Browse > Article
http://dx.doi.org/10.1016/j.jgr.2017.12.008

Panax ginseng as an adjuvant treatment for Alzheimer's disease  

Kim, Hyeon-Joong (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University)
Jung, Seok-Won (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University)
Kim, Seog-Young (Department of Convergence Medicine, University of Ulsan College of Medicine and Institute of Life Science, Asan Medical Center)
Cho, Ik-Hyun (Department of Convergence Medical Science, College of Korean Medicine, Kyung Hee University)
Kim, Hyoung-Chun (Neuropsychopharmacology and toxicology program, College of Pharmacy, Kangwon National University)
Rhim, Hyewhon (Center for Neuroscience, Korea Institute of Science and Technology)
Kim, Manho (Department of Neurology, Neuroscience Research Center, Seoul National University Hospital)
Nah, Seung-Yeol (Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University)
Publication Information
Journal of Ginseng Research / v.42, no.4, 2018 , pp. 401-411 More about this Journal
Abstract
Longevity in medicine can be defined as a long life without mental or physical deficits. This can be prevented by Alzheimer's disease (AD). Current conventional AD treatments only alleviate the symptoms without reversing AD progression. Recent studies demonstrated that Panax ginseng extract improves AD symptoms in patients with AD, and the two main components of ginseng might contribute to AD amelioration. Ginsenosides show various AD-related neuroprotective effects. Gintonin is a newly identified ginseng constituent that contains lysophosphatidic acids and attenuates AD-related brain neuropathies. Ginsenosides decrease amyloid ${\beta}$-protein ($A{\beta}$) formation by inhibiting ${\beta}$- and ${\gamma}$-secretase activity or by activating the nonamyloidogenic pathway, inhibit acetylcholinesterase activity and $A{\beta}$-induced neurotoxicity, and decrease $A{\beta}$-induced production of reactive oxygen species and neuro-inflammatory reactions. Oral administration of ginsenosides increases the expression levels of enzymes involved in acetylcholine synthesis in the brain and alleviates $A{\beta}$-induced cholinergic deficits in AD models. Similarly, gintonin inhibits $A{\beta}$-induced neurotoxicity and activates the nonamyloidogenic pathway to reduce $A{\beta}$ formation and to increase acetylcholine and choline acetyltransferase expression in the brain through lysophosphatidic acid receptors. Oral administration of gintonin attenuates brain amyloid plaque deposits, boosting hippocampal cholinergic systems and neurogenesis, thereby ameliorating learning and memory impairments. It also improves cognitive functions in patients with AD. Ginsenosides and gintonin attenuate AD-related neuropathology through multiple routes. This review focuses research demonstrating that ginseng constituents could be a candidate as an adjuvant for AD treatment. However, clinical investigations including efficacy and tolerability analyses may be necessary for the clinical acceptance of ginseng components in combination with conventional AD drugs.
Keywords
Adjuvant; Alzheimer's disease; Ginsenoside; Gintonin; Panax ginseng;
Citations & Related Records
Times Cited By KSCI : 1  (Citation Analysis)
연도 인용수 순위
1 Cho IH. Effects of panax ginseng in neurodegenerative diseases. J Ginseng Res 2012;36:342-53. https://doi.org/10.5142/jgr.2012.36.4.342.   DOI
2 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 2012;37:8-29. https://doi.org/10.5142/jgr.2013.37.8.
3 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 Alzheimer's disease: a systematic review. BMC Complement Altern Med 2015;15:386. https://doi.org/10.1186/s12906-015-0894-y.   DOI
4 Pyo MK, Choi SH, Hwang SH, Shin TJ, Lee BH, Lee SM, Lim YH, Kim DH, Nah SY. Novel glycolipoproteins from ginseng. J Ginseng Res 2008;35:92-103.
