Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter February 12, 2019

Application of quercetin in neurological disorders: from nutrition to nanomedicine

Elnaz Amanzadeh, Abolghasem Esmaeili, Soheila Rahgozar and Maryam Nourbakhshnia

Abstract

Quercetin is a polyphenolic flavonoid, which is frequently found in fruits and vegetables. The antioxidant potential of quercetin has been studied from subcellular compartments, that is, mitochondria to tissue levels in the brain. The neurodegeneration process initiates alongside aging of the neurons. It appears in different parts of the brain as Aβ plaques, neurofibrillary tangles, Lewy bodies, Pick bodies, and others, which leads to Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and other diseases. So far, no specific treatment has been identified for these diseases. Despite common treatments that help to prevent the development of disease, the condition of patients with progressive neurodegenerative diseases usually do not completely improve. Currently, the use of flavonoids, especially quercetin for the treatment of neurodegenerative diseases, has been expanded in animal models. It has also been used to treat animal models of neurodegenerative diseases. In addition, improvements in behavioral levels, as well as in cellular and molecular levels, decreased activity of antioxidant and apoptotic proteins, and increased levels of antiapoptotic proteins have been observed. Low bioavailability of quercetin has also led researchers to construct various quercetin-involved nanoparticles. The treatment of animal models of neurodegeneration using quercetin-involved nanoparticles has shown that improvements are observed in shorter periods and with use of lower concentrations. Indeed, intranasal administration of quercetin-involved nanoparticles, constructing superparamagnetic nanoparticles, and combinational treatment using nanoparticles such as quercetin and other drugs are suggested for future studies.

Acknowledgments

All the collaborators and authorities who cooperated are acknowledged.

  1. Conflict of interest statement: The authors declare no conflict of interest.

References

Abraham, M.H. and Acree, W.E. (2014). On the solubility of quercetin. J. Mol. Liquids 197, 157–159.10.1016/j.molliq.2014.05.006Search in Google Scholar

Aditya, N., Macedo, A.S., Doktorovova, S., Souto, E.B., Kim, S., Chang, P.-S., and Ko, S. (2014). Development and evaluation of lipid nanocarriers for quercetin delivery: a comparative study of solid lipid nanoparticles (SLN), nanostructured lipid carriers (NLC), and lipid nanoemulsions (LNE). LWT-Food Sci. Technol. 59, 115–121.10.1016/j.lwt.2014.04.058Search in Google Scholar

Agrawal, M., Saraf, S., Saraf, S., Antimisiaris, S.G., Chougule, M.B., Shoyele, S.A., and Alexander, A. (2018). Nose-to-brain drug delivery: an update on clinical challenges and progress towards approval of anti-Alzheimer drugs. J. Control. Release 281, 139–177.10.1016/j.jconrel.2018.05.011Search in Google Scholar PubMed

Alrawaiq, N.S. and Abdullah, A. (2014). A review of flavonoid quercetin: metabolism, bioactivity and antioxidant properties. Int. J. Pharm.Tech. Res. 6, 933–941.Search in Google Scholar

Ansari, M.A., Abdul, H.M., Joshi, G., Opii, W.O., and Butterfield, D.A. (2009). Protective effect of quercetin in primary neurons against Aβ (1–42): relevance to Alzheimer’s disease. J. Nutrit. Biochem. 20, 269–275.10.1016/j.jnutbio.2008.03.002Search in Google Scholar PubMed PubMed Central

Arredondo, F., Echeverry, C., Abin-Carriquiry, J.A., Blasina, F., Antúnez, K., Jones, D.P., Go, Y.-M., Liang, Y.-L., and Dajas, F. (2010). After cellular internalization, quercetin causes Nrf2 nuclear translocation, increases glutathione levels, and prevents neuronal death against an oxidative insult. Free Radic. Biol. Med. 49, 738–747.10.1016/j.freeradbiomed.2010.05.020Search in Google Scholar PubMed

Athauda, D. and Foltynie, T. (2016). Insulin resistance and Parkinson’s disease: a new target for disease modification? Progr. Neurobiol. 145–146, 98–120.10.1016/j.pneurobio.2016.10.001Search in Google Scholar PubMed

Azad, T.D., Pan, J., Connolly, I.D., Remington, A., Wilson, C.M., and Grant, G.A. (2015). Therapeutic strategies to improve drug delivery across the blood-brain barrier. Neurosurgical Focus 38, E9.10.3171/2014.12.FOCUS14758Search in Google Scholar PubMed PubMed Central

Azuma, K., Ippoushi, K., Ito, H., Higashio, H., and Terao, J. (2002). Combination of lipids and emulsifiers enhances the absorption of orally administered quercetin in rats. J. Agric. Food Chem. 50, 1706–1712.10.1021/jf0112421Search in Google Scholar PubMed

Baba, S., Furuta, T., Fujioka, M., and Goromaru, T. (1983). Studies on drug metabolism by use of isotopes XXVII: urinary metabolites of rutin in rats and the role of intestinal microflora in the metabolism of rutin. J. Pharm. Sci. 72, 1155–1158.10.1002/jps.2600721011Search in Google Scholar PubMed

Bahadir, H.M., Sarigoz, T., Topuz, Ö., Sevim, Y., Ertan, T., and Sarıcı, İ.Ş. (2018). Protective effects of quercetin on hepatic ischemia-reperfusion injury. Istanbul Med. J. 19, 47–51.10.5152/imj.2018.72325Search in Google Scholar

Baulch, J.E., Craver, B.M., Tran, K.K., Yu, L., Chmielewski, N., Allen, B.D., and Limoli, C.L. (2015). Persistent oxidative stress in human neural stem cells exposed to low fluences of charged particles. Redox Biol. 5, 24–32.10.1016/j.redox.2015.03.001Search in Google Scholar PubMed

Beal, M.F. (1998). Mitochondrial dysfunction in neurodegenerative diseases. Biochim. Biophys. Acta Bioenerg. 1366, 211–223.10.1016/S0005-2728(98)00114-5Search in Google Scholar

Bekris, L.M., Yu, C.E., Bird, T.D., and Tsuang, D.W. (2010). Genetics of Alzheimer disease. J. Geriatr. Psychiatry. Neurol. 23, 213–227.10.1177/0891988710383571Search in Google Scholar PubMed PubMed Central

Bien-Ly, N., Boswell, C.A., Jeet, S., Beach, T.G., Hoyte, K., Luk, W., Shihadeh, V., Ulufatu, S., Foreman, O., and Lu, Y. (2015). Lack of widespread BBB disruption in Alzheimer’s disease models: focus on therapeutic antibodies. Neuron 88, 289–297.10.1016/j.neuron.2015.09.036Search in Google Scholar PubMed

