Planta Med 2014; 80(15): 1249-1258
DOI: 10.1055/s-0034-1383038
Reviews
Georg Thieme Verlag KG Stuttgart · New York

Mechanisms of Action of Phytochemicals from Medicinal Herbs in the Treatment of Alzheimerʼs Disease

Mi Hye Kim
1   College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, Seoul, Korea
,
Sung-Hoon Kim
2   Cancer Preventive Material Development Research Center, College of Korean Medicine, Kyung Hee University, Seoul, Korea
,
Woong Mo Yang
1   College of Korean Medicine and Institute of Korean Medicine, Kyung Hee University, Seoul, Korea
› Author Affiliations
Further Information

Publication History

received 08 July 2013
revised 07 July 2014

accepted 05 August 2014

Publication Date:
11 September 2014 (online)

Abstract

Alzheimerʼs disease is a chronic neurodegenerative disorder characterized by progressive dementia and deterioration of cognitive function. Although several drugs currently used for the treatment of Alzheimerʼs disease delay its onset and slow its progression, still there is no drug with profound disease-modifying effects. Studies aiming the treatment of this neurodegenerative disorder explore various disease mechanisms. Since antiquity, medicinal herbs have been used in traditional medicine. Recent studies suggest that the neurobiological effects of phytochemicals from medicinal herbs may contribute to clinical benefits in in vitro and in vivo models of Alzheimerʼs disease. This review focuses on five phytochemicals, berberine, curcumin, ginsenoside Rg1, puerarin, and silibinin, which have been mostly investigated to treat the development and progression of this neurodegenerative disorder.

