Computer-aided identification of protein targets of four polyphenols in Alzheimer's disease(AD)and validation in a mouse AD model
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摘要
Natural polyphenols are a large class of phytochemicals with neuroprotective effects. Four polyphenolic compounds: hesperidin, icariin, dihydromyricetin and baicalin were selected to evaluate their effects on Alzheimer's disease(AD). We analyzed by an inverse docking procedure(INVDOCK) the potential protein targets of these polyphenols within the KEGG AD pathway. Consequently, their therapeutic effects were evaluated and compared in a transgenic APP/PS1 mouse model of AD. These polyphenols were docked to several targets, including APP, BACE,PSEN, IDE, CASP, calpain and TNF-a, suggesting potential in vivo activities. Five month old transgenic mice were treated with these polyphenols. Icariin and hesperidin restored behavioral deficits and ameliorated Aβ deposits in both the cortex and hippocampus while baicalin and dihydromyricetin showed no substantial effects. Our findings suggest that hesperidin and icariin could be considered potential therapeutic candidates of human AD.
Natural polyphenols are a large class of phytochemicals with neuroprotective effects. Four polyphenolic compounds: hesperidin, icariin, dihydromyricetin and baicalin were selected to evaluate their effects on Alzheimer's disease(AD). We analyzed by an inverse docking procedure(INVDOCK) the potential protein targets of these polyphenols within the KEGG AD pathway. Consequently, their therapeutic effects were evaluated and compared in a transgenic APP/PS1 mouse model of AD. These polyphenols were docked to several targets, including APP, BACE,PSEN, IDE, CASP, calpain and TNF-a, suggesting potential in vivo activities. Five month old transgenic mice were treated with these polyphenols. Icariin and hesperidin restored behavioral deficits and ameliorated Aβ deposits in both the cortex and hippocampus while baicalin and dihydromyricetin showed no substantial effects. Our findings suggest that hesperidin and icariin could be considered potential therapeutic candidates of human AD.
Natural polyphenols are a large class of phytochemicals with neuroprotective effects. Four polyphenolic compounds: hesperidin, icariin, dihydromyricetin and baicalin were selected to evaluate their effects on Alzheimer's disease(AD). We analyzed by an inverse docking procedure(INVDOCK) the potential protein targets of these polyphenols within the KEGG AD pathway. Consequently, their therapeutic effects were evaluated and compared in a transgenic APP/PS1 mouse model of AD. These polyphenols were docked to several targets, including APP, BACE,PSEN, IDE, CASP, calpain and TNF-a, suggesting potential in vivo activities. Five month old transgenic mice were treated with these polyphenols. Icariin and hesperidin restored behavioral deficits and ameliorated Aβ deposits in both the cortex and hippocampus while baicalin and dihydromyricetin showed no substantial effects. Our findings suggest that hesperidin and icariin could be considered potential therapeutic candidates of human AD.
引文
[1] Querfurth HW, LaFerla FM. Alzheimer's disease[J]. N Engl J Med, 2010, 362(4):329-344.
[2] Mattson MP. Pathways towards and away from Alzheimer's disease[J]. Nature, 2004, 430(7000):631-639.
[3] Porat Y, Abramowitz A, Gazit E. Inhibition of amyloid fibril formation by polyphenols:structural similarity and aromatic interactions as a common inhibition mechanism[J]. Chem Biol Drug Des, 2006, 67(1):27-37.
[4] Chen Z, Nihei K, Tanaka H, et al. Identification of a nitric oxidegeneration-stimulative principle in Scutellariae radix[J].Biosci Biotechnol Biochem, 2013, 77(3):657-659.
[5] Crozier A, Jaganath IB, Clifford MN. Dietary phenolics:chemistry, bioavailability and effects on health[J]. Nat Prod Rep, 2009, 26(8):1001-1043.
[6] Chen YZ, Zhi DG. Ligand-protein inverse docking and its potential use in the computer search of protein targets of a small molecule[J]. Proteins, 2001, 43(2):217-226.