Bing, K.F., Howles, G.P., Qi, Y., Palmeri, M.L., and Nightingale, K.R. (2009). Blood-brain barrier (BBB) disruption using a diagnostic ultrasound scanner and Definity® in mice. Ultrasound Med. Biol. 35, 1298–1308.10.1016/j.ultrasmedbio.2009.03.012Search in Google Scholar PubMed PubMed Central

Birks, J. and Harvey, R. (2018). Donepezil for dementia due to Alzheimer’s disease. Cochrane Database Syst. Rev. 6, CD001190.10.1002/14651858.CD001190Search in Google Scholar PubMed

Biswal, S., Barhwal, K.K., Das, D., Dhingra, R., Dhingra, N., Nag, T.C., and Hota, S.K. (2018). Salidroside mediated stabilization of Bcl-xL prevents mitophagy in CA3 hippocampal neurons during hypoxia. Neurobiol. Dis. 116, 39–52.10.1016/j.nbd.2018.04.019Search in Google Scholar PubMed

Blasina, F., Vaamonde, L., Silvera, F., Tedesco, A.C., and Dajas, F. (2015). Intravenous nanosomes of quercetin improve brain function and hemodynamic instability after severe hypoxia in newborn piglets. Neurochem. Int. 89, 149–156.10.1016/j.neuint.2015.08.007Search in Google Scholar PubMed

Bonechi, C., Donati, A., Tamasi, G., Leone, G., Consumi, M., Rossi, C., Lamponi, S., and Magnani, A. (2018). Protective effect of quercetin and rutin encapsulated liposomes on induced oxidative stress. Biophys. Chem. 233, 55–63.10.1016/j.bpc.2017.11.003Search in Google Scholar PubMed

Caddeo, C., Nacher, A., Vassallo, A., Armentano, M.F., Pons, R., Fernàndez-Busquets, X., Carbone, C., Valenti, D., Fadda, A.M., and Manconi, M. (2016). Effect of quercetin and resveratrol co-incorporated in liposomes against inflammatory/oxidative response associated with skin cancer. Int. J. Pharm. 513, 153–163.10.1016/j.ijpharm.2016.09.014Search in Google Scholar PubMed

Cadena, P.G., Pereira, M.A., Cordeiro, R.B., Cavalcanti, I.M., Neto, B.B., Maria do Carmo, C., Lima Filho, J.L., Silva, V.L., and Santos-Magalhães, N.S. (2013). Nanoencapsulation of quercetin and resveratrol into elastic liposomes. Biochim. Biophys. Acta Biomemb. 1828, 309–316.10.1016/j.bbamem.2012.10.022Search in Google Scholar PubMed

Calderon Garciduenas, L., Melo-Sanchez, G., Vargas-Martinez, J., Macias-Escobedo, E., Hernandez-Orona, V.L., Cano-Gutierrez, G., Avila-Ramirez, J., and Torres-Jardon, R. (2015). Air pollution and children: barrier breakdown, inflammation, brain immunity and neurodegeneration. J. Neurol. Sci. 357, e509.10.1016/j.jns.2015.09.333Search in Google Scholar

Camandola, S., Plick, N., and Mattson, M.P. (2018). Impact of coffee and cacao purine metabolites on neuroplasticity and neurodegenerative disease. Neurochem. Res. 1–14. [Epub ahead of print].10.1007/s11064-018-2492-0Search in Google Scholar PubMed PubMed Central

Chakraborty, S., Stalin, S., Das, N., Choudhury, S.T., Ghosh, S., and Swarnakar, S. (2012). The use of nano-quercetin to arrest mitochondrial damage and MMP-9 upregulation during prevention of gastric inflammation induced by ethanol in rat. Biomaterials 33, 2991–3001.10.1016/j.biomaterials.2011.12.037Search in Google Scholar PubMed

Chen, Z. (2018). Common cues wire the spinal cord: axon guidance molecules in spinal neuron migration. Semin. Cell Dev. Biol. (in press).10.1016/j.semcdb.2017.12.012Search in Google Scholar PubMed

Chen, X. and Pan, W. (2014). The treatment strategies for neurodegenerative diseases by integrative medicine. Integr. Med. Int. 1, 223–225.10.1159/000381546Search in Google Scholar

Chen, J., Deng, X., Liu, N., Li, M., Liu, B., Fu, Q., Qu, R., and Ma, S. (2016). Quercetin attenuates tau hyperphosphorylation and improves cognitive disorder via suppression of ER stress in a manner dependent on AMPK pathway. J. Funct. Foods 22, 463–476.10.1016/j.jff.2016.01.036Search in Google Scholar

Cheng, S., Gao, W., Xu, X., Fan, H., Wu, Y., Li, F., Zhang, J., Zhu, X., and Zhang, Y. (2016). Methylprednisolone sodium succinate reduces BBB disruption and inflammation in a model mouse of intracranial haemorrhage. Brain Res. Bull. 127, 226–233.10.1016/j.brainresbull.2016.10.007Search in Google Scholar PubMed

Cheng, Y., Desse, S., Martinez, A., Worthen, R.J., Jope, R.S., and Beurel, E. (2018). TNFα disrupts blood brain barrier integrity to maintain prolonged depressive-like behavior in mice. Brain Behav. Immun. 69, 556–567.10.1016/j.bbi.2018.02.003Search in Google Scholar PubMed PubMed Central

Chiang, M.-C., Nicol, C.J., Cheng, Y.-C., Lin, K.-H., Yen, C.-H., and Lin, C.-H. (2016). Rosiglitazone activation of PPARγ-dependent pathways is neuroprotective in human neural stem cells against amyloid-beta–induced mitochondrial dysfunction and oxidative stress. Neurobiol. Aging 40, 181–190.10.1016/j.neurobiolaging.2016.01.132Search in Google Scholar PubMed

Choi, G.N., Kim, J.H., Kwak, J.H., Jeong, C.-H., Jeong, H.R., Lee, U., and Heo, H.J. (2012). Effect of quercetin on learning and memory performance in ICR mice under neurotoxic trimethyltin exposure. Food Chem. 132, 1019–1024.10.1016/j.foodchem.2011.11.089Search in Google Scholar

Choi, N.-Y., Choi, H., Park, H.-H., Lee, E.-H., Yu, H.-J., Lee, K.-Y., Lee, Y.J., and Koh, S.-H. (2014). Neuroprotective effects of amlodipine besylate and benidipine hydrochloride on oxidative stress-injured neural stem cells. Brain Res. 1551, 1–12.10.1016/j.brainres.2014.01.016Search in Google Scholar PubMed