 
  • References

  • 1 Burns A, Zaudig M. Mild cognitive impairment in older people. Lancet 2002; 360: 1963-1965
  • 2 Novakovic D, Feligioni M, Scaccianoce S, Caruso A, Piccinin S, Schepisi C, Errico F, Mercuri NB, Nicoletti F, Nistico R. Profile of gantenerumab and its potential in the treatment of Alzheimerʼs disease. Drug Des Devel Ther 2013; 7: 1359-1364
  • 3 Yan H, Li L, Tang XC. Treating senile dementia with traditional Chinese medicine. Clin Interv Aging 2007; 2: 201-208
  • 4 Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J, Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D, Seubert P, Suomensaari SM, Wang S, Walker D, Zhao J, McConlogue L, John V. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature 1999; 402: 537-540
  • 5 Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, Luo Y, Fisher S, Fuller J, Edenson S, Lile J, Jarosinski MA, Biere AL, Curran E, Burgess T, Louis JC, Collins F, Treanor J, Rogers G, Citron M. Beta-secretase cleavage of Alzheimerʼs amyloid precursor protein by the transmembrane aspartic protease BACE. Science 1999; 286: 735-741
  • 6 Yankner BA, Lu T. Amyloid beta-protein toxicity and the pathogenesis of Alzheimer disease. J Biol Chem 2009; 284: 4755-4759
  • 7 De Strooper B, Vassar R, Golde T. The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol 2010; 6: 99-107
  • 8 Asai M, Iwata N, Yoshikawa A, Aizaki Y, Ishiura S, Saido TC, Maruyama K. Berberine alters the processing of Alzheimerʼs amyloid precursor protein to decrease Abeta secretion. Biochem Biophys Res Commun 2007; 352: 498-502
  • 9 Roychaudhuri R, Yang M, Hoshi MM, Teplow DB. Amyloid beta-protein assembly and Alzheimer disease. J Biol Chem 2009; 284: 4749-4753
  • 10 Mrak RE, Griffin WS. Glia and their cytokines in progression of neurodegeneration. Neurobiol Aging 2005; 26: 349-354
  • 11 Matsuoka Y, Picciano M, La Francois J, Duff K. Fibrillar beta-amyloid evokes oxidative damage in a transgenic mouse model of Alzheimerʼs disease. Neuroscience 2001; 104: 609-613
  • 12 Ye J, Zhang Y. Curcumin protects against intracellular amyloid toxicity in rat primary neurons. Int J Clin Exp Med 2012; 5: 44-49
  • 13 Doggui S, Belkacemi A, Paka GD, Perrotte M, Pi R, Ramassamy C. Curcumin protects neuronal-like cells against acrolein by restoring Akt and redox signaling pathways. Mol Nutr Food Res 2013; 57: 1660-1670
  • 14 Chishti MA, Yang DS, Janus C, Phinney AL, Horne P, Pearson J, Strome R, Zuker N, Loukides J, French J, Turner S, Lozza G, Grilli M, Kunicki S, Morissette C, Paquette J, Gervais F, Bergeron C, Fraser PE, Carlson GA, George-Hyslop PS, Westaway D. Early-onset amyloid deposition and cognitive deficits in transgenic mice expressing a double mutant form of amyloid precursor protein 695. J Biol Chem 2001; 276: 21562-21570
  • 15 Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L. High-level neuronal expression of abeta 1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci 2000; 20: 4050-4058
  • 16 Caspersen C, Wang N, Yao J, Sosunov A, Chen X, Lustbader JW, Xu HW, Stern D, McKhann G, Yan SD. Mitochondrial Abeta: a potential focal point for neuronal metabolic dysfunction in Alzheimerʼs disease. FASEB J 2005; 19: 2040-2041
  • 17 Kmietowicz Z. NICE proposes to withdraw Alzheimerʼs drugs from NHS. BMJ 2005; 330: 495
  • 18 Flicker L, Grimley Evans G. Piracetam for dementia or cognitive impairment. Cochrane Database Syst Rev 2001; CD001011
  • 19 Stermitz FR, Lorenz P, Tawara JN, Zenewicz LA, Lewis K. Synergy in a medicinal plant: antimicrobial action of berberine potentiated by 5′-methoxyhydnocarpin, a multidrug pump inhibitor. Proc Natl Acad Sci U S A 2000; 97: 1433-1437
  • 20 Kuo CL, Chi CW, Liu TY. The anti-inflammatory potential of berberine in vitro and in vivo . Cancer Lett 2004; 203: 127-137
  • 21 Sack RB, Froehlich JL. Berberine inhibits intestinal secretory response of Vibrio cholerae and Escherichia coli enterotoxins. Infect Immun 1982; 35: 471-475
  • 22 Kim KW, Ha KT, Park CS, Jin UH, Chang HW, Lee IS, Kim CH. Polygonum cuspidatum, compared with baicalin and berberine, inhibits inducible nitric oxide synthase and cyclooxygenase-2 gene expressions in RAW 264.7 macrophages. Vascul Pharmacol 2007; 47: 99-107