[7] Ma C, Tang K, Liu Q, et al. Calmodulin as a potential target by which berberine induces cell cycle arrest in human hepatoma Bel7402 cells[J]. Chem Biol Drug Des, 2013, 81(6):775-783.
[8] Kanehisa M, Goto S. KEGG:kyoto encyclopedia of genes and genomes[J]. Nucleic Acids Res, 2000, 28(1):27-30.
[9] Radde R, Bolmont T, Kaeser SA, et al. Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology[J]. EMBO Rep, 2006, 7(9):940-946.
[10] Zhang ZY, Daniels R, Schluesener HJ. Oridonin ameliorates neuropathological changes and behavioural deficits in a mouse model of cerebral amyloidosis[J]. J Cell Mol Med, 2013, 17(12):1566-1576.
[11] Wesson DW, Wilson DA. Age and gene overexpression interact to abolish nesting behavior in Tg2576 amyloid precursor protein(APP)mice[J]. Behav Brain Res, 2011, 216(1):408-413.
[12] Bolivar VJ, Walters SR, Phoenix JL. Assessing autism-like behavior in mice:variations in social interactions among inbred strains[J]. Behav Brain Res,2007, 176(1):21-26.
[13] Hibbits N, Pannu R, Wu TJ, et al. Cuprizone demyelination of the corpus callosum in mice correlates with altered social interaction and impaired bilateral sensorimotor coordination[J].ASN Neuro, 2009, 1(3):153-164.
[14] de Chaumont F, Dallongeville S, Chenouard N, et al. Icy:an open bioimage informatics platform for extended reproducible research[J]. Nat Methods,2012, 9(7):690-696.
[15] Ogata H, Goto S, Sato K, et al. KEGG:Kyoto Encyclopedia of Genes and Genomes[J]. Nucleic Acids Res, 1999, 27(1):29-34.
[16] Zhang ZY,Li C, Zug C,et al. Icariin ameliorates neuropathological changes, TGF-β1 accumulation and behavioral deficits in a mouse model of cerebral amyloidosis[J]. PLoS One, 2014,9(8):e104616.
[17] Wesson DW, Wilson DA. Age and gene overexpression interact to abolish nesting behavior in Tg2576 amyloid precursor protein(APP)mice[J]. Behav Brain Res, 2011, 216(1):408-413.
[18] Li C, Zug C, Qu H, et al. Hesperidin ameliorates behavioral impairments and neuropathology of transgenic APP/PS1 mice[J]. Behav Brain Rest 2015, 281:32-42.
[19] Bastianetto S, Dumont Y, Han Y, et al. Comparative neuroprotective properties of stilbene and catechin analogs:action via a plasma membrane receptor site?[J]. CNS Neurosci Ther, 2009, 15(1):76-83.
[20] Bastianetto S, Ramassamy C, Dore S, et al. The Ginkgo biloba extract(EGb 761)protects hippocampal neurons against celldeath induced by beta-amyloid[J]. Eur JNeurosci, 2000,12(6):1882-1890.
[21] Alvarez JC. High-throughput docking as a source of novel drug leads[J]. Curr Opin Chem Biol, 2004, 8(4):365-370.
[22] O'Brien RJ, Wong PC. Amyloid precursor protein processing and Alzheimer's disease[J].Annu Rev Neurosci, 2011, 34:185-204.
[23] Cai H, Wang Y, McCarthy D, et al. BACE1 is the major betasecretase for generation of Abeta peptides by neurons[J]. Nat Neurosci, 2001, 4(3):233-234.
[24] Selkoe DJ. The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer's disease[J]. Trends Cell Biol,1998, 8(11):447-453.
[25] Imbimbo BP, Giardino L, Sivilia S, et al. CHF5074, a novel gamma-secretase modulator, restores hippocampal neurogenesis potential and reverses contextual memory deficit in a transgenic mouse model of Alzheimer's disease[J]. J Alzheimers Dis, 2010, 20(1):159-173.