Chowdhury, P., Nagesh, P.K., Khan, S., Hafeez, B.B., Chauhan, S.C., Jaggi, M., and Yallapu, M.M. (2018). Development of polyvinylpyrrolidone/paclitaxel self-assemblies for breast cancer. Acta Pharmaceutica Sinica B8, 602–614.10.1016/j.apsb.2017.10.004Search in Google Scholar PubMed PubMed Central

Chu, P.-C., Chai, W.-Y., Tsai, C.-H., Kang, S.-T., Yeh, C.-K., and Liu, H.-L. (2016). Focused ultrasound-induced blood-brain barrier opening: association with mechanical index and cavitation index analyzed by dynamic contrast-enhanced magnetic-resonance imaging. Sci. Rep. 6, 33264.10.1038/srep33264Search in Google Scholar PubMed PubMed Central

Costa, L.G. (2017). Chapter one – traffic-related air pollution and neurodegenerative diseases: epidemiological and experimental evidence, and potential underlying mechanisms. In: Advances in Neurotoxicology. M. Aschner and L.G. Costa, eds. (Cambridge, MA, USA: Academic Press). pp. 1–46.Search in Google Scholar

Crowe, T.P., Greenlee, M.H.W., Kanthasamy, A.G., and Hsu, W.H. (2018). Mechanism of intranasal drug delivery directly to the brain. Life Sci. 195, 44–52.10.1016/j.lfs.2017.12.025Search in Google Scholar PubMed

D’Andrea, G. (2015). Quercetin: a flavonol with multifaceted therapeutic applications? Fitoterapia 106, 256–271.10.1016/j.fitote.2015.09.018Search in Google Scholar PubMed

Dajas, F. (2012). Life or death: neuroprotective and anticancer effects of quercetin. J. Ethnopharmacol. 143, 383–396.10.1016/j.jep.2012.07.005Search in Google Scholar PubMed

del Rio, D., Rodriguez-Mateos, A., Spencer, J.P., Tognolini, M., Borges, G., and Crozier, A. (2013). Dietary (poly) phenolics in human health: structures, bioavailability, and evidence of protective effects against chronic diseases. Antioxid. Redox Signal 18, 1818–1892.10.1089/ars.2012.4581Search in Google Scholar PubMed PubMed Central

Dhaouadi, Z., Nsangou, M., Garrab, N., Anouar, E.H., Marakchi, K., and Lahmar, S. (2009). DFT study of the reaction of quercetin with ·O2– and ·OH radicals. J. Mol. Struct: THEOCHEM. 904, 35–42.10.1016/j.theochem.2009.02.034Search in Google Scholar

Dhawan, S., Kapil, R., and Singh, B. (2011). Formulation development and systematic optimization of solid lipid nanoparticles of quercetin for improved brain delivery. J. Pharm. Pharmacol. 63, 342–351.10.1111/j.2042-7158.2010.01225.xSearch in Google Scholar PubMed

Dheer, A., Jain, V., Kushwah, N., Kumar, R., Prasad, D., and Singh, S.B. (2018). Temporal and spatial changes in glial cells during chronic hypobaric hypoxia: role in neurodegeneration. Neuroscience 383, 235–246.10.1016/j.neuroscience.2018.04.026Search in Google Scholar PubMed

Di Marco, L.Y., Venneri, A., Farkas, E., Evans, P.C., Marzo, A., and Frangi, A.F. (2015). Vascular dysfunction in the pathogenesis of Alzheimer’s disease – a review of endothelium-mediated mechanisms and ensuing vicious circles. Neurobiol. Dis. 82, 593–606.10.1016/j.nbd.2015.08.014Search in Google Scholar PubMed

Díaz, M., Vaamonde, L., and Dajas, F. (2015). Assessment of the protective capacity of nanosomes of quercetin in an experimental model of parkinsons disease in the rat. Gen. Med. (Los Angel) 3, 207.Search in Google Scholar

El-Rahmanand, S.N.A. and Suhailah, S. (2014). Quercetin nanoparticles: preparation and characterization. Indian J. Drugs 2, 96–103.Search in Google Scholar

Enriquez, G.G., Rizvi, S.A., D’Souza, M.J., and Do, D.P. (2013). Formulation and evaluation of drug-loaded targeted magnetic microspheres for cancer therapy. Int. J. Nanomed. 8, 1393.10.2147/IJN.S43479Search in Google Scholar PubMed PubMed Central

Erlund, I. (2004). Review of the flavonoids quercetin, hesperetin, and naringenin. Dietary sources, bioactivities, bioavailability, and epidemiology. Nutrit. Res. 24, 851–874.10.1016/j.nutres.2004.07.005Search in Google Scholar

Espinoza, L.C., Vacacela, M., Clares, B., Garcia, M.L., Fabrega, M.-J., and Calpena, A.C. (2018). Development of a Nasal Donepezil-loaded microemulsion for the treatment of Alzheimer’s disease: in vitro and ex vivo characterization. CNS Neurol. Disord. Drug Targets 17, 43–53.10.2174/1871527317666180104122347Search in Google Scholar PubMed

Fan, C.-H., Lin, C.-Y., Liu, H.-L., and Yeh, C.-K. (2017). Ultrasound targeted CNS gene delivery for Parkinson’s disease treatment. J. Control. Release 261, 246–262.10.1016/j.jconrel.2017.07.004Search in Google Scholar PubMed

Fernandes, C., Pinto, M., Martins, C.u., Gomes, M.J.o., Sarmento, B., Oliveira, P.J., Remião, F., and Borges, F. (2018). Development of a PEGylated-based platform for efficient delivery of dietary antioxidants across the blood–brain barrier. Bioconjug. Chem. 29, 1677–1689.10.1021/acs.bioconjchem.8b00151Search in Google Scholar PubMed

Friedman, J.H. (2018). Dementia with Lewy bodies and Parkinson disease dementia: it is the same disease! Parkinsonism Relat. Disord. 46, S6–S9.10.1016/j.parkreldis.2017.07.013Search in Google Scholar PubMed

Galho, A.R., Cordeiro, M.F., Ribeiro, S.A., Marques, M.S., Antunes, M.F., Luz, D.C., Hädrich, G., Muccillo-Baisch, A.L., Barros, D.M., Lima, J.V., et al. (2016). Protective role of free and quercetin-loaded nanoemulsion against damage induced by intracerebral haemorrhage in rats. Nanotechnology 27, 175101.10.1088/0957-4484/27/17/175101Search in Google Scholar PubMed

Gao, L., Liu, G., Wang, X., Liu, F., Xu, Y., and Ma, J. (2011). Preparation of a chemically stable quercetin formulation using nanosuspension technology. Int. J. Pharm. 404, 231–237.10.1016/j.ijpharm.2010.11.009Search in Google Scholar PubMed