  • 23 Hu JP, Nishishita K, Sakai E, Yoshida H, Kato Y, Tsukuba T, Okamoto K. Berberine inhibits RANKL-induced osteoclast formation and survival through suppressing the NF-kappaB and Akt pathways. Eur J Pharmacol 2008; 580: 70-79
  • 24 Zhu F, Wu F, Ma Y, Liu G, Li Z, Sun Y, Pei Z. Decrease in the production of beta-amyloid by berberine inhibition of the expression of beta-secretase in HEK293 cells. BMC Neurosci 2011; 12: 125
  • 25 Jia L, Liu J, Song Z, Pan X, Chen L, Cui X, Wang M. Berberine suppresses amyloid-beta-induced inflammatory response in microglia by inhibiting nuclear factor-kappaB and mitogen-activated protein kinase signalling pathways. J Pharm Pharmacol 2012; 64: 1510-1521
  • 26 Xu J, Zhang H, Yang F, Yu JX. [Intervention effect of berberine on expressions of TNF-alpha and receptor type I in Abeta25-35-induced inflammatory reaction in SH-SY5Y cell lines]. Zhongguo Zhong Yao Za Zhi 2013; 38: 1327-1330
  • 27 Durairajan SS, Liu LF, Lu JH, Chen LL, Yuan Q, Chung SK, Huang L, Li XS, Huang JD, Li M. Berberine ameliorates beta-amyloid pathology, gliosis, and cognitive impairment in an Alzheimerʼs disease transgenic mouse model. Neurobiol Aging 2012; 33: 2903-2919
  • 28 Reinke AA, Gestwicki JE. Structure-activity relationships of amyloid beta-aggregation inhibitors based on curcumin: influence of linker length and flexibility. Chem Biol Drug Des 2007; 70: 206-215
  • 29 Huang HC, Tang D, Xu K, Jiang ZF. Curcumin attenuates amyloid-beta-induced tau hyperphosphorylation in human neuroblastoma SH-SY5Y cells involving PTEN/Akt/GSK-3beta signaling pathway. J Recept Signal Transduct Res 2014; 34: 26-37
  • 30 Xiong Z, Hongmei Z, Lu S, Yu L. Curcumin mediates presenilin-1 activity to reduce beta-amyloid production in a model of Alzheimerʼs Disease. Pharmacol Rep 2011; 63: 1101-1108
  • 31 Hoppe JB, Coradini K, Frozza RL, Oliveira CM, Meneghetti AB, Bernardi A, Pires ES, Beck RC, Salbego CG. Free and nanoencapsulated curcumin suppress beta-amyloid-induced cognitive impairments in rats: involvement of BDNF and Akt/GSK-3beta signaling pathway. Neurobiol Learn Mem 2013; 106: 134-144
  • 32 Chang Y, Huang WJ, Tien LT, Wang SJ. Ginsenosides Rg1 and Rb1 enhance glutamate release through activation of protein kinase A in rat cerebrocortical nerve terminals (synaptosomes). Eur J Pharmacol 2008; 578: 28-36
  • 33 Wang YH, Du GH. Ginsenoside Rg1 inhibits beta-secretase activity in vitro and protects against Abeta-induced cytotoxicity in PC12 cells. J Asian Nat Prod Res 2009; 11: 604-612
  • 34 Li W, Chu Y, Zhang L, Yin L, Li L. Ginsenoside Rg1 attenuates tau phosphorylation in SK-N-SH induced by Abeta-stimulated THP-1 supernatant and the involvement of p 38 pathway activation. Life Sci 2012; 91: 809-815
  • 35 Li W, Chu Y, Zhang L, Yin L, Li L. Ginsenoside Rg1 prevents SK-N-SH neuroblastoma cell apoptosis induced by supernatant from Abeta1-40-stimulated THP-1 monocytes. Brain Res Bull 2012; 88: 501-506
  • 36 Huang T, Fang F, Chen L, Zhu Y, Zhang J, Chen X, Yan SS. Ginsenoside Rg1 attenuates oligomeric Abeta(1–42)-induced mitochondrial dysfunction. Curr Alzheimer Res 2012; 9: 388-395
  • 37 Wu JY, Shen YY, Zhu WJ, Chen MY, Wang ZQ, Liu Y, Zhu DY, Lou YJ. [Ginsenoside Rg1 antagonizes beta-amyloid peptide-induced apoptosis in primarily cultured rat neurons via mitochondrial pathway]. Zhejiang Da Xue Xue Bao Yi Xue Ban 2012; 41: 393-401
  • 38 Gong L, Li SL, Li H, Zhang L. Ginsenoside Rg1 protects primary cultured rat hippocampal neurons from cell apoptosis induced by beta-amyloid protein. Pharm Biol 2011; 49: 501-507
  • 39 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: 286-292
  • 40 Qicheng F. Some current study and research approaches relating to the use of plants in the traditional Chinese medicine. J Ethnopharmacol 1980; 2: 57-63
  • 41 Fan LL, Sun LH, Li J, Yue XH, Yu HX, Wang SY. The protective effect of puerarin against myocardial reperfusion injury. Study on cardiac function. Chin Med J (Engl) 1992; 105: 11-17
  • 42 Zou Y, Hong B, Fan L, Zhou L, Liu Y, Wu Q, Zhang X, Dong M. Protective effect of puerarin against beta-amyloid-induced oxidative stress in neuronal cultures from rat hippocampus: involvement of the GSK-3beta/Nrf2 signaling pathway. Free Radic Res 2013; 47: 55-63
  • 43 Lin F, Xie B, Cai F, Wu G. Protective effect of Puerarin on beta-amyloid-induced neurotoxicity in rat hippocampal neurons. Arzneimittelforschung 2012; 62: 187-193