5 Hwang SH, Shin TJ, Choi SH, Cho HJ, Lee BH, Pyo MK, Lee JH, Kang J, Kim HJ, Park CW, et al. Gintonin, newly identified compounds from ginseng, is novel lysophosphatidic acids-protein complexes and activates G protein-coupled lysophosphatidic acid receptors with high affinity. Mol Cells 2012;33:151-62. https://doi.org/10.1007/s10059-012-2216-z.   DOI
6 Wang YH, Du GH. Ginsenoside Rg1 inhibits ${\beta}$-secretase activity in vitro and protects against $PPAR{\gamma}$-induced cytotoxicity in PC12 cells. J Asian Nat Prod Res 2009;11:604-12. https://doi.org/10.1080/10286020902843152.   DOI
7 Qiu J, Li W, Feng SH, Wang M, He ZY. Ginsenoside Rh2 promotes nonamyloidgenic cleavage of amyloid precursor protein via a cholesteroldependent pathway. Genet Mol Res 2014;13:3586-98. https://doi.org/10.4238/2014.May.9.2.   DOI
8 Zhao H, Di J, Liu W, Liu H, Lai H, Lu Y. Involvement of GSK3 and PP2A in ginsenoside Rb1's attenuation of aluminum-induced tau hyperphosphorylation. Behav Brain Res 2013;241:228-34. https://doi.org/10.1016/j.bbr.2012.11.037.   DOI
9 Li L, Liu J, Yan X, Qin K, Shi M, Lin T, Zhu Y, Kang T, Zhao G. Protective effects of ginsenoside Rd against okadaic acid-induced neurotoxicity in vivo and in vitro. J Ethnopharmacol 2011;138:135-41. https://doi.org/10.1016/j.jep.2011.08.068.   DOI
10 Li H, Kang T, Qi B, Kong L, Jiao Y, Cao Y, Zhang J, Yang J. Neuroprotective effects of ginseng protein on PI3K/Akt signaling pathway in the hippocampus of Dgalactose/AlCl3 inducing rats model of Alzheimer's disease. J Ethnopharmacol 2016;179:162-9. https://doi.org/10.1016/j.jep.2015.12.020.   DOI
11 Hwang SH, Shin EJ, Shin TJ, Lee BH, Choi SH, Kang J, Kim HJ, Kwon SH, Jang CG, Lee JH, et al. Gintonin, a ginseng-derived lysophosphatidic acid receptor ligand, attenuates Alzheimer's disease-related neuropathies: involvement of non-amyloidogenic processing. J Alzheimer's Dis 2012;31:207-23.   DOI
12 Moon J, Choi SH, Shim JY, Park HJ, Oh MJ, Kim M, Nah SY. Gintonin administration is safe and potentially beneficial in cognitively impaired elderly. Alzheimer Dis Assoc Disord 2017;Oct 12. https://doi.org/10.1097/WAD.0000000000000213 [ahead of print].
13 Lee BH, Choi SH, Kim HJ, Jung SW, Kim HK, Nah SY. Plant lysophosphatidic acids: a rich source for bioactive lysophosphatidic acids and their pharmacological applications. Biol Pharm Bull 2016;3:156-62. https://doi.org/10.1248/bpb.b15-00575.
14 Choi SH, Hong MK, Kim HJ, Ryoo N, Rhim H, Nah SY, Kang LW. Structure of ginseng major latex-like protein 151 and its proposed lysophosphatidic acidbinding mechanism. Acta Crystallogr D Biol Crystallogr 2015;71:1039-50. https://doi.org/10.1107/S139900471500259X.   DOI
15 Salous AK, Panchatcharam M, Sunkara M, Mueller P, Dong A, Wang Y, Graf GA, Smyth SS, Morris AJ. Mechanism of rapid elimination of lysophosphatidic acid and related lipids from the circulation of mice. J Lipid Res 2013;54:2775-84. https://doi.org/10.1194/jlr.M039685.   DOI
16 Kim MS, Yu JM, Kim HJ, Kim HB, Kim ST, Jang SK, Choi YW, Lee DI, Joo SS. Ginsenoside Re and Rd enhance the expression of cholinergic markers and neuronal differentiation in Neuro-2a cells. Biol Pharm Bull 2014;37:826-33.   DOI
17 Kim HJ, Kim DJ, Shin EJ, Lee BH, Choi SH, Hwang SH, Rhim H, Cho IH, Kim HC, Nah SY. Effects of gintonin-enriched fraction on hippocampal cell proliferation in wild-type mice and an APPswe/PSEN-1 double Tg mouse model of Alzheimer's disease. Neurochem Int 2016;101:56-65. https://doi.org/10.1016/j.neuint.2016.10.006.   DOI
18 Kim HJ, Park SD, Lee RM, Lee BH, Choi SH, Hwang SH, Rhim H, Kim HC, Nah SY. Gintonin attenuates depressive-like behaviors associated with alcohol withdrawal in mice. J Affect Disord 2017;215:23-9.   DOI
19 Kim S, Kim MS, Park K, Kim HJ, Jung SW, Nah SY, Han JS, Chung C. Hippocampus-dependent cognitive enhancement induced by systemic gintonin administration. J Ginseng Res 2016;40:55-61. https://doi.org/10.1016/j.jgr.2015.05.001.   DOI
20 Schmitt FA, Cragar D, Ashford JW, Reisberg B, Ferris S, Mobius HJ, Stoffler A. Measuring cognition in advanced Alzheimer's disease for clinical trials. J Neural Transm Suppl 2002;62:135-48.