Gao, X., Wang, B., Wei, X., Men, K., Zheng, F., Zhou, Y., Zheng, Y., Gou, M., Huang, M., and Guo, G. (2012). Anticancer effect and mechanism of polymer micelle-encapsulated quercetin on ovarian cancer. Nanoscale 4, 7021–7030.10.1039/c2nr32181eSearch in Google Scholar PubMed

Gao, Y., Chen, X., and Liu, H. (2018). A facile approach for synthesis of nano-CeO2 particles loaded co-polymer matrix and their colossal role for blood-brain barrier permeability in cerebral ischemia. J. Photochem. Photobiol. B 187, 184–189.10.1016/j.jphotobiol.2018.05.003Search in Google Scholar PubMed

Garcia, G., Nanni, S., Figueira, I., Ivanov, I., McDougall, G.J., Stewart, D., Ferreira, R.B., Pinto, P., Silva, R.F., and Brites, D. (2017). Bioaccessible (poly) phenol metabolites from raspberry protect neural cells from oxidative stress and attenuate microglia activation. Food Chem. 215, 274–283.10.1016/j.foodchem.2016.07.128Search in Google Scholar PubMed

Gastfriend, B.D., Palecek, S.P., and Shusta, E.V. (2018). Modeling the blood–brain barrier: beyond the endothelial cells. Curr. Opin. Biomed. Eng. 5, 6–12.10.1016/j.cobme.2017.11.002Search in Google Scholar PubMed PubMed Central

Ghosh, A., Sarkar, S., Mandal, A.K., and Das, N. (2013). Neuroprotective role of nanoencapsulated quercetin in combating ischemia-reperfusion induced neuronal damage in young and aged rats. PLoS One 8, e57735.10.1371/journal.pone.0057735Search in Google Scholar PubMed PubMed Central

Ghosh, S., Sarkar, S., Choudhury, S.T., Ghosh, T., and Das, N. (2017). Triphenyl phosphonium coated nano-quercetin for oral delivery: neuroprotective effects in attenuating age related global moderate cerebral ischemia reperfusion injury in rats. Nanomedicine 13, 2439–2450.10.1016/j.nano.2017.08.002Search in Google Scholar PubMed

Gonçalves, V., Rodríguez-Rojo, S., De Paz, E., Mato, C., Martín, Á., and Cocero, M.J. (2015). Production of water soluble quercetin formulations by pressurized ethyl acetate-in-water emulsion technique using natural origin surfactants. Food Hydrocoll. 51, 295–304.10.1016/j.foodhyd.2015.05.006Search in Google Scholar

Guan, X., Gao, M., Xu, H., Zhang, C., Liu, H., Lv, L., Deng, S., Gao, D., and Tian, Y. (2016). Quercetin-loaded poly (lactic-co-glycolic acid)-d-alpha-tocopheryl polyethylene glycol 1000 succinate nanoparticles for the targeted treatment of liver cancer. Drug Deliv. 23, 3307–3318.10.1080/10717544.2016.1176087Search in Google Scholar PubMed

Gumay, A.R., Bakri, S., and Pudjonarko, D. (2018). The effect of green tea epigallocatechin-3-gallate on spatial memory function, malondialdehyde and TNF-α level in d-galactose-induced BALB/C mice. Hiroshima J. Med. Sci. 67, 41–48.Search in Google Scholar

Gumerlock, M.K., Belshe, B.D., Madsen, R., and Watts, C. (1992). Osmotic blood-brain barrier disruption and chemotherapy in the treatment of high grade malignant glioma: patient series and literature review. J. Neuro-Oncol. 12, 33–46.10.1007/BF00172455Search in Google Scholar PubMed

Guo, Y. and Bruno, R.S. (2015). Endogenous and exogenous mediators of quercetin bioavailability. J. Nutr. Biochem. 26, 201–210.10.1016/j.jnutbio.2014.10.008Search in Google Scholar PubMed

Haider, M.F., Khan, S., Gaba, B., Alam, T., Baboota, S., Ali, J., and Ali, A. (2018). Optimization of rivastigmine nanoemulsion for enhanced brain delivery: in-vivo and toxicity evaluation. J. Mol. Liquids 255, 384–396.10.1016/j.molliq.2018.01.123Search in Google Scholar

Hao, J., Guo, B., Yu, S., Zhang, W., Zhang, D., Wang, J., and Wang, Y. (2017). Encapsulation of the flavonoid quercetin with chitosan-coated nano-liposomes. LWT-Food Sci. Technol. 85, 37–44.10.1016/j.lwt.2017.06.048Search in Google Scholar

Hashimoto, M., Wei, J., Nakai, M., and Fujita, M. (2007). Molecular mechanism of neurodegeneration caused by familial mutations (P123H and V70M) of β-synuclein. Neurosci Res. 58, S58.10.1016/j.neures.2007.06.342Search in Google Scholar

He, Q., Liu, J., Liang, J., Liu, X., Li, W., Liu, Z., Ding, Z., and Tuo, D. (2018). Towards improvements for penetrating the blood–brain barrier – recent progress from a material and pharmaceutical perspective. Cells 7, 24.10.3390/cells7040024Search in Google Scholar

Heim, K.E., Tagliaferro, A.R., and Bobilya, D.J. (2002). Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships. J. Nutr. Biochem. 13, 572–584.10.1016/S0955-2863(02)00208-5Search in Google Scholar PubMed

Hollman, P.C.H. and Arts, I.C.W. (2000). Flavonols, flavones and flavanols–nature, occurrence and dietary burden. J. Sci. of Food and Agric. 80, 1081–1093.10.1002/(SICI)1097-0010(20000515)80:7<1081::AID-JSFA566>3.0.CO;2-GSearch in Google Scholar

Hu, J., Wang, J., Wang, G., Yao, Z., and Dang, X. (2016). Pharmacokinetics and antitumor efficacy of DSPE-PEG2000 polymeric liposomes loaded with quercetin and temozolomide: analysis of their effectiveness in enhancing the chemosensitization of drug-resistant glioma cells. Int. J. Mol. Med. 37, 690–702.10.3892/ijmm.2016.2458Search in Google Scholar PubMed

Huang, J., Wang, Q., Li, T., Xia, N., and Xia, Q. (2017). Nanostructured lipid carrier (NLC) as a strategy for encapsulation of quercetin and linseed oil: preparation and in vitro characterization studies. J. Food Eng. 215, 1–12.10.1016/j.jfoodeng.2017.07.002Search in Google Scholar

