Login Register Cart 0
Generic placeholder image

Current Pharmaceutical Biotechnology

Editor-in-Chief

ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Inhibition of Amyloid β Aggregation Using Optimized Nano-Encapsulated Formulations of Plant Extracts with High Metal Chelator Activities

Author(s): Fatma Kazdal, Fatemeh Bahadori*, Burak Celik, Abdulselam Ertas and Gulacti Topcu

Volume 21, Issue 8, 2020

Page: [681 - 701] Pages: 21

DOI: 10.2174/1389201021666191210125851

Price: $65

Abstract

Background: The role of Fe+2, Cu+2 and Zn+2 in facilitating aggregation of Amyloid β (Aβ) and consequently, the progression of Alzheimer's disease (AD) is well established.

Objective: Development of non-toxic metal chelators is an emerging era in the treatment of AD, in which complete success has not been fully achieved. The purpose of this study was to determine plant extracts with high metal chelator and to encapsulate them in nano-micellar systems with the ability to pass through the Blood Brain Barrier (BBB).

Methods: Extracts of 36 different Anatolian plants were prepared, total phenolic and flavonoid contents were determined, and the extracts with high content were examined for their Fe+2, Cu+2 and Zn+2 chelating activities. Apolipoprotein E4 (Apo E) decorated nano-formulations of active extracts were prepared using Poly (Lactide-co-Glycolide) (PLGA) (final product ApoEPLGA) to provide BBB penetrating property.

Results: Verbascum flavidum aqueous extract was found as the most active sample, incubation of which, with Aβ before and after metal-induced aggregation, resulted in successful inhibition of aggregate formation, while re-solubilization of pre-formed aggregates was not effectively achieved. The same results were obtained using ApoEPLGA.

Conclusion: An optimized metal chelator nano-formulation with BBB penetrating ability was prepared and presented for further in-vivo studies.

Keywords: Alzheimer, apo E4, metal chelator, nano-drug delivery, polyphenol, amyloid β.