  • 44 Zhang HY, Liu YH, Wang HQ, Xu JH, Hu HT. Puerarin protects PC12 cells against beta-amyloid-induced cell injury. Cell Biol Int 2008; 32: 1230-1237
  • 45 Zhang H, Liu Y, Lao M, Ma Z, Yi X. Puerarin protects Alzheimerʼs disease neuronal cybrids from oxidant-stress induced apoptosis by inhibiting pro-death signaling pathways. Exp Gerontol 2011; 46: 30-37
  • 46 Li J, Wang G, Liu J, Zhou L, Dong M, Wang R, Li X, Li X, Lin C, Niu Y. Puerarin attenuates amyloid-beta-induced cognitive impairment through suppression of apoptosis in rat hippocampus in vivo. Eur J Pharmacol 2010; 649: 195-201
  • 47 Gazak R, Walterova D, Kren V. Silybin and silymarin–new and emerging applications in medicine. Curr Med Chem 2007; 14: 315-338
  • 48 Youn CK, Park SJ, Lee MY, Cha MJ, Kim OH, You HJ, Chang IY, Yoon SP, Jeon YJ. Silibinin inhibits LPS-induced macrophage activation by blocking p 38 MAPK in RAW 264.7 cells. Biomol Ther (Seoul) 2013; 21: 258-263
  • 49 Trouillas P, Marsal P, Svobodova A, Vostalova J, Gazak R, Hrbac J, Sedmera P, Kren V, Lazzaroni R, Duroux JL, Walterova D. Mechanism of the antioxidant action of silybin and 2, 3-dehydrosilybin flavonolignans: a joint experimental and theoretical study. J Phys Chem A 2008; 112: 1054-1063
  • 50 Yin F, Liu J, Ji X, Wang Y, Zidichouski J, Zhang J. Silibinin: a novel inhibitor of Abeta aggregation. Neurochem Int 2011; 58: 399-403
  • 51 Lu P, Mamiya T, Lu LL, Mouri A, Zou L, Nagai T, Hiramatsu M, Ikejima T, Nabeshima T. Silibinin prevents amyloid beta peptide-induced memory impairment and oxidative stress in mice. Br J Pharmacol 2009; 157: 1270-1277
  • 52 Lu P, Mamiya T, Lu LL, Mouri A, Niwa M, Hiramatsu M, Zou LB, Nagai T, Ikejima T, Nabeshima T. Silibinin attenuates amyloid beta(25–35) peptide-induced memory impairments: implication of inducible nitric-oxide synthase and tumor necrosis factor-alpha in mice. J Pharmacol Exp Ther 2009; 331: 319-326
  • 53 Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, Keller P, Runz H, Kuhl S, Bertsch T, von Bergmann K, Hennerici M, Beyreuther K, Hartmann T. Simvastatin strongly reduces levels of Alzheimerʼs disease beta-amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo . Proc Natl Acad Sci U S A 2001; 98: 5856-5861
  • 54 Xiu J, Nordberg A, Qi X, Guan ZZ. Influence of cholesterol and lovastatin on alpha-form of secreted amyloid precursor protein and expression of alpha7 nicotinic receptor on astrocytes. Neurochem Int 2006; 49: 459-465
  • 55 Famer D, Crisby M. Rosuvastatin reduces caspase-3 activity and up-regulates alpha-secretase in human neuroblastoma SH-SY5Y cells exposed to A beta. Neurosci Lett 2004; 371: 209-214
  • 56 Nawrot B. Targeting BACE with small inhibitory nucleic acids – a future for Alzheimerʼs disease therapy?. Acta Biochim Pol 2004; 51: 431-444
  • 57 Frame S, Cohen P. GSK3 takes centre stage more than 20 years after its discovery. Biochem J 2001; 359: 1-16
  • 58 Chang KA, Kim HS, Ha TY, Ha JW, Shin KY, Jeong YH, Lee JP, Park CH, Kim S, Baik TK, Suh YH. Phosphorylation of amyloid precursor protein (APP) at Thr668 regulates the nuclear translocation of the APP intracellular domain and induces neurodegeneration. Mol Cell Biol 2006; 26: 4327-4338
  • 59 Judge M, Hornbeck L, Potter H, Padmanabhan J. Mitosis-specific phosphorylation of amyloid precursor protein at threonine 668 leads to its altered processing and association with centrosomes. Mol Neurodegener 2011; 6: 80
  • 60 Martin D, Salinas M, Lopez-Valdaliso R, Serrano E, Recuero M, Cuadrado A. Effect of the Alzheimer amyloid fragment Abeta(25–35) on Akt/PKB kinase and survival of PC12 cells. J Neurochem 2001; 78: 1000-1008
  • 61 Phiel CJ, Wilson CA, Lee VM, Klein PS. GSK-3alpha regulates production of Alzheimerʼs disease amyloid-beta peptides. Nature 2003; 423: 435-439
  • 62 Jaworski T, Dewachter I, Lechat B, Gees M, Kremer A, Demedts D, Borghgraef P, Devijver H, Kugler S, Patel S, Woodgett JR, Van Leuven F. GSK-3alpha/beta kinases and amyloid production in vivo . Nature 2011; 480: E4-5 discussion E6
  • 63 Nimmerjahn A, Kirchhoff F, Helmchen F. Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo . Science 2005; 308: 1314-1318
  • 64 McGeer EG, McGeer PL. Inflammatory processes in Alzheimerʼs disease. Prog Neuropsychopharmacol Biol Psychiatry 2003; 27: 741-749