Huebbe, P., Wagner, A.E., Boesch-Saadatmandi, C., Sellmer, F., Wolffram, S., and Rimbach, G. (2010). Effect of dietary quercetin on brain quercetin levels and the expression of antioxidant and Alzheimer’s disease relevant genes in mice. Pharmacol. Res. 61, 242–246.10.1016/j.phrs.2009.08.006Search in Google Scholar PubMed

Ishisaka, A., Ichikawa, S., Sakakibara, H., Piskula, M.K., Nakamura, T., Kato, Y., Ito, M., Miyamoto, K.-i., Tsuji, A., and Kawai, Y. (2011). Accumulation of orally administered quercetin in brain tissue and its antioxidative effects in rats. Free Radic. Biol Med. 51, 1329–1336.10.1016/j.freeradbiomed.2011.06.017Search in Google Scholar PubMed

Ishisaka, A., Mukai, R., Terao, J., Shibata, N., and Kawai, Y. (2014). Specific localization of quercetin-3-O-glucuronide in human brain. Arch. Biochem. Biophys. 557, 11–17.10.1016/j.abb.2014.05.025Search in Google Scholar PubMed

Islam, M.R., Zaman, A., Jahan, I., Chakravorty, R., and Chakraborty, S. (2013). In silico QSAR analysis of quercetin reveals its potential as therapeutic drug for Alzheimer’s disease. J. Young Pharm. 5, 173–179.10.1016/j.jyp.2013.11.005Search in Google Scholar PubMed PubMed Central

Jain, A.K., Thanki, K., and Jain, S. (2013). Co-encapsulation of tamoxifen and quercetin in polymeric nanoparticles: implications on oral bioavailability, antitumor efficacy, and drug-induced toxicity. Mol. Pharm. 10, 3459–3474.10.1021/mp400311jSearch in Google Scholar PubMed

Jalili-Baleh, L., Babaei, E., Abdpour, S., Nasir Abbas Bukhari, S., Foroumadi, A., Ramazani, A., Sharifzadeh, M., Abdollahi, M., and Khoobi, M. (2018). A review on flavonoid-based scaffolds as multi-target-directed ligands (MTDLs) for Alzheimer’s disease. Eur. J. Med. Chem. 152, 570–589.10.1016/j.ejmech.2018.05.004Search in Google Scholar PubMed

Jazvinscak Jembrek, M., Slade, N., Hof, P.R., and Simic, G. (2018). The interactions of p53 with tau and Ass as potential therapeutic targets for Alzheimer’s disease. Prog. Neurobiol. 168, 104–12710.1016/j.pneurobio.2018.05.001Search in Google Scholar PubMed

Ji, W.-H., Xiao, Z.-B., Liu, G.-Y., and Zhang, X. (2017). Development and application of nano-flavor-drug carriers in neurodegenerative diseases. Chin Chem Lett. 28, 1829–1834.10.1016/j.cclet.2017.06.024Search in Google Scholar

Jiang, Y., Gao, H., and Turdu, G. (2017). Traditional Chinese medicinal herbs as potential AChE inhibitors for anti-Alzheimer’s disease: a review. Bioorg. Chem. 75, 50–61.10.1016/j.bioorg.2017.09.004Search in Google Scholar PubMed

Jo, D.H., Kim, J.H., Lee, T.G., and Kim, J.H. (2015). Size, surface charge, and shape determine therapeutic effects of nanoparticles on brain and retinal diseases. Nanomedicine 11, 1603–1611.10.1016/j.nano.2015.04.015Search in Google Scholar PubMed

Jogani, V.V., Shah, P.J., Mishra, P., Mishra, A.K., and Misra, A.R. (2008). Intranasal mucoadhesive microemulsion of tacrine to improve brain targeting. Alzheimer Dis. Assoc. Disord. 22, 116–124.10.1097/WAD.0b013e318157205bSearch in Google Scholar PubMed

Johnson, I. and Williamson, G. (2003). Phytochemical Functional Foods (Boca Raton, FL, USA: CRC Press).10.1533/9781855736986Search in Google Scholar

Justino, G.C., Santos, M.R., Canário, S., Borges, C., Florêncio, M.H., and Mira, L. (2004). Plasma quercetin metabolites: structure–antioxidant activity relationships. Arch. Biochem. Biophys. 432, 109–121.10.1016/j.abb.2004.09.007Search in Google Scholar PubMed

Kakran, M., Sahoo, N.G., Li, L., and Judeh, Z. (2012a). Fabrication of quercetin nanoparticles by anti-solvent precipitation method for enhanced dissolution. Powder Technol. 223, 59–64.10.1016/j.powtec.2011.08.021Search in Google Scholar

Kakran, M., Shegokar, R., Sahoo, N.G., Al Shaal, L., Li, L., and Müller, R.H. (2012b). Fabrication of quercetin nanocrystals: comparison of different methods. Eur. J. Pharm. Biopharm. 80, 113–121.10.1016/j.ejpb.2011.08.006Search in Google Scholar PubMed

Kaneda, Y., Tsutsumi, Y., Yoshioka, Y., Kamada, H., Yamamoto, Y., Kodaira, H., Tsunoda, S.-i., Okamoto, T., Mukai, Y., and Shibata, H. (2004). The use of PVP as a polymeric carrier to improve the plasma half-life of drugs. Biomaterials 25, 3259–3266.10.1016/j.biomaterials.2003.10.003Search in Google Scholar PubMed

Karuppagounder, S., Madathil, S., Pandey, M., Haobam, R., Rajamma, U., and Mohanakumar, K. (2013). Quercetin up-regulates mitochondrial complex-I activity to protect against programmed cell death in rotenone model of Parkinson’s disease in rats. Neuroscience 236, 136–148.10.1016/j.neuroscience.2013.01.032Search in Google Scholar PubMed

Keogh, M.J. and Chinnery, P.F. (2015). Mitochondrial DNA mutations in neurodegeneration. Biochim. Biophys. Acta (BBA) – Bioenerg. 1847, 1401–1411.10.1016/j.bbabio.2015.05.015Search in Google Scholar PubMed

Khan, A.R., Liu, M., Khan, M.W., and Zhai, G. (2017). Progress in brain targeting drug delivery system by nasal route. J. Control. Release 28, 364–389.10.1016/j.jconrel.2017.09.001Search in Google Scholar PubMed

Killin, L.O.J., Starr, J.M., Shiue, I.J., and Russ, T.C. (2016). Environmental risk factors for dementia: a systematic review. BMC Geriatr. 16, 175.10.1186/s12877-016-0342-ySearch in Google Scholar PubMed PubMed Central

Kim, M.K., Park, K.-S., Yeo, W.-S., Choo, H., and Chong, Y. (2009). In vitro solubility, stability and permeability of novel quercetin–amino acid conjugates. Bioorg. Med. Chem. 17, 1164–1171.10.1016/j.bmc.2008.12.043Search in Google Scholar PubMed

