Network Pharmacology and Mechanism Studies of the Protective Effect of Ginseng against Alzheimerʼs Disease Based on Aβ Pathogenesis

Abstract

Alzheimerʼs disease (AD) is a critical neurodegenerative disease that manifests as progressive intellectual decline and is pathologically characterized by a progressive loss of neurons in the brain. Despite extensive research on this topic, the pathogenesis of AD is not fully understood, while the beta-amyloid (Aβ) hypothesis remains the dominant one and only a few symptomatic drugs are approved for the treatment of AD. Ginseng has been widely reported as an effective herbal medicine for the treatment of neurodegenerative diseases such as dementia. Therefore, we explore the protective effects of ginseng in AD by a network pharmacological approach based on the pathogenesis of Aβ. Twenty-one major ginsenosides are screened based on ultraperformance liquid chromatography-mass spectrometry/mass spectrometry (HPLC-MS/MS) data. Among them, MAPK8, MAPK9, BACE1, FLT1, CDK2, and CCR5 are the core targets. By molecular docking and validation with the in vitro cell model APPswe-SH-SY5Y, we find that ginsenosides Rg3 and Ro have good neuroprotective effects and can reduce the expression of Aβ _1 – 42 in APPswe-SH-SY5Y. Finally, through RT-qPCR experiment, we find that ginsenoside Rg3 targeted MAPK8, FLT1, and CCR5, while ginsenoside Ro targeted MAPK8, MAPK9, FLT1, and CCR5 for its potential anti-AD efficacy.

Key words

Ginseng - Araliaceae - Alzheimerʼs disease - beta-amyloid - network pharmacology - targets

