Xu M, Ma Q, Fan CL, Chen X, Zhang HM, Tang M. Ginsenosides Rb1 and Rg1 protect primary cultured astrocytes against oxygen-glucose deprivation/reoxygenation-induced injury via improving mitochondrial function. Int J Mol Sci 2019;20(23):6086. https://doi.org/10.3390/ijms20236086
  31. Shin EJ, Jo SG, Choi SB, Cho CW, Lim WC, Hong HD, Lim TG, Jang YJ, Jang M, Byun S, et al. Red ginseng improves exercise endurance by promoting mitochondrial biogenesis and myoblast differentiation. Molecules 2020;25(4):865. https://doi.org/10.3390/molecules25040865
  32. Huttemann M, Helling S, Sanderson TH, Sinkler C, Samavati L, Mahapatra G, Varughese A, Lu GR, Liu J, Ramzan R, et al. Regulation of mitochondrial respiration and apoptosis through cell signaling: cytochrome C oxidase and cytochrome C in ischemia/reperfusion injury and inflammation. Biochim Biophys Acta 2012;1817(4):598-609. https://doi.org/10.1016/j.bbabio.2011.07.001
  33. Archer SL. Mitochondrial dynamics d mitochondrial fission and fusion in human diseases. N Engl J Med 2013;369(23):2236-51. https://doi.org/10.1056/NEJMra1215233
  34. Manczak M, Kandimalla R, Yin XL, Reddy PH. Mitochondrial division inhibitor 1 reduces dynamin-related protein 1 and mitochondrial fission activity. Hum Mol Genet 2018;28(2):177-99. https://doi.org/10.1093/hmg/ddy335
  35. Dong GT, Chen TB, Ren XC, Zhang ZF, Huang WX, Liu L, Luo P, Zhou H. Rg1 prevents myocardial hypoxia/reoxygenation injury by regulating mitochondrial dynamics imbalance via modulation of glutamate dehydrogenase and mitofusin 2. Mitochondrion 2016;26:7-18. https://doi.org/10.1016/j.mito.2015.11.003
  36. Filadi R, Pendin D, Pizzo P. Mitofusin 2: from functions to disease. Cell Death Dis 2018;9(3).
  37. Ong SB, Kalkhoran SB, Cabrera-Fuentes HA, Hausenloy DJ. Mitochondrial fusion and fission proteins as novel therapeutic targets for treating cardiovascular disease. Eur J Pharmacol 2015;763:104-14. https://doi.org/10.1016/j.ejphar.2015.04.056
  38. Wang W, Liao QP, Quan LH, Liu CY, Chang Q, Liu XM, Liao YH. The effect of Acorus gramineus on the bio-availabilities and brain concentrations of ginsenosides Rg1, Re and Rb1 after oral administration of Kai-Xin-San preparations in rats. J Ethnopharmacol 2010;131(2):313-20. https://doi.org/10.1016/j.jep.2010.06.034
  39. Liang WY, Xu W, Zhu J, Zhu YD, Gu QL, Li YP, Guo CJ, Huang YJ, Yu JF, Wang WX, et al. Ginkgo biloba extract improves brain uptake of ginsenosides by increasing blood-brain barrier permeability via activating A1 adenosine receptor signaling pathway. J Ethnopharmacol 2020;246:112243. https://doi.org/10.1016/j.jep.2019.112243
  40. Liu Z, Qi Y, Cheng Z, Zhu X, Fan C, Yu SY. The effects of ginsenoside Rg1 on chronic stress induced depression-like behaviors, BDNF expression and the phosphorylation of PKA and CREB in rats. Neuroscience 2016;322:358-69. https://doi.org/10.1016/j.neuroscience.2016.02.050
  41. Van Kampen JM, Baranowski DB, Shaw CA, Kay DG. Panax ginseng is neuroprotective in a novel progressive model of Parkinson's disease. Exp Gerontol 2014;50:95-105. https://doi.org/10.1016/j.exger.2013.11.012
  42. Tian J, Shi J, Wei M, Qin R, Ni J, Zhang X, Li T, Wang Y. The efficacy and safety of Fufangdanshen tablets (Radix Salviae miltiorrhizae formula tablets) for mild to moderate vascular dementia: a study protocol for a randomized controlled trial. Trials 2016;17:281. https://doi.org/10.1186/s13063-016-1410-5

Cited by

  1. Ginsenoside Rd: A promising natural neuroprotective agent vol.95, 2021, https://doi.org/10.1016/j.phymed.2021.153883