Kwak, J.-H., Seo, J.M., Kim, N.-H., Arasu, M.V., Kim, S., Yoon, M.K., and Kim, S.-J. (2017). Variation of quercetin glycoside derivatives in three onion (Allium cepa L.) varieties. Saudi J. Biol. Sci. 24, 1387–1391.10.1016/j.sjbs.2016.05.014Search in Google Scholar PubMed PubMed Central

Le Nest, G., Caille, O., Woudstra, M., Roche, S., Guerlesquin, F., and Lexa, D. (2004). Zn–polyphenol chelation: complexes with quercetin,(+)-catechin, and derivatives: I optical and NMR studies. Inorg. Chim. Acta 357, 775–784.10.1016/j.ica.2003.09.014Search in Google Scholar

Lee, C.W., Seo, J.Y., Lee, J., Choi, J.W., Cho, S., Bae, J.Y., Sohng, J.K., Kim, S.O., Kim, J., and Park, Y.I. (2017). 3-O-Glucosylation of quercetin enhances inhibitory effects on the adipocyte differentiation and lipogenesis. Biomed. Pharmacother. 95, 589–598.10.1016/j.biopha.2017.08.002Search in Google Scholar PubMed

Lesjak, M., Beara, I., Simin, N., Pintać, D., Majkić, T., Bekvalac, K., Orčić, D., and Mimica-Dukić, N. (2018). Antioxidant and anti-inflammatory activities of quercetin and its derivatives. J. Funct. Foods 40, 68–75.10.1016/j.jff.2017.10.047Search in Google Scholar

Li, B., Konecke, S., Harich, K., Wegiel, L., Taylor, L.S., and Edgar, K.J. (2013). Solid dispersion of quercetin in cellulose derivative matrices influences both solubility and stability. Carbohydr. Polym. 92, 2033–2040.10.1016/j.carbpol.2012.11.073Search in Google Scholar PubMed

Li, J., Shi, M., Ma, B., Niu, R., Zhang, H., and Kun, L. (2017). Antitumor activity and safety evaluation of nanaparticle-based delivery of quercetin through intravenous administration in mice. Mater. Sci. Eng. C 77, 803–810.10.1016/j.msec.2017.03.191Search in Google Scholar PubMed

Li, X., Zhou, N., Wang, J., Liu, Z., Wang, X., Zhang, Q., Liu, Q., Gao, L., and Wang, R. (2018). Quercetin suppresses breast cancer stem cells (CD44+/CD24−) by inhibiting the PI3K/Akt/mTOR-signaling pathway. Life Sci. 196, 56–62.10.1016/j.lfs.2018.01.014Search in Google Scholar PubMed

Lin, M.T. and Beal, M.F. (2006). Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787–795.10.1038/nature05292Search in Google Scholar PubMed

Lu, J., Zheng, Y.-L., Luo, L., Wu, D.-M., Sun, D.-X., and Feng, Y.-J. (2006). Quercetin reverses D-galactose induced neurotoxicity in mouse brain. Behav. Brain Res. 171, 251–260.10.1016/j.bbr.2006.03.043Search in Google Scholar PubMed

Lu, M., Ho, C.-T., and Huang, Q. (2017). Improving quercetin dissolution and bioaccessibility with reduced crystallite sizes through media milling technique. J. Funct. Foods 37, 138–146.10.1016/j.jff.2017.07.047Search in Google Scholar

Manca, M.L., Castangia, I., Caddeo, C., Pando, D., Escribano, E., Valenti, D., Lampis, S., Zaru, M., Fadda, A.M., and Manconi, M. (2014). Improvement of quercetin protective effect against oxidative stress skin damages by incorporation in nanovesicles. Colloids Surf. B: Biointerfaces 123, 566–574.10.1016/j.colsurfb.2014.09.059Search in Google Scholar PubMed

Martinez-Coria, H., Green, K.N., Billings, L.M., Kitazawa, M., Albrecht, M., Rammes, G., Parsons, C.G., Gupta, S., Banerjee, P., and LaFerla, F.M. (2010). Memantine improves cognition and reduces Alzheimer’s-like neuropathology in transgenic mice. Am. J. Pathol. 176, 870–880.10.2353/ajpath.2010.090452Search in Google Scholar PubMed

McKay, T.B. and Karamichos, D. (2017). Quercetin and the ocular surface: what we know and where we are going. Exp. Biol. Med. (Maywood) 242, 565–572.10.1177/1535370216685187Search in Google Scholar

Mehta, V., Parashar, A., and Udayabanu, M. (2017). Quercetin prevents chronic unpredictable stress induced behavioral dysfunction in mice by alleviating hippocampal oxidative and inflammatory stress. Physiol Behav. 171, 69–78.10.1016/j.physbeh.2017.01.006Search in Google Scholar PubMed

Mittal, A.K., Kumar, S., and Banerjee, U.C. (2014). Quercetin and gallic acid mediated synthesis of bimetallic (silver and selenium) nanoparticles and their antitumor and antimicrobial potential. J. Colloid Interface Sci. 431, 194–199.10.1016/j.jcis.2014.06.030Search in Google Scholar PubMed

Mittal, D., Md, S., Hasan, Q., Fazil, M., Ali, A., Baboota, S., and Ali, J. (2016). Brain targeted nanoparticulate drug delivery system of rasagiline via intranasal route. Drug Deliv. 23, 130–139.10.3109/10717544.2014.907372Search in Google Scholar PubMed

Miyake, J., Kihara, T., and Nakamura, C. (2007). Nano-cell surgery of human cells. Nanomedicine 3, 341.10.1016/j.nano.2007.10.031Search in Google Scholar

Modi, G., Pillay, V., Choonara, Y.E., Ndesendo, V.M.K., du Toit, L.C., and Naidoo, D. (2009). Nanotechnological applications for the treatment of neurodegenerative disorders. Progr. Neurobiol. 88, 272–285.10.1016/j.pneurobio.2009.05.002Search in Google Scholar

Modrego, P.J. (2010). Depression in Alzheimer’s disease. Pathophysiology, diagnosis, and treatment. J Alzheimers Dis. 21, 1077–1087.10.3233/JAD-2010-100153Search in Google Scholar PubMed

Murota, K. and Terao, J. (2005). Quercetin appears in the lymph of unanesthetized rats as its phase II metabolites after administered into the stomach. FEBS Lett. 579, 5343–5346.10.1016/j.febslet.2005.08.060Search in Google Scholar PubMed

Naidu, P.S., Singh, A., and Kulkarni, S.K. (2003). Quercetin, a bioflavonoid, attenuates haloperidol-induced orofacial dyskinesia. Neuropharmacology 44, 1100–1106.10.1016/S0028-3908(03)00101-1Search in Google Scholar PubMed