« Previous Next »
Graphical Abstract

[1]
Alzheimer, A.; Stelzmann, R.A.; Schnitzlein, H.N.; Murtagh, F.R. An English translation of Alzheimer’s 1907 paper, “Uber eine eigenartige Erkankung der Hirnrinde”. Clin. Anat., 1995, 8(6), 429-431.
[http://dx.doi.org/10.1002/ca.980080612] [PMID: 8713166]
[2]
Caballero, A.B.; Terol-Ordaz, L.; Espargaró, A.; Vázquez, G.; Nicolás, E.; Sabaté, R.; Gamez, P. Histidine-rich oligopeptides to lessen copper-mediated amyloid-β toxicity. Chemistry, 2016, 22(21), 7268-7280.
[http://dx.doi.org/10.1002/chem.201600286] [PMID: 27071336]
[3]
Pal, R.; Rai, J.P. Phytochelatins: peptides involved in heavy metal detoxification. Appl. Biochem. Biotechnol., 2010, 160(3), 945-963.
[http://dx.doi.org/10.1007/s12010-009-8565-4] [PMID: 19224399]
[4]
Asagba, S.O. Role of diet in absorption and toxicity of oral cadmium-A review of literature. Afr. J. Biotechnol., 2009, 8(25), 7428-7436.
[5]
Rooney, J.P. The role of thiols, dithiols, nutritional factors and interacting ligands in the toxicology of mercury. Toxicology, 2007, 234(3), 145-156.
[http://dx.doi.org/10.1016/j.tox.2007.02.016] [PMID: 17408840]
[6]
Kreuter, J.; Shamenkov, D.; Petrov, V.; Ramge, P.; Cychutek, K.; Koch-Brandt, C.; Alyautdin, R. Apolipoprotein-mediated transport of nanoparticle-bound drugs across the blood-brain barrier. J. Drug Target., 2002, 10(4), 317-325.
[http://dx.doi.org/10.1080/10611860290031877] [PMID: 12164380]
[7]
Segal, D.H. Physiology of the CSF and Blood-Brain Barriers; CRC Press: Boca Raton, 1996. 832 pages.
[8]
Ertas, A.; Boga, M.; Yilmaz, M.A.; Yesil, Y.; Tel, G.; Temel, H.; Hasimi, N.; Gazioglu, I.; Ozturk, M.; Ugurlu, P.J.I.C. A detailed study on the chemical and biological profiles of essential oil and methanol extract of Thymus nummularius (Anzer tea): Rosmarinic acid. Ind. Crops Prod., 2015, 67, 336-345.
[http://dx.doi.org/10.1016/j.indcrop.2015.01.064]
[9]
Moreno, M.I.N.; Isla, M.I.; Sampietro, A.R.; Vattuone, M.A. Comparison of the free radical-scavenging activity of propolis from several regions of Argentina. J. Ethnopharmacol., 2000, 71(1-2), 109-114.
[http://dx.doi.org/10.1016/S0378-8741(99)00189-0] [PMID: 10904153]
[10]
Slinkard, K.; Singleton, V.L. Total phenol analysis: Automation and comparison with manual methods. Am. J. Enol. Vitic., 1977, 28(1), 49-55.
[11]
Decker, E.A.; Welch, B. Role of ferritin as a lipid oxidation catalyst in muscle food. J. Agric. Food Chem., 1990, 38(3), 674-677.
[http://dx.doi.org/10.1021/jf00093a019]
[12]
Karamać, M. Chelation of Cu(II), Zn(II), and Fe(II) by tannin constituents of selected edible nuts. Int. J. Mol. Sci., 2009, 10(12), 5485-5497.
[http://dx.doi.org/10.3390/ijms10125485] [PMID: 20054482]
[13]
Paul, S.; Bhattacharyya, S.S.; Boujedaini, N.; Khuda-Bukhsh, A.R. Anticancer potentials of root extract of Polygala senega and its PLGA nanoparticles-encapsulated form. Evidence Based Complement. Altern. Med., 2011, 2011,517204.
[14]
Banerjee, A.; Onyuksel, H. Human pancreatic polypeptide in a phospholipid-based micellar formulation. Pharm. Res., 2012, 29(6), 1698-1711.
[http://dx.doi.org/10.1007/s11095-012-0718-4] [PMID: 22399387]
[15]
Boğa, M.; Ertaş, A.; Haşimi, N.; Demirci, S.; Abdullah, M. Phenolic profile, fatty acid and essential oil composition analysis and antioxidant, antialzheimer and antibacterial activities of Verbascum flavidum extracts. Warasan Khana Witthayasat Maha Witthayalai Chiang Mai, 2016, 43(5), 1089-1100.
[16]
Chaudhri, S.; Bangar, J.; Akuskar, G.; Ratnaparkhi, M. Development and validation of UV spectrophotometric method for simultaneous estimation of rutin and quercetin in niosome formulation. Der Pharmacia Lettre, 2014, 6(3), 271-276.
[17]
Navarra, G.; Moschetti, M.; Guarrasi, V.; Mangione, M.; Militello, V.; Leone, M. Simultaneous determination of caffeine and chlorogenic acids in green coffee by UV/Vis spectroscopy. J. Chem.,, 2017, 2017
