Journal of Ginseng Research

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

DOI QR Code

A UPLC/MS-based metabolomics investigation of the protective effect of ginsenosides Rg1 and Rg2 in mice with Alzheimer's disease

  • Li, Naijing (Department of Gerontology, The Shengjing Affiliated Hospital, China Medical University) ;
  • Liu, Ying (College of Pharmacy, Shenyang Pharmaceutical University) ;
  • Li, Wei (College of Pharmacy, Shenyang Pharmaceutical University) ;
  • Zhou, Ling (College of Pharmacy, Shenyang Pharmaceutical University) ;
  • Li, Qing (College of Pharmacy, Shenyang Pharmaceutical University) ;
  • Wang, Xueqing (Department of Gastroenterology, The Shengjing Affiliated Hospital, China Medical University) ;
  • He, Ping (Department of Gerontology, The Shengjing Affiliated Hospital, China Medical University)
  • Received : 2015.01.29
  • Accepted : 2015.04.20
  • Published : 2016.01.15
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Alzheimer's disease (AD) is a progressive brain disease, for which there is no effective drug therapy at present. Ginsenoside Rg1 (G-Rg1) and G-Rg2 have been reported to alleviate memory deterioration. However, the mechanism of their anti-AD effect has not yet been clearly elucidated. Methods: Ultra performance liquid chromatography tandem MS (UPLC/MS)-based metabolomics was used to identify metabolites that are differentially expressed in the brains of AD mice with or without ginsenoside treatment. The cognitive function of mice and pathological changes in the brain were also assessed using the Morris water maze (MWM) and immunohistochemistry, respectively. Results: The impaired cognitive function and increased hippocampal $A{\beta}$ deposition in AD mice were ameliorated by G-Rg1 and G-Rg2. In addition, a total of 11 potential biomarkers that are associated with the metabolism of lysophosphatidylcholines (LPCs), hypoxanthine, and sphingolipids were identified in the brains of AD mice and their levels were partly restored after treatment with G-Rg1 and G-Rg2. G-Rg1 and G-Rg2 treatment influenced the levels of hypoxanthine, dihydrosphingosine, hexadecasphinganine, LPC C 16:0, and LPC C 18:0 in AD mice. Additionally, G-Rg1 treatment also influenced the levels of phytosphingosine, LPC C 13:0, LPC C 15:0, LPC C 18:1, and LPC C 18:3 in AD mice. Conclusion: These results indicate that the improvements in cognitive function and morphological changes produced by G-Rg1 and G-Rg2 treatment are caused by regulation of related brain metabolic pathways. This will extend our understanding of the mechanisms involved in the effects of G-Rg1 and G-Rg2 on AD.