21 Bodick NC, Offen WW, Shannon HE, Satterwhite J, Lucas R, van Lier R, Paul SM. The selective muscarinic agonist xanomeline improves both the cognitive deficits and behavioral symptoms of Alzheimer disease. Alzheimer Dis Assoc Disord 1997;11(Suppl. 4):S16-22.   DOI
22 Schmitt B, Bernhardt T, Moeller HJ, Heuser I, Frolich L. Combination therapy in Alzheimer's disease: a review of current evidence. CNS Drugs 2004;18(13):827-44.   DOI
23 Lu X, Wang HT, Li CL, Gao XH, Ding JL, Zhao HH, Lu YL. Ginsenoside Rb1 protects PC12 cells against ${\beta}$-amyloid-induced cell injury. Mol Med Rep 2010;3:635-9. https://doi.org/10.3892/mmr_00000308.
24 Patel L, Grossberg GT. Combination therapy for Alzheimer's disease. Drugs Aging 2011;28(7):539-46. https://doi.org/10.2165/11591860-000000000-00000.   DOI
25 Manoharan S, Guillemin GJ, Abiramasundari RS, Essa MM, Akbar M, Akbar MD. The role of reactive oxygen species in the pathogenesis of Alzheimer's disease, Parkinson's disease, and Huntington's disease: a mini review. Oxid Med Cell Longev 2016;2016, 8590578. https://doi.org/10.1155/2016/8590578.
26 Choi SH, Jung SW, Lee BH, Kim HJ, Hwang SH, Kim HK, Nah SY. Ginseng pharmacology: a new paradigm based on gintonin-lysophosphatidic acid receptor interactions. Front Pharmacol 2015;6:245. https://doi.org/10.3389/fphar.2015.00245.
27 Seo JS, Yun JH, Baek IS, Leem YH, Kang HW, Cho HK, Lyu YS, Son HJ, Han PL. Oriental medicine Jangwonhwan reduces Abeta(1-42) level and beta-amyloid deposition in the brain of Tg-APPswe/PS1dE9 mouse model of Alzheimer disease. J Ethnopharmacol 2010;128:206-12. https://doi.org/10.1016/j.jep.2010.01.014.   DOI
28 Kim J, Kim SH, Lee DS, Lee DJ, Kim SH, Chung S, Yang HO. Effects of fermented ginseng on memory impairment and ${\beta}$-amyloid reduction in Alzheimer's disease experimental models. J Ginseng Res 2013;37:100-7. https://doi.org/10.5142/jgr.2013.37.100.   DOI
29 Shin K, Guo H, Cha Y, Ban YH, Seo DW, Choi Y, Kim TS, Lee SP, Kim JC, Choi EK, et al. $Cereboost^{TM}$, an American ginseng extract, improves cognitive function via up-regulation of choline acetyltransferase expression and neuroprotection. Regul Toxicol Pharmacol 2016;78:53-8. https://doi.org/10.1016/j.yrtph.2016.04.006.   DOI
30 Kim HJ, Shin EJ, Lee BH, Choi SH, Jung SW, Cho IH, Hwang SH, Kim JY, Han JS, Chung C, et al. Oral administration of gintonin attenuates cholinergic impairments by scopolamine, amyloid-${\beta}$ protein, and mouse model of Alzheimer's disease. Mol Cells 2015;38:796-805. https://doi.org/10.14348/molcells.2015.0116.   DOI
31 Creeley CE, Wozniak DF, Nardi A, Farber NB, Olney JW. Donepezil markedly potentiates memantine neurotoxicity in the adult rat brain. Neurobiol Aging 2008;29:153-67. https://doi.org/10.1016/j.neurobiolaging.2006.10.020.   DOI
32 Zadori D, Veres G, Szalardy L, Klivenyi P, Toldi J, Vecsei L. Glutamatergic dysfunctioning in Alzheimer's disease and related therapeutic targets. J Alzheimers Dis 2014;42(Suppl. 3):S177-87. https://doi.org/10.3233/JAD-132621.   DOI
33 Lazarov O, Hollands C. Hippocampal neurogenesis: learning to remember. Prog Neurobiol 2016;138-140:1-18. https://doi.org/10.1016/j.pneurobio.2015.12.006.   DOI