Natesan, S., Pandian, S., Ponnusamy, C., Palanichamy, R., Muthusamy, S., and Kandasamy, R. (2017). Co-encapsulated resveratrol and quercetin in chitosan and peg modified chitosan nanoparticles: for efficient intra ocular pressure reduction. Int. J. Biol. Macromol. 104, 1837-1845.10.1016/j.ijbiomac.2017.04.117Search in Google Scholar PubMed

O’Keeffe, E. and Campbell, M. (2016). Modulating the paracellular pathway at the blood–brain barrier: current and future approaches for drug delivery to the CNS. Drug Discov. Today Technol. 20, 35–39.10.1016/j.ddtec.2016.07.008Search in Google Scholar PubMed

Ola, M.S., Ahmed, M.M., Shams, S., and Al-Rejaie, S.S. (2017). Neuroprotective effects of quercetin in diabetic rat retina. Saudi J. Biol. Sci. 24, 1186–1194.10.1016/j.sjbs.2016.11.017Search in Google Scholar PubMed

Ossola, B., Kääriäinen, T.M., Raasmaja, A., and Männistö, P.T. (2008). Time-dependent protective and harmful effects of quercetin on 6-OHDA-induced toxicity in neuronal SH-SY5Y cells. Toxicology 250, 1–8.10.1016/j.tox.2008.04.001Search in Google Scholar PubMed

Oyama, Y., Fuchs, P.A., Katayama, N., and Noda, K. (1994). Myricetin and quercetin, the flavonoid constituents of Ginkgo biloba extract, greatly reduce oxidative metabolism in both resting and Ca2+-loaded brain neurons. Brain Res. 635, 125–129.10.1016/0006-8993(94)91431-1Search in Google Scholar

Pandey, A.K., Verma, S., Bhattacharya, P., Paul, S., Mishra, A., and Patnaik, R. (2012). An in-silico strategy to explore neuroprotection by quercetin in cerebral ischemia: a novel hypothesis based on inhibition of matrix metalloproteinase (MMPs) and acid sensing ion channel 1a (ASIC1a). Med. Hypotheses 79, 76–81.10.1016/j.mehy.2012.04.005Search in Google Scholar PubMed

Pang, X., Lu, Z., Du, H., Yang, X., and Zhai, G. (2014). Hyaluronic acid-quercetin conjugate micelles: synthesis, characterization, in vitro and in vivo evaluation. Colloids Surf. B Biointerfaces 123, 778–786.10.1016/j.colsurfb.2014.10.025Search in Google Scholar PubMed

Pangeni, R., Kang, S.-W., Oak, M., Park, E.Y., and Park, J.W. (2017). Oral delivery of quercetin in oil-in-water nanoemulsion: in vitro characterization and in vivo anti-obesity efficacy in mice. J. Funct. Foods 38, 571–581.10.1016/j.jff.2017.09.059Search in Google Scholar

Patel, R.V., Mistry, B.M., Shinde, S.K., Syed, R., Singh, V., and Shin, H.-S. (2018). Therapeutic potential of quercetin as a cardiovascular agent. Eur. J. Med. Chem. 155, 889–904.10.1016/j.ejmech.2018.06.053Search in Google Scholar PubMed

Pei, B., Yang, M., Qi, X., Shen, X., Chen, X., and Zhang, F. (2016). Quercetin ameliorates ischemia/reperfusion-induced cognitive deficits by inhibiting ASK1/JNK3/caspase-3 by enhancing the Akt signaling pathway. Biochem. Biophys. Res. Commun. 478, 199–205.10.1016/j.bbrc.2016.07.068Search in Google Scholar PubMed

Petersen, B., Egert, S., Bosy-Westphal, A., Müller, M.J., Wolffram, S., Hubbermann, E.M., Rimbach, G., and Schwarz, K. (2016). Bioavailability of quercetin in humans and the influence of food matrix comparing quercetin capsules and different apple sources. Food Res. Int. 88, 159–165.10.1016/j.foodres.2016.02.013Search in Google Scholar PubMed

Piskula, M.K. and Terao, J. (1998). Quercetin’s solubility affects its accumulation in rat plasma after oral administration. J. Agric. Food Chem. 46, 4313–4317.10.1021/jf980117vSearch in Google Scholar

Priprem, A., Watanatorn, J., Sutthiparinyanont, S., Phachonpai, W., and Muchimapura, S. (2008). Anxiety and cognitive effects of quercetin liposomes in rats. Nanomedicine 4, 70–78.10.1016/j.nano.2007.12.001Search in Google Scholar PubMed

Qi, Z., Liang, J., Pan, R., Dong, W., Shen, J., Yang, Y., Zhao, Y., Shi, W., Luo, Y., Ji, X., et al. (2016). Zinc contributes to acute cerebral ischemia-induced blood–brain barrier disruption. Neurobiol. Dis. 95, 12–21.10.1016/j.nbd.2016.07.003Search in Google Scholar PubMed

Rinwa, P. and Kumar, A. (2013). Quercetin suppress microglial neuroinflammatory response and induce antidepressent-like effect in olfactory bulbectomized rats. Neuroscience 255, 86–98.10.1016/j.neuroscience.2013.09.044Search in Google Scholar PubMed

Roshanzamir, F. and Yazdanparast, R. (2014). Quercetin attenuates cell apoptosis of oxidant-stressed SK-N-MC cells while suppressing up-regulation of the defensive element, HIF-1α. Neuroscience 277, 780–793.10.1016/j.neuroscience.2014.07.036Search in Google Scholar PubMed

Sahoo, N., Kakran, M., Shaal, L., Li, L., Müller, R., Pal, M., and Tan, L. (2011). Preparation and characterization of quercetin nanocrystals. J. Pharm. Sci. 100, 2379–2390.10.1002/jps.22446Search in Google Scholar PubMed

Sahoo, A.K., Dandapat, J., Dash, U.C., and Kanhar, S. (2018). Features and outcomes of drugs for combination therapy as multi-targets strategy to combat Alzheimer’s disease. J. Ethnopharmacol. 215, 42–73.10.1016/j.jep.2017.12.015Search in Google Scholar PubMed

Sajad, M., Zargan, J., Zargar, M.A., Sharma, J., Umar, S., Arora, R., and Khan, H.A. (2013). Quercetin prevents protein nitration and glycolytic block of proliferation in hydrogen peroxide insulted cultured neuronal precursor cells (NPCs): implications on CNS regeneration. Neurotoxicology 36, 24–33.10.1016/j.neuro.2013.01.008Search in Google Scholar PubMed