[26] Donmez G, Wang D, Cohen DE, et al. SIRT1 suppresses betaamyloid production by activating the alpha-secretase gene ADAM10[J]. Cell, 2010, 142(2):320-332.
[27] Leissring MA, Farris W, Chang AY, et al. Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death[J].Neuron, 2003, 40(6):1087-1093.
[28] Chae SS, Yoo CB, Jo C, et al. Caspases-2 and-8 are involved in the presenilin 1/gamma-secretase-dependent cleavage of amyloid precursor protein after the induction of apoptosis[J]. J Neurosci Res, 2010, 88(9):1926-1933.
[29] Chen Y, McPhie DL, Hirschberg J, et al. The amyloid precursor protein-binding protein APP-BP1 drives the cell cycle through the S-M checkpoint and causes apoptosis in neurons[J]. J Biol Chem, 2000, 275(12):8929-8935.
[30] Wolfe MS,Guenette SY. APP at a glance[J]. J Cell Sci, 2007,120(Pt 18):3157-3161.
[31] Li Y, Nowotny P, Holmans P, et al. Association of late-onset Alzheimer's disease with genetic variation in multiple membersof the GAPD gene family[J]. Proc Natl Acad Sci U S A, 2004,101(44):15688-15693.
[32] Rogers J, Webster S, Lue LF, et al. Inflammation and Alzheimer's disease pathogenesis[J]. Neurobiol Aging, 1996,17(5):681-686.
[33] Saha RN, Liu X, Pahan K. Up-regulation of BDNF in astrocytes by TNF-alpha:a case for the neuroprotective role of cytokine[J]. J Neuroimmune Pharmacol, 2006, 1(3):212-222.
[34] Li C, Ebrahimi A, Schluesener H. Drug pipeline in neurodegeneration based on transgenic mice models of Alzheimer's disease[J]. Ageing Res Rev, 2013, 12(1):116-140.
[35] Liang B, Duan BY, Zhou XP, et al. Calpain activation promotes BACE1 expression, amyloid precursor protein processing, and amyloid plaque formation in a transgenic mouse model of Alzheimer disease[J]. J Biol Chem, 2010, 285(36):27737-27744.
[36] Trinchese F, Fa'M, Liu S, et al. Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease[J]. J Clin Invest, 2008, 118(8):2796-2807.
[37] Huang H, Zhang Y, Yang R, et al. Determination of baicalin in rat cerebrospinal fluid and blood using microdialysis coupled with ultra-performance liquid chromatography-tandem mass spectrometry[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2008, 874(1-2):77-83.
[38] Youdim KA, Dobbie MS, Kuhnle G, et al. Interaction between flavonoids and the blood-brain barrier:in vitro studies[J]. J Neurochem, 2003, 85(1):180-192.
[39] Ye LK, Chen JM, Liu SH, et al. Pharmacokinetics of icariin in rats[J]. Chung Kuo Yao Hsueh Tsa Chih, 1999, 34:33-36.
[40] Xing J, Chen XY, Zhang SQ, et al. Liquid chromatographyelectrospray ion trap mass spectrometry analysis of baicalin and its isomer in rats urine[J]. Chinese Mass Spectrom Societ, 2004,25:129-133.
[41] Li YQ. The studies of quality specification of ampelopsis grossedentata and the pharmacokinetics of its active component dihydromyricetin in rat[D]. Shenyang:Shenyang Pharmaceutical University, 2003.
[2] Mattson MP. Pathways towards and away from Alzheimer's disease[J]. Nature, 2004, 430(7000):631-639.
[3] Porat Y, Abramowitz A, Gazit E. Inhibition of amyloid fibril formation by polyphenols:structural similarity and aromatic interactions as a common inhibition mechanism[J]. Chem Biol Drug Des, 2006, 67(1):27-37.
[4] Chen Z, Nihei K, Tanaka H, et al. Identification of a nitric oxidegeneration-stimulative principle in Scutellariae radix[J].Biosci Biotechnol Biochem, 2013, 77(3):657-659.
