Browse > Article
http://dx.doi.org/10.1016/j.jgr.2015.04.006

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)
Publication Information
Journal of Ginseng Research / v.40, no.1, 2016 , pp. 9-17 More about this Journal
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
Alzheimer's disease; ginseng; ginsenoside Rg1; ginsenoside Rg2; metabolomics;
Citations & Related Records
Times Cited By KSCI : 3  (Citation Analysis)
연도 인용수 순위
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.   DOI
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.   DOI
3 Pratico D. Oxidative stress hypothesis in Alzheimer's disease: a reappraisal. Trends Pharmacol Sci 2008;29:609-15.   DOI
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.   DOI
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.   DOI
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.   DOI
8 Kim JH. Cardiovascular diseases and Panax ginseng: a review on molecular mechanisms and medical applications. J Ginseng Res 2012;36:16-26.   DOI
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.   DOI
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.   DOI
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.   DOI
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.   DOI
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.   DOI
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.   DOI
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.   DOI
16 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.
17 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.   DOI
18 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.   DOI
19 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.   DOI
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.   DOI
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.   DOI
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.   DOI
23 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.   DOI
24 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.   DOI
25 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.   DOI
26 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.   DOI
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.   DOI
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.   DOI
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, 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.   DOI
32 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.   DOI
33 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.   DOI
34 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.   DOI
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.   DOI
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.   DOI
37 Klein J. Membrane breakdown in acute and chronic neurodegeneration: focus on choline-containing phospholipids. J Neural Transm 2000;107:1027-63.   DOI
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.   DOI
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.   DOI
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.   DOI
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.   DOI
42 Alessenko AV. The potential role for sphingolipids in neuropathogenesis of Alzheimer's disease. Biomed Khim 2013;59:25-50.   DOI
43 Kitatani K, Idkowiak-Baldys J, Hannun YA. The sphingolipid salvage pathway in ceramide metabolism and signaling. Cell Signal 2008;20:1010-8.   DOI
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.   DOI
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.   DOI