[18]
Atwood, C.S.; Moir, R.D.; Huang, X.; Scarpa, R.C.; Bacarra, N.M.E.; Romano, D.M.; Hartshorn, M.A.; Tanzi, R.E.; Bush, A.I. Dramatic aggregation of Alzheimer abeta by Cu(II) is induced by conditions representing physiological acidosis. J. Biol. Chem., 1998, 273(21), 12817-12826.
[http://dx.doi.org/10.1074/jbc.273.21.12817] [PMID: 9582309]
[19]
Scientific, T. F. Pierce 660nm Protein Assay Reagent,, 2016. Jun;06
[20]
Bradford, M.M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal. Biochem., 1976, 72(1-2), 248-254.
[http://dx.doi.org/10.1016/0003-2697(76)90527-3] [PMID: 942051]
[21]
Laemmli, U.K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature, 1970, 227(5259), 680-685.
[22]
Damas, B.A.; Wheater, M.A.; Bringas, J.S.; Hoen, M.M. Cytotoxicity comparison of mineral trioxide aggregates and endosequence bioceramic root repair materials. J. Endod., 2011, 37(3), 372-375.
[http://dx.doi.org/10.1016/j.joen.2010.11.027] [PMID: 21329824]
[23]
Mojarrab, M.; Lagzian, M-S.; Emami, S.A.; Asili, J.; Tayarani-Najaran, Z. In vitro anti-proliferative and apoptotic activity of different fractions of Artemisia armeniaca. Rev. Bras. Farmacogn., 2013, 23(5), 783-788.
[http://dx.doi.org/10.1590/S0102-695X2013000500010]
[24]
Haşimi, N.,; Ertaş, A.,; Yilmaz, M. A.,; Boğa, M.,; Temel, H.,; Demirci, S., ; Yılmaz-Özden, T., ; Yener, İ.,; and Kolak, U. LCMS/MS and GC-MS analyses of three endemic Astragalus species from Anatolia towards their total phenolic-flavonoid contents and biological activities. Biologic. Divers. Conserv.,, 2008,, pp 18- 30.
[25]
Boğa, M.; Alkan, H.; Ertaş, A.; Oral, E.V.; Yılmaz, M.A.; Yeşil, Y.; Gören, A.C.; Temel, H.; Kolak, U. Phytochemical profile and some biological activities of three Centaurea species from Turkey. Trop. J. Pharm. Res., 2016, 15(9), 1865-1875.
[http://dx.doi.org/10.4314/tjpr.v15i9.8]
[26]
Boğa, M.; Ertaş, A.; Yılmaz, M.A.; Kızıl, M.; Çeken, B.; Haşimi, N.; Özden, T.Y.; Demirci, S.; Yener, İ.; Deveci, Ö. UHPLC-ESI-MS/MS and GC-MS analyses on phenolic, fatty acid and essential oil of Verbascum pinetorum with antioxidant, anticholinesterase, antimicrobial and DNA damage protection effects. Iran. J. Pharm. Res., 2016, 15(3), 393-405.
[PMID: 27980574]
[27]
Ertas, A.; Boga, M.; Kizil, M.; Ceken, B.; Goren, A.C.; Hasimi, N.; Demirci, S.; Topcu, G.; Kolak, U. Chemical profile and biological activities of Veronica thymoides subsp. pseudocinerea. Pharm. Biol., 2015, 53(3), 334-339.
[http://dx.doi.org/10.3109/13880209.2014.919326] [PMID: 25331745]
[28]
Boga, M.; Ertas, A.; Eroglu-Ozkan, E.; Kizil, M.; Ceken, B.; Topcu, G. Phytochemical analysis, antioxidant, antimicrobial, anticholinesterase and DNA protective effects of Hypericum capitatum var. capitatum extracts. S. Afr. J. Bot., 2016, 104, 249-257.
[http://dx.doi.org/10.1016/j.sajb.2016.02.204]
[29]
Ertaş, A.; Boğa, M.; Yılmaz, M.A.; Yeşil, Y.; Haşimi, N.; Kaya, M.S.; Temel, H.; Kolak, U. Chemical compositions by using LC-MS/MS and GC-MS and biological activities of Sedum sediforme (Jacq.) Pau. J. Agric. Food Chem., 2014, 62(20), 4601-4609.
[http://dx.doi.org/10.1021/jf500067q] [PMID: 24773044]
[30]
Hasimi, N.; Ertaş, A.; Varhan Oral, E.; Alkan, H. Chemical profile of Malva neglecta and Malvella sherardiana by LC-MS/MS, GC/MS and their anticholinesterase, antimicrobial and antioxidant properties with aflatoxin-contents. Marmara Pharm. J., 2017, 471-484.
[http://dx.doi.org/10.12991/marupj.307461]
[31]
Ertaş, A.; Boğa, M.; Haşimi, N.; Yeşil, Y.; Gören, A.C.; Topçu, G.; Kolak, U. Antioxidant, anticholinesterase, and antimicrobial activities and fatty acid constituents of Achillea cappadocica Hausskn. et Bornm. Turk. J. Chem., 2014, 38(4), 592-599.