Keywords

References

  1. Inoue K, Tsutsui H, Akatsu H, Hashizume Y, Matsukawa N, Yamamoto T, Toyo'oka T. Metabolic profiling of Alzheimer's disease brains. Sci Rep 2013;3:2364-72. https://doi.org/10.1038/srep02364
  2. Wan W, Chen H, Li Y. The potential mechanisms of Abeta-receptor for advanced glycation end-products interaction disrupting tight junctions of the blood-brain barrier in Alzheimer's disease. Int J Neurosci 2014;124:75-81. https://doi.org/10.3109/00207454.2013.825258
  3. Pratico D. Oxidative stress hypothesis in Alzheimer's disease: a reappraisal. Trends Pharmacol Sci 2008;29:609-15. https://doi.org/10.1016/j.tips.2008.09.001
  4. Fang F, Chen X, Huang T, Lue LF, Luddy JS, Yan SS. Multi-faced neuroprotective effects of Ginsenoside Rg1 in an Alzheimer mouse model. Biochim Biophys Acta 2012;1822:286-92. https://doi.org/10.1016/j.bbadis.2011.10.004
  5. Tan X, Gu J, Zhao B, Wang S, Yuan J, Wang C, Chen J, Liu J, Feng L, Jia X. Ginseng improves cognitive deficit via the RAGE/$NF-{\kappa}B$ pathway in advanced glycation end product-induced rats. J Ginseng Res 2014;9:1-9.
  6. Liu L, Huang J, Hu X, Li K, Sun C. Simultaneous determination of ginsenoside (G-Re, G-Rg1, G-Rg2, G-F1, G-Rh1) and protopanaxatriol in human plasma and urine by LC-MS/MS and its application in a pharmacokinetics study of G-Re in volunteers. J Chromatogr B 2011;879:2011-7. https://doi.org/10.1016/j.jchromb.2011.05.018
  7. Li N, Liu B, Dluzen DE, Jin Y. Protective effects of ginsenoside Rg2 against glutamate-induced neurotoxicity in PC12 cells. J Ethnopharmacol 2007;111: 458-63. https://doi.org/10.1016/j.jep.2006.12.015
  8. Kim JH. Cardiovascular diseases and Panax ginseng: a review on molecular mechanisms and medical applications. J Ginseng Res 2012;36:16-26. https://doi.org/10.5142/jgr.2012.36.1.16
  9. Chen F, Eckman EA, Eckman CB. Reductions in levels of the Alzheimer's amyloid peptide after oral administration of ginsenosides. Faseb J 2006;20:1269-71. https://doi.org/10.1096/fj.05-5530fje
  10. Shi C, Zheng DD, Fang L, Wu F, Kwong WH, Xu J. Ginsenoside Rg1 promotes nonamyloidgenic cleavage of APP via estrogen receptor signaling to MAPK/ERK and PI3K/Akt. Biochim Biophys Acta 2012;1820:453-60. https://doi.org/10.1016/j.bbagen.2011.12.005
  11. Kim HJ, Kim P, Shin CY. A comprehensive review of the therapeutic and pharmacological effects of ginseng and ginsenosides in central nervous system. J Ginseng Res 2013;37:8-29. https://doi.org/10.5142/jgr.2013.37.8
  12. Nicholson JK, Lindon JC, Holmes E. 'Metabonomics': understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica 1999;29:1181-9. https://doi.org/10.1080/004982599238047
  13. Lan MJ, McLoughlin GA, Griffin JL, Tsang TM, Huang JTJ, Yuan P, Manji H, Holmes E, Bahn S. Metabonomic analysis identifies molecular changes associated with the pathophysiology and drug treatment of bipolar disorder. Mol Psychiatr 2009;14:269-79. https://doi.org/10.1038/sj.mp.4002130
  14. Want EJ, Nordstrom A, Morita H, Siuzdak G. From exogenous to endogenous. the inevitable imprint of mass spectrometry in metabolomics. J Proteome Res 2007;6:459-68. https://doi.org/10.1021/pr060505+
  15. Zheng X, Kang A, Dai C, Liang Y, Xie T, Xie L, Peng Y, Wang G, Hao H. Quantitative analysis of neurochemical panel in rat brain and plasma by liquid chromatography-tandem mass spectrometry. Anal Chem 2012;84:10044-51. https://doi.org/10.1021/ac3025202
  16. Wang X, Yang B, Sun H, Zhang A. Pattern recognition approaches and computational systems tools for ultra performance liquid chromatography-mass spectrometry-based comprehensive metabolomic profiling and pathways analysis of biological data sets. Anal Chem 2012;84:428-39. https://doi.org/10.1021/ac202828r