  • 65 Sasaki Y, Ohsawa K, Kanazawa H, Kohsaka S, Imai Y. Iba1 is an actin-cross-linking protein in macrophages/microglia. Biochem Biophys Res Commun 2001; 286: 292-297
  • 66 Bhat RV, DiRocco R, Marcy VR, Flood DG, Zhu Y, Dobrzanski P, Siman R, Scott R, Contreras PC, Miller M. Increased expression of IL-1beta converting enzyme in hippocampus after ischemia: selective localization in microglia. J Neurosci 1996; 16: 4146-4154
  • 67 McGeer PL, McGeer EG. The inflammatory response system of brain: implications for therapy of Alzheimer and other neurodegenerative diseases. Brain Res Brain Res Rev 1995; 21: 195-218
  • 68 Banati RB, Gehrmann J, Schubert P, Kreutzberg GW. Cytotoxicity of microglia. Glia 1993; 7: 111-118
  • 69 Hull M, Strauss S, Berger M, Volk B, Bauer J. The participation of interleukin-6, a stress-inducible cytokine, in the pathogenesis of Alzheimerʼs disease. Behav Brain Res 1996; 78: 37-41
  • 70 Peterson PK, Hu S, Salak-Johnson J, Molitor TW, Chao CC. Differential production of and migratory response to beta chemokines by human microglia and astrocytes. J Infect Dis 1997; 175: 478-481
  • 71 Kelder W, McArthur JC, Nance-Sproson T, McClernon D, Griffin DE. Beta-chemokines MCP-1 and RANTES are selectively increased in cerebrospinal fluid of patients with human immunodeficiency virus-associated dementia. Ann Neurol 1998; 44: 831-835
  • 72 Ito S, Sawada M, Haneda M, Ishida Y, Isobe K. Amyloid-beta peptides induce several chemokine mRNA expressions in the primary microglia and Ra2 cell line via the PI3K/Akt and/or ERK pathway. Neurosci Res 2006; 56: 294-299
  • 73 Bi W, Zhu L, Wang C, Liang Y, Liu J, Shi Q, Tao E. Rifampicin inhibits microglial inflammation and improves neuron survival against inflammation. Brain Res 2011; 1395: 12-20
  • 74 Pan XD, Chen XC, Zhu YG, Chen LM, Zhang J, Huang TW, Ye QY, Huang HP. Tripchlorolide protects neuronal cells from microglia-mediated beta-amyloid neurotoxicity through inhibiting NF-kappaB and JNK signaling. Glia 2009; 57: 1227-1238
  • 75 Maezawa I, Zimin PI, Wulff H, Jin LW. Amyloid-beta protein oligomer at low nanomolar concentrations activates microglia and induces microglial neurotoxicity. J Biol Chem 2011; 286: 3693-3706
  • 76 Zhou Y, Ling EA, Dheen ST. Dexamethasone suppresses monocyte chemoattractant protein-1 production via mitogen activated protein kinase phosphatase-1 dependent inhibition of Jun N-terminal kinase and p 38 mitogen-activated protein kinase in activated rat microglia. J Neurochem 2007; 102: 667-678
  • 77 Du C, Hu R, Csernansky CA, Hsu CY, Choi DW. Very delayed infarction after mild focal cerebral ischemia: a role for apoptosis?. J Cereb Blood Flow Metab 1996; 16: 195-201
  • 78 Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP, Wang X. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science 1997; 275: 1129-1132
  • 79 Kluck RM, Bossy-Wetzel E, Green DR, Newmeyer DD. The release of cytochrome c from mitochondria: a primary site for Bcl-2 regulation of apoptosis. Science 1997; 275: 1132-1136
  • 80 Li MH, Jang JH, Sun B, Surh YJ. Protective effects of oligomers of grape seed polyphenols against beta-amyloid-induced oxidative cell death. Ann N Y Acad Sci 2004; 1030: 317-329
  • 81 Aksenov MY, Markesbery WR. Changes in thiol content and expression of glutathione redox system genes in the hippocampus and cerebellum in Alzheimerʼs disease. Neurosci Lett 2001; 302: 141-145
  • 82 Dang TN, Arseneault M, Zarkovic N, Waeg G, Ramassamy C. Molecular regulations induced by acrolein in neuroblastoma SK-N-SH cells: relevance to Alzheimerʼs disease. J Alzheimers Dis 2010; 21: 1197-1216
  • 83 Masliah E, Mallory M, Alford M, DeTeresa R, Hansen LA, McKeel jr. DW, Morris JC. Altered expression of synaptic proteins occurs early during progression of Alzheimerʼs disease. Neurology 2001; 56: 127-129
  • 84 Schulte-Herbruggen O, Braun A, Rochlitzer S, Jockers-Scherubl MC, Hellweg R. Neurotrophic factors–a tool for therapeutic strategies in neurological, neuropsychiatric and neuroimmunological diseases?. Curr Med Chem 2007; 14: 2318-2329
  • 85 Gincel D, Shoshan-Barmatz V. The synaptic vesicle protein synaptophysin: purification and characterization of its channel activity. Biophys J 2002; 83: 3223-3229