34 Uzun S, Kozumplik O, Folnegovic-Smalc V. Alzheimer's dementia: current data review. Coll Antropol 2011;35:1333-7.
35 Hugel HM. Brain food for Alzheimer-free ageing: focus on herbal medicines. Adv Exp Med Biol 2015;863:95-116. https://doi.org/10.1007/978-3-319-18365-7-5.
36 Pangalos MN, Schechter LE, Hurko O. Drug development for CNS disorders: strategies for balancing risk and reducing attrition. Nat Rev Drug Discov 2007;6:521-32. https://doi.org/10.1038/nrd2094.   DOI
37 Tian J, Shi J, Zhang X, Wang Y. Herbal therapy: a new pathway for the treatment of Alzheimer's disease. Alzheimers Res Ther 2010;2:30. https://doi.org/10.1186/alzrt54.   DOI
38 Wang Y, Yang G, Gong J, Lu F, Diao Q, Sun J, Zhang K, Tian J, Liu J. Ginseng for Alzheimer's disease: a systematic review and meta-analysis of randomized controlled trials. Curr Top Med Chem 2016;16(5):529-36.   DOI
39 Choi JG, Kim N, Huh E, Lee H, Oh MH, Park JD, Pyo MK, Oh MS. White ginseng protects mouse hippocampal cells against amyloid-beta oligomer toxicity. Phytother Res 2017;31:497-506. https://doi.org/10.1002/ptr.5776.   DOI
40 Lee MR, Yun BS, In OH, Sung CK. Comparative study of korean white, red, and black ginseng extract on cholinesterase inhibitory activity and cholinergic function. J Ginseng Res 2011;35:421-8. https://doi.org/10.5142/jgr.2011.35.4.421.   DOI
41 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 Alzheimer's disease. Eur J Neurol 2008;15:865-8. https://doi.org/10.1111/j.1468-1331.2008.02157.x.   DOI
42 Heo JH, Lee ST, Oh MJ, Park HJ, Shim JY, Chu K, Kim M. Improvement of cognitive deficit in Alzheimer's disease patients by long term treatment with Korean red ginseng. J Ginseng Res 2011;35:457-61. https://doi.org/10.5142/jgr.2011.35.4.457.   DOI
43 Lee ST, Chu K, Sim JY, Heo JH, Kim M. Panax ginseng enhances cognitive performance in Alzheimer disease. Alzheimer Dis Assoc Disord 2008;22:222-6. https://doi.org/10.1097/WAD.0b013-31816c92-6.   DOI
44 Zuroff L, Daley D, Black KL, Koronyo-Hamaoui M. Clearance of cerebral $A{\beta}$ in Alzheimer's disease: reassessing the role of microglia and monocytes. Cell Mol Life Sci 2017;74:2167-201. https://doi.org/10.1007/s00018-017-2463-7.   DOI
45 Wu J, Yang H, Zhao Q, Zhang X, Lou Y. Ginsenoside Rg1 exerts a protective effect against $A{\beta}25$-35-induced toxicity in primary cultured rat cortical neurons through the $NF-{\kappa}B/NO$ pathway. Int J Mol Med 2016;37:781-8. https://doi.org/10.3892/ijmm.2016.2485.   DOI
46 Liu J, Yan X, Qi L, Li L, Hu G, Li P, Zhao G. Ginsenoside Rd attenuates $A{\beta}25$-35-induced oxidative stress and apoptosis in primary cultured hippocampal neurons. Chem Biol Interact 2015;239:12-8. https://doi.org/10.1016/j.cbi.2015.06.030.   DOI
47 Huang T, Fang F, Chen L, Zhu Y, Zhang J, Chen X, Yan SS. Ginsenoside Rg1 attenuates oligomeric $A{\beta}(1-42)$-induced mitochondrial dysfunction. Curr Alzheimer Res 2012;9:388-95.   DOI
48 Bolos M, Perea JR, Avila J. Alzheimer's disease as an inflammatory disease. Biomol Concepts 2017;8:37-43. https://doi.org/10.1515/bmc-2016-0029.