  17. Dai W, Wei C, Kong H, Jia Z, Han J, Zhang F, Wu Z, Gu Y, Chen S, Gu Q, et al. Effect of the traditional Chinese medicine tongxinluo on endothelial dysfunction rats studied by using urinary metabonomics based on liquid chromatography-mass spectrometry. J Pharmaceut Biomed 2011;56:86-92. https://doi.org/10.1016/j.jpba.2011.04.020
  18. Li NJ, Liu WT, Li W, Li SQ, Chen XH, Bi KS, He P. Plasma metabolic profiling of Alzheimer's disease by liquid chromatography/mass spectrometry. Clin Biochem 2010;43:992-7. https://doi.org/10.1016/j.clinbiochem.2010.04.072
  19. Liu Y, Li NJ, Zhou L, Li Q, Li W. Plasma metabolic profiling of mild cognitive impairment and Alzheimer's disease using liquid chromatography/mass spectrometry. Cent Nerv Syst Agents Med Chem 2014;14:113-20.
  20. Li X, Zhao X, Xu X, Mao X, Liu Z, Li H, Guo L, Bi K, Jia Y. Schisantherin A recovers Abeta-induced neurodegeneration with cognitive decline in mice. Physiol Behav 2014;132:10-6. https://doi.org/10.1016/j.physbeh.2014.04.046
  21. Liu Z, Zhao X, Liu B, Liu AJ, Li H, Mao X, Wu B, Bi KS, Jia Y, Jujuboside A. a neuroprotective agent from semen Ziziphi Spinosae ameliorates behavioral disorders of the dementia mouse model induced by Abeta 1-42. Eur J Pharmacol 2014;738:206-13. https://doi.org/10.1016/j.ejphar.2014.05.041
  22. Li Y, Ma Y, Zong L-X, Xing X-N, Guo R, Jiang T-Z, Sha S, Liu L, Cao Y-P. Intranasal inoculation with an adenovirus vaccine encoding ten repeats of $A{\beta}3-10$ reduces AD-like pathology and cognitive impairment in Tg-APPswe/PSEN1dE9 mice. J Neuroimmunol 2012;249:16-26. https://doi.org/10.1016/j.jneuroim.2012.04.014
  23. Ma Y, Li Y, Zong LX, Xing XN, Zhang WG, Cao YP. Improving memory and decreasing cognitive impairment in Tg-APPswe/PSEN1dE9 mice with Abeta3-10 repeat fragment plasmid by reducing Abeta deposition and inflammatory response. Brain Res 2011;1400:112-24. https://doi.org/10.1016/j.brainres.2011.05.030
  24. Yin P, Mohemaiti P, Chen J, Zhao X, Lu X, Yimiti A, Upur H, Xu G. Serum metabolic profiling of abnormal savda by liquid chromatography/mass spectrometry. J Chromatogr B 2008;871:322-7. https://doi.org/10.1016/j.jchromb.2008.05.043
  25. Huo T, Cai S, Lu X, Sha Y, Yu M, Li F. Metabonomic study of biochemical changes in the serum of type 2 diabetes mellitus patients after the treatment of metformin hydrochloride. J Pharmaceut Biomed 2009;49:976-82. https://doi.org/10.1016/j.jpba.2009.01.008
  26. Zhang H, Gao Y, Qiao PF, Zhao FL, Yan Y. Fenofibrate reduces amyloidogenic processing of APP in APP/PS1transgenic mice via PPAR-$\alpha$/PI3-K pathway. Int J Dev Neurosci 2014;38:223-31. https://doi.org/10.1016/j.ijdevneu.2014.10.004
  27. Kim HY, Kim HV, Yoon JH, Kang BR, Cho SM, Lee S, Kim JY, Kim JW, Cho Y, Woo J, et al. Taurine in drinking water recovers learning and memory in the adult APP/PS1 mouse model of Alzheimer's disease. Sci Rep 2014;4:7467-73.
  28. Bavaresco CS, Chiarani F, Matte C, Wajner M, Netto CA, de Souza Wyse AT. Effect of hypoxanthine on Na+, K+-ATPase activity and some parameters of oxidative stress in rat striatum. Brain Res 2005;1041:198-204. https://doi.org/10.1016/j.brainres.2005.02.012
  29. Gonzalez-Dominguez R, Garcia-Barrera T, Vitorica J, Gomez-Ariza JL. Metabolomic screening of regional brain alterations in the APP/PS1 transgenic model of Alzheimer's disease by direct infusion mass spectrometry. J Pharmaceut Biomed 2015;102:425-35. https://doi.org/10.1016/j.jpba.2014.10.009