[5] Crozier A, Jaganath IB, Clifford MN. Dietary phenolics:chemistry, bioavailability and effects on health[J]. Nat Prod Rep, 2009, 26(8):1001-1043.
[6] Chen YZ, Zhi DG. Ligand-protein inverse docking and its potential use in the computer search of protein targets of a small molecule[J]. Proteins, 2001, 43(2):217-226.
[7] Ma C, Tang K, Liu Q, et al. Calmodulin as a potential target by which berberine induces cell cycle arrest in human hepatoma Bel7402 cells[J]. Chem Biol Drug Des, 2013, 81(6):775-783.
[8] Kanehisa M, Goto S. KEGG:kyoto encyclopedia of genes and genomes[J]. Nucleic Acids Res, 2000, 28(1):27-30.
[9] Radde R, Bolmont T, Kaeser SA, et al. Abeta42-driven cerebral amyloidosis in transgenic mice reveals early and robust pathology[J]. EMBO Rep, 2006, 7(9):940-946.
[10] Zhang ZY, Daniels R, Schluesener HJ. Oridonin ameliorates neuropathological changes and behavioural deficits in a mouse model of cerebral amyloidosis[J]. J Cell Mol Med, 2013, 17(12):1566-1576.
[11] Wesson DW, Wilson DA. Age and gene overexpression interact to abolish nesting behavior in Tg2576 amyloid precursor protein(APP)mice[J]. Behav Brain Res, 2011, 216(1):408-413.
[12] Bolivar VJ, Walters SR, Phoenix JL. Assessing autism-like behavior in mice:variations in social interactions among inbred strains[J]. Behav Brain Res,2007, 176(1):21-26.
[13] Hibbits N, Pannu R, Wu TJ, et al. Cuprizone demyelination of the corpus callosum in mice correlates with altered social interaction and impaired bilateral sensorimotor coordination[J].ASN Neuro, 2009, 1(3):153-164.
[14] de Chaumont F, Dallongeville S, Chenouard N, et al. Icy:an open bioimage informatics platform for extended reproducible research[J]. Nat Methods,2012, 9(7):690-696.
[15] Ogata H, Goto S, Sato K, et al. KEGG:Kyoto Encyclopedia of Genes and Genomes[J]. Nucleic Acids Res, 1999, 27(1):29-34.
[16] Zhang ZY,Li C, Zug C,et al. Icariin ameliorates neuropathological changes, TGF-β1 accumulation and behavioral deficits in a mouse model of cerebral amyloidosis[J]. PLoS One, 2014,9(8):e104616.
[17] Wesson DW, Wilson DA. Age and gene overexpression interact to abolish nesting behavior in Tg2576 amyloid precursor protein(APP)mice[J]. Behav Brain Res, 2011, 216(1):408-413.
[18] Li C, Zug C, Qu H, et al. Hesperidin ameliorates behavioral impairments and neuropathology of transgenic APP/PS1 mice[J]. Behav Brain Rest 2015, 281:32-42.
[19] Bastianetto S, Dumont Y, Han Y, et al. Comparative neuroprotective properties of stilbene and catechin analogs:action via a plasma membrane receptor site?[J]. CNS Neurosci Ther, 2009, 15(1):76-83.
[20] Bastianetto S, Ramassamy C, Dore S, et al. The Ginkgo biloba extract(EGb 761)protects hippocampal neurons against celldeath induced by beta-amyloid[J]. Eur JNeurosci, 2000,12(6):1882-1890.
[21] Alvarez JC. High-throughput docking as a source of novel drug leads[J]. Curr Opin Chem Biol, 2004, 8(4):365-370.
[22] O'Brien RJ, Wong PC. Amyloid precursor protein processing and Alzheimer's disease[J].Annu Rev Neurosci, 2011, 34:185-204.
[23] Cai H, Wang Y, McCarthy D, et al. BACE1 is the major betasecretase for generation of Abeta peptides by neurons[J]. Nat Neurosci, 2001, 4(3):233-234.