[32]
Boğa, M. Chemical constituents, cytotoxic, antioxidant and cholinesterases ınhibitory activities of Silene compacta (fischer) extracts. Marmara Pharm. J., 2017, 445-454.
[http://dx.doi.org/10.12991/marupj.306789]
[33]
Boğa, M.; Ertaş, A.; Yeşil, Y.; Haşimi, N.; Yılmaz, M.A.; and Özaslan, C. Phytochemical analysis and antioxidant and anticholinesterase activities of Pulicaria dysenterica from Turkey. DUFED, 2014, 3(1), 53-60.
[34]
Bilto, Y.Y.; Alabdallat, N.G.; Salim, M. Antioxidant properties of twelve selected medicinal plants commonly used in Jordan. Br. J. Pharm. Res., 2015, 6(2), 121-130.
[http://dx.doi.org/10.9734/BJPR/2015/16136]
[35]
Ertaş, A.; Boğa, M.; Haşimi, N.; Yılmaz, M.A. Fatty acid and essential oil compositions of Trifolium angustifolium var. angustifolium with antioxidant, anticholinesterase and antimicrobial activities. Iran. J. Pharm. Res., 2015, 14(1), 233-241.
[PMID: 25561929]
[36]
Masoud, M.; Kassem, T.; Shaker, M.; Ali, A. Studies on transition metal murexide complexes. J. Therm. Anal. Calorim., 2006, 84(3), 549-555.
[http://dx.doi.org/10.1007/s10973-005-9991-3]
[37]
Sullivan, M. 2018.http://alzheimer.ca
[38]
Cuajungco, M.P.; Goldstein, L.E.; Nunomura, A.; Smith, M.A.; Lim, J.T.; Atwood, C.S.; Huang, X.; Farrag, Y.W.; Perry, G.; Bush, A.I. Evidence that the β-amyloid plaques of Alzheimer’s disease represent the redox-silencing and entombment of abeta by zinc. J. Biol. Chem., 2000, 275(26), 19439-19442.
[http://dx.doi.org/10.1074/jbc.C000165200] [PMID: 10801774]
[39]
Sayre, L.M.; Perry, G.; Harris, P.L.; Liu, Y.; Schubert, K.A.; Smith, M.A. In situ oxidative catalysis by neurofibrillary tangles and senile plaques in Alzheimer’s disease: A central role for bound transition metals. J. Neurochem., 2000, 74(1), 270-279.
[http://dx.doi.org/10.1046/j.1471-4159.2000.0740270.x] [PMID: 10617129]
[40]
Atwood, C.S.; Scarpa, R.C.; Huang, X.; Moir, R.D.; Jones, W.D.; Fairlie, D.P.; Tanzi, R.E.; Bush, A.I. Characterization of copper interactions with alzheimer amyloid β peptides: identification of an attomolar-affinity copper binding site on amyloid β1-42. J. Neurochem., 2000, 75(3), 1219-1233.
[http://dx.doi.org/10.1046/j.1471-4159.2000.0751219.x] [PMID: 10936205]
[41]
Duce, J.A.; Tsatsanis, A.; Cater, M.A.; James, S.A.; Robb, E.; Wikhe, K.; Leong, S.L.; Perez, K.; Johanssen, T.; Greenough, M.A.; Cho, H.H.; Galatis, D.; Moir, R.D.; Masters, C.L.; McLean, C.; Tanzi, R.E.; Cappai, R.; Barnham, K.J.; Ciccotosto, G.D.; Rogers, J.T.; Bush, A.I. Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer’s disease. Cell, 2010, 142(6), 857-867.
[http://dx.doi.org/10.1016/j.cell.2010.08.014] [PMID: 20817278]
[42]
Wild, K.; August, A.; Pietrzik, C.U.; Kins, S. Structure and synaptic function of metal binding to the amyloid precursor protein and its proteolytic fragments. Front. Mol. Neurosci., 2017, 10, 21.
[http://dx.doi.org/10.3389/fnmol.2017.00021] [PMID: 28197076]
[43]
Smith, M.A.; Casadesus, G.; Joseph, J.A.; Perry, G. Amyloid-β and τ serve antioxidant functions in the aging and Alzheimer brain. Free Radic. Biol. Med., 2002, 33(9), 1194-1199.
[http://dx.doi.org/10.1016/S0891-5849(02)01021-3] [PMID: 12398927]
[44]
Hayashi, T.; Shishido, N.; Nakayama, K.; Nunomura, A.; Smith, M.A.; Perry, G.; Nakamura, M. Lipid peroxidation and 4-hydroxy-2-nonenal formation by copper ion bound to amyloid-β peptide. Free Radic. Biol. Med., 2007, 43(11), 1552-1559.
[http://dx.doi.org/10.1016/j.freeradbiomed.2007.08.013] [PMID: 17964426]
[45]
Yan, S.D.; Yan, S.F.; Chen, X.; Fu, J.; Chen, M.; Kuppusamy, P.; Smith, M.A.; Perry, G.; Godman, G.C.; Nawroth, P. Non-enzymatically glycated tau in Alzheimer’s disease induces neuronal oxidant stress resulting in cytokine gene expression and release of amyloid β-peptide. Nat. Med., 1995, 1(7), 693-699.