  30. Xiang Z, Xu M, Liao M, Jiang Y, Jiang Q, Feng R, Zhang L, Ma G, Wang G, Chen Z, et al. Integrating genome-wide association study and brain expression data highlights cell adhesion molecules and purine metabolism in Alzheimer's disease. Mol Neurobiol 2014;09:1-8.
  31. Bavaresco CS, Chiarani F, Kolling J, Netto CA, Souza Wyse ATD. Biochemical effects of pretreatment with vitamins E and C in rats submitted to intrastriatal hypoxanthine administration. Neurochem Int 2008;52:1276-83. https://doi.org/10.1016/j.neuint.2008.01.008
  32. Wamser MN, Leite EF, Ferreira VV, Delwing-de Lima D, da Cruz JGP, Wyse ATS, Delwing-Dal Magro D. Effect of hypoxanthine, antioxidants and allopurinol on cholinesterase activities in rats. J Neural Transm 2013;120:1359-67. https://doi.org/10.1007/s00702-013-0989-x
  33. Melo JB, Agostinho P, Oliveira CR. Involvement of oxidative stress in the enhancement of acetylcholinesterase activity induced by amyloid beta-peptide. Neurosci Res 2003;45:117-27. https://doi.org/10.1016/S0168-0102(02)00201-8
  34. Bavaresco CS, Chiarani F, Duringon E, Ferro MM, Cunha CD, Netto CA, Wyse AT. Intrastriatal injection of hypoxanthine reduces striatal serotonin content and impairs spatial memory performance in rats. Metab Brain Dis 2007;22:67-76. https://doi.org/10.1007/s11011-006-9038-x
  35. Gonzalez-Dominguez R, Garcia-Barrera T, Gomez-Ariza JL. Combination of metabolomic and phospholipid-profiling approaches for the study of Alzheimer's disease. J Proteomics 2014;104:37-47. https://doi.org/10.1016/j.jprot.2014.01.014
  36. Frisardi V, Panza F, Seripa D, Farooqui T, Farooqui AA. Glycerophospholipids and glycerophospholipid-derived lipid mediators: a complex meshwork in Alzheimer's disease pathology. Prog Lipid Res 2011;50:313-30. https://doi.org/10.1016/j.plipres.2011.06.001
  37. Klein J. Membrane breakdown in acute and chronic neurodegeneration: focus on choline-containing phospholipids. J Neural Transm 2000;107:1027-63. https://doi.org/10.1007/s007020070051
  38. Vestergaard MC, Morita M, Hamada T, Takagi M. Membrane fusion and vesicular transformation induced by Alzheimer's amyloid beta. Biochim Biophys Acta 2013;1828:1314-21. https://doi.org/10.1016/j.bbamem.2013.01.015
  39. Chan RB, Oliveira TG, Cortes EP, Honig LS, Duff KE, Small SA, Wenk MR, Shui G, Paolo GD. Comparative lipidomic analysis of mouse and human brain with Alzheimer disease. J Biol Chem 2012;287:2678-88. https://doi.org/10.1074/jbc.M111.274142
  40. Axelsen PH, Murphy RC. Quantitative analysis of phospholipids containing arachidonate and docosahexaenoate chains in microdissected regions of mouse brain. J Lipid Res 2010;51:660-71. https://doi.org/10.1194/jlr.D001750
  41. Haughey NJ, Bandaru VV, Bae M, Mattson MP. Roles for dysfunctional sphingolipid metabolism in Alzheimer's disease neuropathogenesis. Biochim Biophys Acta 2010;1801:878-86. https://doi.org/10.1016/j.bbalip.2010.05.003
  42. Alessenko AV. The potential role for sphingolipids in neuropathogenesis of Alzheimer's disease. Biomed Khim 2013;59:25-50. https://doi.org/10.18097/pbmc20135901025
  43. Kitatani K, Idkowiak-Baldys J, Hannun YA. The sphingolipid salvage pathway in ceramide metabolism and signaling. Cell Signal 2008;20:1010-8. https://doi.org/10.1016/j.cellsig.2007.12.006
  44. Mielke MM, Bandaru VV, Haughey NJ, Rabins PV, Lyketsos CG, Carlson MC. Serum sphingomyelins and ceramides are early predictors of memory impairment. Neurobiol Aging 2010;31:17-24. https://doi.org/10.1016/j.neurobiolaging.2008.03.011
  45. Mielke MM, Lyketsos CG. Alterations of the sphingolipid pathway in Alzheimer's disease: new biomarkers and treatment targets? Neuromol Med 2010;12:331-40. https://doi.org/10.1007/s12017-010-8121-y