49 Heo JH, Park MH, Lee JH. Effect of Korean red ginseng on cognitive function and quantitative EEG in patients with Alzheimer's disease: a preliminary study. J Altern Complement Med 2016;22:280-5. https://doi.org/10.1089/acm.2015.0265.   DOI
50 Habib A, Sawmiller D, Tan J. Restoring soluble amyloid precursor protein ${\alpha}$ functions as a potential treatment for Alzheimer's disease. J Neurosci Res 2017;95:973-91. https://doi.org/10.1002/jnr.23823.   DOI
51 Wang Y, Liu J, Zhang Z, Bi P, Qi Z, Zhang C. Anti-neuroinflammation effect of ginsenoside Rbl in a rat model of Alzheimer disease. Neurosci Lett 2011;487:70-2. https://doi.org/10.1016/j.neulet.2010.09.076.   DOI
52 Joo SS, Lee DI. Potential effects of microglial activation induced by ginsenoside Rg3 in rat primary culture: enhancement of type A Macrophage Scavenger Receptor expression. Arch Pharm Res 2005;28:1164-9.   DOI
53 Nah SY. Ginseng ginsenoside pharmacology in the nervous system: involvement in the regulation of ion channels and receptors. Front Physiol 2014;5:98. https://doi.org/10.3389/fphys.2014.00098.
54 Wang ZY, Liu JG, Li H, Yang HM. Pharmacological effects of active components of Chinese herbal medicine in the treatment of Alzheimer's disease: a review. Am J Chin Med 2016;44(8):1525-41.   DOI
55 Yang WT, Zheng XW, Chen S, Shan CS, Xu QQ, Zhu JZ, Bao XY, Lin Y, Zheng GQ, Wang Y. Chinese herbal medicine for Alzheimer's disease: clinical evidence and possible mechanism of neurogenesis. Biochem Pharmacol 2017;141:143-55. https://doi.org/10.1016/j.bcp.2017.07.002.   DOI
56 Brekhman II, Dardymov IV. New substances of plant origin which increase nonspecific resistance. Annu Rev Pharmacol 1969;9:419-30. https://doi.org/10.1146/annurev.pa.09.040169.002223.   DOI
57 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. https://doi.org/10.1111/j.1527-3458.2007.00023.x.
58 Dai D, Zhang CF, Williams S, Yuan CS, Wang CZ. Ginseng on cancer: potential role in modulating inflammation-mediated angiogenesis. Am J Chin Med 2017;45(1):13-22. https://doi.org/10.1142/S0192415X17500021.   DOI
59 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(3):463-88. https://doi.org/10.1142/S0192415X16500269.   DOI
60 Choi RJ, Roy A, Jung HJ, Ali MY, Min BS, Park CH, Yokozawa T, Fan TP, Choi JS, Jung HA. BACE1 molecular docking and anti-Alzheimer's disease activities of ginsenosides. J Ethnopharmacol 2016;190:219-30. https://doi.org/10.1016/j.jep.2016.06.013.   DOI
61 Karpagam V, Sathishkumar N, Sathiyamoorthy S, Rasappan P, Shila S, Kim YJ, Yang DC. Identification of BACE1 inhibitors from Panax ginseng saponins-An Insilco approach. Comput Biol Med 2013;43:1037-44. https://doi.org/10.1016/j.compbiomed.2013.05.009.   DOI
62 Yan X, Hu G, Yan W, Chen Y, Yang F, Zhang X, Zhao G, Liu J. Ginsenoside Rd promotes non-amyloidogenic pathway of amyloid precursor protein processing by regulating phosphorylation of estrogen receptor alpha. Life Sci 2017;168:16-23. https://doi.org/10.1016/j.lfs.2016.11.002.   DOI
63 Cao G, Su P, Zhang S, Guo L, Zhang H, Liang Y, Qin C, Zhang W. Ginsenoside Re reduces $PPAR{\gamma}$ production by activating $PPAR{\gamma}$ to inhibit BACE1 in N2a/APP695 cells. Eur J Pharmacol 2016;793:101-8. https://doi.org/10.1016/j.ejphar.2016.11.006.   DOI
64 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.   DOI
65 Shi C, Zheng D, 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.   DOI
66 Qiao C, Den R, Kudo K, Yamada K, Takemoto K, Wati H, Kanba S. Ginseng enhances contextual fear conditioning and neurogenesis in rats. Neurosci Res 2005;51:31-8. https://doi.org/10.1016/j.neures.2004.09.004.   DOI
67 Saba E, Jeon BR, Jeong DH, Lee K, Goo YK, Kwak D, Kim S, Roh SS, Kim SD, Nah SY, et al. A novel Korean red ginseng compound gintonin inhibited inflammation by MAPK and $NF-{\kappa}B$ pathways and recovered the levels of mir-34a and mir-93 in RAW 264.7 cells. Evid Based Complement Alternat Med 2015;2015, 624132. https://doi.org/10.1155/2015/624132.