[24] Selkoe DJ. The cell biology of beta-amyloid precursor protein and presenilin in Alzheimer's disease[J]. Trends Cell Biol,1998, 8(11):447-453.
[25] Imbimbo BP, Giardino L, Sivilia S, et al. CHF5074, a novel gamma-secretase modulator, restores hippocampal neurogenesis potential and reverses contextual memory deficit in a transgenic mouse model of Alzheimer's disease[J]. J Alzheimers Dis, 2010, 20(1):159-173.
[26] Donmez G, Wang D, Cohen DE, et al. SIRT1 suppresses betaamyloid production by activating the alpha-secretase gene ADAM10[J]. Cell, 2010, 142(2):320-332.
[27] Leissring MA, Farris W, Chang AY, et al. Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death[J].Neuron, 2003, 40(6):1087-1093.
[28] Chae SS, Yoo CB, Jo C, et al. Caspases-2 and-8 are involved in the presenilin 1/gamma-secretase-dependent cleavage of amyloid precursor protein after the induction of apoptosis[J]. J Neurosci Res, 2010, 88(9):1926-1933.
[29] Chen Y, McPhie DL, Hirschberg J, et al. The amyloid precursor protein-binding protein APP-BP1 drives the cell cycle through the S-M checkpoint and causes apoptosis in neurons[J]. J Biol Chem, 2000, 275(12):8929-8935.
[30] Wolfe MS,Guenette SY. APP at a glance[J]. J Cell Sci, 2007,120(Pt 18):3157-3161.
[31] Li Y, Nowotny P, Holmans P, et al. Association of late-onset Alzheimer's disease with genetic variation in multiple membersof the GAPD gene family[J]. Proc Natl Acad Sci U S A, 2004,101(44):15688-15693.
[32] Rogers J, Webster S, Lue LF, et al. Inflammation and Alzheimer's disease pathogenesis[J]. Neurobiol Aging, 1996,17(5):681-686.
[33] Saha RN, Liu X, Pahan K. Up-regulation of BDNF in astrocytes by TNF-alpha:a case for the neuroprotective role of cytokine[J]. J Neuroimmune Pharmacol, 2006, 1(3):212-222.
[34] Li C, Ebrahimi A, Schluesener H. Drug pipeline in neurodegeneration based on transgenic mice models of Alzheimer's disease[J]. Ageing Res Rev, 2013, 12(1):116-140.
[35] Liang B, Duan BY, Zhou XP, et al. Calpain activation promotes BACE1 expression, amyloid precursor protein processing, and amyloid plaque formation in a transgenic mouse model of Alzheimer disease[J]. J Biol Chem, 2010, 285(36):27737-27744.
[36] Trinchese F, Fa'M, Liu S, et al. Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease[J]. J Clin Invest, 2008, 118(8):2796-2807.
[37] Huang H, Zhang Y, Yang R, et al. Determination of baicalin in rat cerebrospinal fluid and blood using microdialysis coupled with ultra-performance liquid chromatography-tandem mass spectrometry[J]. J Chromatogr B Analyt Technol Biomed Life Sci, 2008, 874(1-2):77-83.
[38] Youdim KA, Dobbie MS, Kuhnle G, et al. Interaction between flavonoids and the blood-brain barrier:in vitro studies[J]. J Neurochem, 2003, 85(1):180-192.
[39] Ye LK, Chen JM, Liu SH, et al. Pharmacokinetics of icariin in rats[J]. Chung Kuo Yao Hsueh Tsa Chih, 1999, 34:33-36.
[40] Xing J, Chen XY, Zhang SQ, et al. Liquid chromatographyelectrospray ion trap mass spectrometry analysis of baicalin and its isomer in rats urine[J]. Chinese Mass Spectrom Societ, 2004,25:129-133.
[41] Li YQ. The studies of quality specification of ampelopsis grossedentata and the pharmacokinetics of its active component dihydromyricetin in rat[D]. Shenyang:Shenyang Pharmaceutical University, 2003.