Publication History

Received: 15 October 2022

Accepted after revision: 16 January 2023

Accepted Manuscript online:
17 January 2023

Article published online:
14 July 2023

• References

• 1 Mattson MP. Pathways towards and away from Alzheimerʼs disease. Nature 2004; 430: 631-639
• 2 Wimo A. Long-term effects of Alzheimerʼs disease treatment. Lancet Neurol 2015; 14: 1145-1146
• 3 Hinz FI, Geschwind DH. Molecular genetics of neurodegenerative dementias. Cold Spring Harb Perspect Biol 2017; 9: a023705
• 4 Paroni G, Bisceglia P, Seripa D. Understanding the amyloid hypothesis in Alzheimerʼs disease. J Alzheimers Dis 2019; 68: 493-510
• 5 Hung SY, Fu WM. Drug candidates in clinical trials for Alzheimerʼs disease. J Biomed Sci 2017; 24: 47
• 6 Mangialasche F, Solomon A, Winblad B, Mecocc P, Kivipelto M. Alzheimerʼs disease: Clinical trials and drug development. Lancet Neurol 2010; 9: 702-716:
• 7 Fillit H, Green A. Aducanumab and the FDA – where are we now?. Nat Rev Neurol 2021; 17: 129-130
• 8 Zhao B, Lv C, Lu J. Natural occurring polysaccharides from Panax ginseng C. A. Meyer: A review of isolation, structures, and bioactivities. Int J Biol Macromol 2019; 133: 324-336
• 9 Kim HJ, Jung SW, Kim SY, Cho IH, Kim HC, Rhim H, Kim M, Nah SY. Panax ginseng as an adjuvant treatment for Alzheimerʼs disease. J Ginseng Res 2018; 42: 401-411
• 10 Shin SJ, Jeon SG, Kim JI, Jeong YO, Kim S, Park YH, Lee SK, Park HH, Hong SB, Oh S, Hwang JY, Kim HS, Park H, Nam Y, Lee YY, Kim JJ, Park SH, Kim JS, Moon M. Red ginseng attenuates Aβ-induced mitochondrial dysfunction and Aβ-mediated pathology in an animal model of Alzheimerʼs disease. Int J Mol Sci 2019; 20: 3030
• 11 Ong WY, Farooqui T, Koh HL, Farooqui AA, Ling EA. Protective effects of ginseng on neurological disorders. Front Aging Neurosci 2015; 7: 129
• 12 Heo JH, Lee ST, Chu K, Oh MJ, Park HJ, Shim JY, Kim M. An open-label trial of Korean red ginseng as an adjuvant treatment for cognitive impairment in patients with Alzheimerʼs disease. Eur J Neurol 2008; 15: 865-868
• 13 Nah SY. Ginseng ginsenoside pharmacology in the nervous system: involvement in the regulation of ion channels and receptors. Front Physiol 2014; 5: 98
• 14 Nah SY, Kim DH, Rhim H. Ginsenosides: Are any of them candidates for drugs acting on the central nervous system?. CNS Drug Rev 2007; 13: 381-404
• 15 Kim JW, Han SW, Cho JY, Chung IJ, Kim JG, Lee KH, Park KU, Baek SK, Oh SC, Lee MA, Oh D, Shim B, Ahn JB, Shin D, Lee JW, Kim YH. Korean red ginseng for cancer-related fatigue in colorectal cancer patients with chemotherapy: A randomised phase III trial. Eur J Cancer 2020; 130: 51-62
• 16 Li X, Chu S, Lin M, Gao Y, Liu Y, Yang S, Zhou X, Zhang Y, Hu Y, Wang H, Chen N. Anticancer property of ginsenoside Rh2 from ginseng. Eur J Med Chem 2020; 203: 112627
• 17 Zhu H, Liu H, Zhu JH, Wang SY, Zhou SS, Kong M, Mao Q, Long F, Fang ZJ, Li SL. Efficacy of ginseng and its ingredients as adjuvants to chemotherapy in non-small cell lung cancer. Food Funct 2021; 12: 2225-2241
• 18 Jiao R, Liu Y, Gao H, Xiao J, So KF. The anti-oxidant and antitumor properties of plant polysaccharides. Am J Chin Med 2016; 44: 463-488
• 19 Lee CH, Kim JH. A review on the medicinal potentials of ginseng and ginsenosides on cardiovascular diseases. J Ginseng Res 2014; 38: 161-166
• 20 Nag SA, Qin JJ, Wang W, Wang MH, Wang H, Zhang R. Ginsenosides as anticancer agents: In vitro and in vivo activities, structure-activity relationships, and molecular mechanisms of action. Front Pharmacol 2012; 3: 25
• 21 Cho IH. Effects of panax ginseng in neurodegenerative diseases. J Ginseng Res 2012; 36: 342-353
• 22 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
• 23 Sheng C, Peng W, Xia ZA, Wang Y, Chen Z, Su N, Wang Z. The impact of ginsenosides on cognitive deficits in experimental animal studies of Alzheimerʼs disease: a systematic review. BMC Complement Altern Med 2015; 15: 386
• 24 Thal DR, Walter J, Saido TC, Fändrich M. Neuropathology and biochemistry of Aβ and its aggregates in Alzheimerʼs disease. Acta Neuropathol 2015; 129: 167-182
• 25 Kam TI, Gwon Y, Jung YK. Amyloid beta receptors responsible for neurotoxicity and cellular defects in Alzheimerʼs disease. Cell Mol Life Sci 2014; 71: 4803-4813
• 26 Tiwari S, Atluri V, Kaushik A, Yndart A, Nair M. Alzheimerʼs disease: Pathogenesis, diagnostics, and therapeutics. Int J Nanomedicine 2019; 14: 5541-5554
• 27 Ma C, Hong F, Yang S. Amyloidosis in Alzheimerʼs disease: Pathogeny, etiology, and related therapeutic directions. Molecules 2022; 27: 1210
• 28 Chen W, Balan P, Popovich DG. Analysis of ginsenoside content (Panax ginseng) from different regions. Molecules 2019; 24: 3491
• 29 Daina A, Michielin O, Zoete V. SwissTargetPrediction: Updated data and new features for efficient prediction of protein targets of small molecules. Nucleic Acids Res 2019; 47: W357-W364
• 30 Xu M, Zhang DF, Luo R, Wu Y, Zhou H, Kong LL, Bi R, Yao YG. A systematic integrated analysis of brain expression profiles reveals YAP1 and other prioritized hub genes as important upstream regulators in Alzheimerʼs disease. Alzheimers Dement 2018; 14: 215-229
• 31 Zhang T, Yu J, Wang G, Zhang R. Amyloid precursor protein binds with TNFRSF21 to induce neural inflammation in Alzheimerʼs Disease. Eur J Pharm Sci 2021; 157: 105598
• 32 Guglielmotto M, Monteleone D, Piras A, Valsecchi V, Tropiano M, Ariano S, Fornaro M, Vercelli A, Puyal J, Arancio O, Tabaton M, Tamagno E. Aβ1–42 monomers or oligomers have different effects on autophagy and apoptosis. Autophagy 2014; 10: 1827-1843
• 33 Moussa-Pacha NM, Abdin SM, Omar HA, Alniss H, Al-Tel TH. BACE1 inhibitors: Current status and future directions in treating Alzheimerʼs disease. Med Res Rev 2020; 40: 339-384
• 34 Lau SF, Cao H, Fu AKY, Ip NY. Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimerʼs disease. Proc Natl Acad Sci U S A 2020; 117: 25800-25809
• 35 Nguyen MD, Mushynski WE, Julien JP. Cycling at the interface between neurodevelopment and neurodegeneration. Cell Death Differ 2002; 9: 1294-1306
• 36 Necula D, Riviere-Cazaux C, Shen Y, Zhou M. Insight into the roles of CCR5 in learning and memory in normal and disordered states. Brain Behav Immun 2021; 92: 1-9
• 37 Sanchez A, Wadhwani S, Grammas P. Multiple neurotrophic effects of VEGF on cultured neurons. Neuropeptides 2010; 44: 323-331
• 38 Ryu JK, Cho T, Choi HB, Wang YT, McLarnon JG. Microglial VEGF receptor response is an integral chemotactic component in Alzheimerʼs disease pathology. J Neurosci 2009; 29: 3-13
• 39 Zeng P, Wang XM, Ye CY, Su HF, Tian Q. The main alkaloids in Uncaria Rhynchophylla and their anti-Alzheimerʼs disease mechanism determined by a network pharmacology approach. Int J Mol Sci 2021; 22: 3612
• 40 Szklarczyk D, Gable AL, Lyon D, Junge A, Wyder S, Huerta-Cepas J, Simonovic M, Doncheva NT, Morris JH, Bork P, Jensen LJ, Mering CV. STRING v11: Protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res 2019; 47: D607-D613
• 41 Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowsk B, Ideker T. Cytoscape: A software environment for integrated models of biomolecular interaction networks. Genome Res 2003; 13: 2498-2504
• 42 Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, Benner C, Chanda SK. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun 2019; 10: 1523
• 43 Liu Y, Grimm M, Dai WT, Hou MC, Xiao ZX, Cao Y. CB-Dock: a web server for cavity detection-guided protein-ligand blind docking. Acta Pharmacol Sin 2020; 41: 138-144
• 44 Wang Q, Jiang H, Wang L, Yi H, Li Z, Liu R. Vitegnoside mitigates neuronal injury, mitochondrial apoptosis, and inflammation in an Alzheimerʼs disease cell model via the p 38 MAPK/JNK pathway. J Alzheimers Dis 2019; 72: 199-214