68 Lee BH, Kim HK, Jang M, Kim HJ, Choi SH, Hwang SH, Kim HC, Rhim H, Cho IH, Nah SY. Effects of gintonin-enriched fraction in an atopic dermatitis animal model: involvement of autotaxin regulation. Biol Pharm Bull 2017;40:1063-70. https://doi.org/10.1248/bpb.b17-00124.   DOI
69 Yu Y, He J, Zhang Y, Luo H, Zhu S, Yang Y, Zhao T, Wu J, Huang Y, Kong J, et al. Increased hippocampal neurogenesis in the progressive stage of Alzheimer's disease phenotype in an APP/PS1 double transgenic mouse model. Hippocampus 2009;19:1247-53. https://doi.org/10.1002/hipo.20587.   DOI
70 Sun GG, Shih JH, Chiou SH, Hong CJ, Lu SW, Pao LH. Chinese herbal medicines promote hippocampal neuroproliferation, reduce stress hormone levels, inhibit apoptosis, and improve behavior in chronically stressed mice. J Ethnopharmacol 2016;193:159-68. https://doi.org/10.1016/j.jep.2016.07.025.   DOI
71 Hooper NM. Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prion protein. Biochem Soc Trans 2005;33:335-8. https://doi.org/10.1042/BST0330335.   DOI
72 Lee CH, Kim JH. A review on the medicinal potentials of ginseng and ginsenosides on cardiovascular diseases. J Ginseng Res 2014;38(3):161-6. https://doi.org/10.1016/j.jgr.2014.03.001.   DOI
73 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. https://doi.org/10.3389/fphar.2012.00025.
74 Burns A, Iliffe S. Alzheimer's disease. BMJ 2009;338:b158.   DOI
75 Querfurth HW, LaFerla FM. Alzheimer's disease. N Engl J Med 2010;362:329-44. https://doi.org/10.1056/NEJMra0909142.   DOI
76 Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer's disease. Trends Pharmacol Sci 1991;12:383-8.   DOI
77 Hollands C, Bartolotti N, Lazarov O. Alzheimer's disease and hippocampal adult neurogenesis; exploring shared mechanisms. Front Neurosci 2016;10:178. https://doi.org/10.3389/fnins.2016.00178.
78 Mudher A, Lovestone S. Alzheimer's disease-do tauists and baptists finally shake hands? Trends Neurosci 2002;25:22-6.   DOI
79 Francis PT, Palmer AM, Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimer's disease: a review of progress. J Neurol Neurosurg Psychiatry 1999;66:137-47.   DOI
80 Martorana A, Esposito Z, Koch G. Beyond the cholinergic hypothesis: do current drugs work in Alzheimer's disease? CNS Neurosci Ther 2010;16:235-45. https://doi.org/10.1111/j.1755-5949.2010.00175.x.
81 Bagyinszky E, Giau VV, Shim K, Suk K, An SSA, Kim S. Role of inflammatory molecules in the Alzheimer's disease progression and diagnosis. J Neurol Sci 2017;376:242-54. https://doi.org/10.1016/j.jns.2017.03.031.   DOI
82 Hroudov J, Singh N, Fisar Z. Mitochondrial dysfunctions in neurodegenerative diseases: relevance to Alzheimer's disease. Biomed Res Int 2014;2014:1-9. https://doi.org/10.1155/2014/175062.