Cited by

  1. Evaluation of structure-activity relationships of ginsenosides against amyloid β induced pathological behaviours in transgenic Caenorhabditis elegans vol.7, pp.64, 2017, https://doi.org/10.1039/c7ra05717b
  2. Early Effect of Amyloid β -Peptide on Hippocampal and Serum Metabolism in Rats Studied by an Integrated Method of NMR-Based Metabolomics and ANOVA-Simultaneous Component Analysis vol.2017, pp.None, 2017, https://doi.org/10.1155/2017/3262495
  3. Ginsenoside Rg1 Attenuates Cigarette Smoke-Induced Pulmonary Epithelial-Mesenchymal Transition via Inhibition of the TGF- β 1/Smad Pathway vol.2017, pp.None, 2016, https://doi.org/10.1155/2017/7171404
  4. In vitro assessment of selected Korean plants for antioxidant and antiacetylcholinesterase activities vol.55, pp.1, 2016, https://doi.org/10.1080/13880209.2017.1397179
  5. Chondroprotective Effects of Ginsenoside Rg1 in Human Osteoarthritis Chondrocytes and a Rat Model of Anterior Cruciate Ligament Transection vol.9, pp.3, 2016, https://doi.org/10.3390/nu9030263
  6. Protective effects of ginsenoside Rg2 and astaxanthin mixture against UVB-induced DNA damage vol.22, pp.6, 2016, https://doi.org/10.1080/19768354.2018.1523806
  7. Microbial bioconversion of ginsenosides in Panax ginseng and their improved bioactivities vol.34, pp.7, 2018, https://doi.org/10.1080/87559129.2018.1424183
  8. Complete conversion of all typical glycosylated protopanaxatriol ginsenosides to aglycon protopanaxatriol by combined bacterial β-glycosidases vol.8, pp.None, 2016, https://doi.org/10.1186/s13568-018-0543-1
  9. Transcriptome Profiling Analysis Reveals the Potential Mechanisms of Three Bioactive Ingredients of Fufang E’jiao Jiang During Chemotherapy-Induced Myelosuppression in Mice vol.9, pp.None, 2018, https://doi.org/10.3389/fphar.2018.00616
  10. Anti-aging Effects of Ginseng and Ginsenosides on the Nervous System vol.14, pp.8, 2016, https://doi.org/10.3923/ijp.2018.1188.1197
  11. Ginsenosides: A Potential Neuroprotective Agent vol.2018, pp.None, 2018, https://doi.org/10.1155/2018/8174345
  12. A UPLC‐TOF/MS‐based metabolomics study of rattan stems of Schisandra chinensis effects on Alzheimer's disease rats model vol.32, pp.2, 2016, https://doi.org/10.1002/bmc.4037
  13. Complete Biotransformation of Protopanaxatriol-Type Ginsenosides in Panax ginseng Leaf Extract to Aglycon Protopanaxatriol by β-Glycosidases from Dictyoglomus turgidum and Pyrococcus furiosus vol.28, pp.2, 2016, https://doi.org/10.4014/jmb.1709.09053
  14. LC‐MS based metabolic and metabonomic studies of Panax ginseng vol.29, pp.4, 2018, https://doi.org/10.1002/pca.2752
  15. Procyanidin B2 protects against D-galactose-induced mimetic aging in mice: Metabolites and microbiome analysis vol.119, pp.None, 2016, https://doi.org/10.1016/j.fct.2018.05.017
  16. UHPLC-QTOF/MS-based metabolomics investigation for the protective mechanism of Danshen in Alzheimer’s disease cell model induced by Aβ1-42 vol.15, pp.2, 2019, https://doi.org/10.1007/s11306-019-1473-x
  17. Panax ginseng components and the pathogenesis of Alzheimer's disease vol.19, pp.4, 2016, https://doi.org/10.3892/mmr.2019.9972
  18. Autophagy in Alzheimer's disease and promising modulatory effects of herbal medicine vol.119, pp.None, 2016, https://doi.org/10.1016/j.exger.2019.01.027
  19. The Relevance of Mass Spectrometry Analysis for Personalized Medicine through Its Successful Application in Cancer “Omics” vol.20, pp.10, 2019, https://doi.org/10.3390/ijms20102576
  20. Neuroprotective Effects of Ginseng Phytochemicals: Recent Perspectives vol.24, pp.16, 2016, https://doi.org/10.3390/molecules24162939
  21. Alterations of Gut Microbiome and Metabolite Profiling in Mice Infected by Schistosoma japonicum vol.11, pp.None, 2016, https://doi.org/10.3389/fimmu.2020.569727
  22. Nontargeted urine metabolomics analysis of the protective and therapeutic effects of Citri Reticulatae Chachiensis Pericarpium on high‐fat feed‐induced hyperlipidemia in rats vol.34, pp.4, 2016, https://doi.org/10.1002/bmc.4795
  23. Effect of Herbal Medicinal Compounds on Alzheimer’s Disease Pathology in APP/PS1 Transgenic Mouse Model vol.15, pp.8, 2016, https://doi.org/10.1177/1934578x20948986
  24. Panax quinquefolium saponin liposomes prepared by passive drug loading for improving intestinal absorption vol.46, pp.10, 2016, https://doi.org/10.1080/03639045.2020.1820036
  25. Redox signaling and Alzheimer’s disease: from pathomechanism insights to biomarker discovery and therapy strategy vol.8, pp.1, 2016, https://doi.org/10.1186/s40364-020-00218-z
  26. Protective Effect of Total Panax Notoginseng Saponins on Retinal Ganglion Cells of an Optic Nerve Crush Injury Rat Model vol.2021, pp.None, 2021, https://doi.org/10.1155/2021/4356949
  27. Protective Effects of Nicotinamide Adenine Dinucleotide and Related Precursors in Alzheimer’s Disease: A Systematic Review of Preclinical Studies vol.71, pp.7, 2021, https://doi.org/10.1007/s12031-021-01842-6
  28. Total saponins from stems and leaves of Panax quinquefolius L. ameliorate podophyllotoxin‐induced myelosuppression and gastrointestinal toxicity vol.36, pp.2, 2016, https://doi.org/10.1002/bmc.5266