[http://dx.doi.org/10.1038/nm0795-693] [PMID: 7585153]
[46]
Smith, M.A.; Hirai, K.; Hsiao, K.; Pappolla, M.A.; Harris, P.L.; Siedlak, S.L.; Tabaton, M.; Perry, G. Amyloid-β deposition in Alzheimer transgenic mice is associated with oxidative stress. J. Neurochem., 1998, 70(5), 2212-2215.
[http://dx.doi.org/10.1046/j.1471-4159.1998.70052212.x] [PMID: 9572310]
[47]
Dwyer, F. Chelating agents and metal chelates; Elsevier, 2012.
[48]
Kenche, V.B.; Barnham, K.J. Alzheimer’s disease & metals: Therapeutic opportunities. Br. J. Pharmacol., 2011, 163(2), 211-219.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01221.x] [PMID: 21232050]
[49]
Liu, G.; Bruenger, F.W.; Miller, S.C.; Arif, A.M. Molecular structure and biological and pharmacological properties of 3-hydroxy-2-methyl-1-(β-D-ribofuranosyl or pyranosyl)-4-pyridinone: Potential iron overload drugs for oral administration. Bioorg. Med. Chem. Lett., 1998, 8(21), 3077-3080.
[http://dx.doi.org/10.1016/S0960-894X(98)00569-1] [PMID: 9873679]
[50]
Shen, L.; Zhang, H-Y.; Ji, H-F. A theoretical study on Cu (II)-chelating properties of curcumin and its implications for curcumin as a multipotent agent to combat Alzheimer’s disease. J. Mol. Struct. Theochem., 2005, 757(1-3), 199-202.
[http://dx.doi.org/10.1016/j.theochem.2005.05.016]
[51]
Mansell, D.; Rattray, N.; Etchells, L.L.; Schwalbe, C.H.; Blake, A.J.; Torres, J.; Kremer, C.; Bichenkova, E.V.; Barker, C.J.; Freeman, S. Conformational analysis of the natural iron chelator myo-inositol 1,2,3-trisphosphate using a pyrene-based fluorescent mimic. Org. Biomol. Chem., 2010, 8(12), 2850-2858.
[http://dx.doi.org/10.1039/c001078b] [PMID: 20428590]
[52]
Sears, M.E. Chelation: Harnessing and enhancing heavy metal detoxification--a review. ScientificWorldJournal, 2013, 2013219840
[http://dx.doi.org/10.1155/2013/219840] [PMID: 23690738]
[53]
Moore, J.J. Chemical metallurgy; Elsevier, 2013, p. 456.
[54]
Mahley, R.W.; Weisgraber, K.H.; Huang, Y.; Apolipoprotein, E.; Apolipoprotein, E. Structure determines function, from atherosclerosis to Alzheimer’s disease to AIDS. J. Lipid Res., 2009, 50(Suppl.), S183-S188.
[http://dx.doi.org/10.1194/jlr.R800069-JLR200] [PMID: 19106071]
[55]
Ritchie, C.W.; Bush, A.I.; Masters, C.L. Metal-protein attenuating compounds and Alzheimer’s disease. Expert Opin. Investig. Drugs, 2004, 13(12), 1585-1592.
[http://dx.doi.org/10.1517/13543784.13.12.1585] [PMID: 15566316]
[56]
Cherny, R.A.; Atwood, C.S.; Xilinas, M.E.; Gray, D.N.; Jones, W.D.; McLean, C.A.; Barnham, K.J.; Volitakis, I.; Fraser, F.W.; Kim, Y.; Huang, X.; Goldstein, L.E.; Moir, R.D.; Lim, J.T.; Beyreuther, K.; Zheng, H.; Tanzi, R.E.; Masters, C.L.; Bush, A.I. Treatment with a copper-zinc chelator markedly and rapidly inhibits β-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron, 2001, 30(3), 665-676.
[http://dx.doi.org/10.1016/S0896-6273(01)00317-8] [PMID: 11430801]
[57]
Ritchie, C.W.; Bush, A.I.; Mackinnon, A.; Macfarlane, S.; Mastwyk, M.; MacGregor, L.; Kiers, L.; Cherny, R.; Li, Q-X.; Tammer, A.; Carrington, D.; Mavros, C.; Volitakis, I.; Xilinas, M.; Ames, D.; Davis, S.; Beyreuther, K.; Tanzi, R.E.; Masters, C.L. Metal-protein attenuation with iodochlorhydroxyquin (clioquinol) targeting Abeta amyloid deposition and toxicity in Alzheimer disease: A pilot phase 2 clinical trial. Arch. Neurol., 2003, 60(12), 1685-1691.
[http://dx.doi.org/10.1001/archneur.60.12.1685] [PMID: 14676042]
[58]
Liu, G.; Men, P.; Perry, G.; Smith, M.A. Metal chelators coupled with nanoparticles as potential therapeutic agents for Alzheimer’s disease. J. Nanoneurosci., 2009, 1(1), 42-55.
[http://dx.doi.org/10.1166/jns.2009.005] [PMID: 19936278]

Rights & Permissions Print Cite
Article Metrics
9
1
© 2024 Bentham Science Publishers | Privacy Policy