Saraiva, C., Praça, C., Ferreira, R., Santos, T., Ferreira, L., and Bernardino, L. (2016). Nanoparticle-mediated brain drug delivery: overcoming blood–brain barrier to treat neurodegenerative diseases. J. Control. Release 235, 34–47.10.1016/j.jconrel.2016.05.044Search in Google Scholar PubMed

Serwer, P. (2018). Hypothesis for the cause and therapy of neurodegenerative diseases. Med. Hypotheses 110, 60–63.10.1016/j.mehy.2017.11.001Search in Google Scholar PubMed

Sharma, D.R., Sunkaria, A., Wani, W.Y., Sharma, R.K., Verma, D., Priyanka, K., Bal, A., and Gill, K.D. (2015). Quercetin protects against aluminium induced oxidative stress and promotes mitochondrial biogenesis via activation of the PGC-1α signaling pathway. NeuroToxicol. 51, 116–137.10.1016/j.neuro.2015.10.002Search in Google Scholar

Sharma, D.R., Wani, W.Y., Sunkaria, A., Kandimalla, R.J., Sharma, R.K., Verma, D., Bal, A., and Gill, K.D. (2016a). Quercetin attenuates neuronal death against aluminum-induced neurodegeneration in the rat hippocampus. Neuroscience 324, 163–176.10.1016/j.neuroscience.2016.02.055Search in Google Scholar

Sharma, S., Parmar, A., Kori, S., and Sandhir, R. (2016b). PLGA-based nanoparticles: A new paradigm in biomedical applications. TrAC Trends Anal. Chem. 80, 30–40.10.1016/j.trac.2015.06.014Search in Google Scholar

Shetty, A.K. and Bates, A. (2016). Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer’s and Parkinson’s diseases. Brain Res. 1638, 74–87.10.1016/j.brainres.2015.09.019Search in Google Scholar PubMed

Singla, P., Singh, O., Chabba, S., and Mahajan, R.K. (2018). Pluronic-SAILs (surface active ionic liquids) mixed micelles as efficient hydrophobic quercetin drug carriers. J. Mol. Liquids 249, 294–303.10.1016/j.molliq.2017.11.044Search in Google Scholar

Skaper, S.D., Fabris, M., Ferrari, V., Dalle Carbonare, M., and Leon, A. (1997). Quercetin protects cutaneous tissue-associated cell types including sensory neurons from oxidative stress induced by glutathione depletion: cooperative effects of ascorbic acid. Free Radic. Biol. Med. 22, 669–678.10.1016/S0891-5849(96)00383-8Search in Google Scholar PubMed

Skowronska, M., Kmiec, T., Jurkiewicz, E., Malczyk, K., Kurkowska-Jastrzębska, I., and Czlonkowska, A. (2017). Evolution and novel radiological changes of neurodegeneration associated with mutations in C19orf12. Parkinsonism Relat. Disord. 39, 71–76.10.1016/j.parkreldis.2017.03.013Search in Google Scholar PubMed

Spiegel, R., Kalla, R., Mantokoudis, G., Maire, R., Mueller, H., Hoerr, R., and Ihl, R. (2018). Ginkgo biloba extract eGb 761® alleviates neurosensory symptoms in patients with dementia: a meta-analysis of treatment effects on tinnitus and dizziness in randomized, placebo-controlled trials. Clin. Intervent. Aging 13, 1121–1127.10.2147/CIA.S157877Search in Google Scholar

Spillantini, M.G. and Goedert, M. (1998). Tau protein pathology in neurodegenerative diseases. Trends Neurosci. 21, 428–433.10.1016/S0166-2236(98)01337-XSearch in Google Scholar PubMed

Srinivas, K., King, J.W., Howard, L.R., and Monrad, J.K. (2010). Solubility and solution thermodynamic properties of quercetin and quercetin dihydrate in subcritical water. J. Food Eng. 100, 208–218.10.1016/j.jfoodeng.2010.04.001Search in Google Scholar

Suematsu, N., Hosoda, M., and Fujimori, K. (2011). Protective effects of quercetin against hydrogen peroxide-induced apoptosis in human neuronal SH-SY5Y cells. Neurosci. Lett. 504, 223–227.10.1016/j.neulet.2011.09.028Search in Google Scholar PubMed

Sun, S., Gong, F., Liu, P., and Miao, Q. (2018). Metformin combined with quercetin synergistically repressed prostate cancer cells via inhibition of VEGF/PI3K/Akt signaling pathway. Gene 664, 50–57.10.1016/j.gene.2018.04.045Search in Google Scholar PubMed

Talegaonkar, S. and Mishra, P. (2004). Intranasal delivery: an approach to bypass the blood brain barrier. Indian J. Pharmacol. 36, 140–147.Search in Google Scholar

Tam, V.H., Sosa, C., Liu, R., Yao, N., and Priestley, R.D. (2016). Nanomedicine as a non-invasive strategy for drug delivery across the blood brain barrier. Int. J. Pharm. 515, 331–342.10.1016/j.ijpharm.2016.10.031Search in Google Scholar PubMed

Terao, J. (2017). Factors modulating bioavailability of quercetin-related flavonoids and the consequences of their vascular function. Biochem. Pharmacol. 139, 15–23.10.1016/j.bcp.2017.03.021Search in Google Scholar PubMed

Toniazzo, T., Peres, M.S., Ramos, A.P., and Pinho, S.C. (2017). Encapsulation of quercetin in liposomes by ethanol injection and physicochemical characterization of dispersions and lyophilized vesicles. Food Biosci. 19, 17–25.10.1016/j.fbio.2017.05.003Search in Google Scholar

Tyas, S.L. (2001). Alcohol use and the risk of developing Alzheimer’s disease. Alcohol Res. Health. 25, 299–307.Search in Google Scholar PubMed

Vafeiadou, K., Vauzour, D., Rodriguez-Mateos, A., Whiteman, M., Williams, R.J., and Spencer, J.P. (2008). Glial metabolism of quercetin reduces its neurotoxic potential. Arch. Biochem. Biophys. 478, 195–200.10.1016/j.abb.2008.07.014Search in Google Scholar PubMed

van der Woude, H., Boersma, M.G., Alink, G.M., Vervoort, J., and Rietjens, I.M. (2006). Consequences of quercetin methylation for its covalent glutathione and DNA adduct formation. Chem. Biol. Interact. 160, 193–203.10.1016/j.cbi.2005.12.005Search in Google Scholar PubMed

Ventola, C.L. (2012). The nanomedicine revolution: part 1: emerging concepts. Pharm. Ther. 37, 512–525.Search in Google Scholar

Wach, A., Pyrzyńska, K., and Biesaga, M. (2007). Quercetin content in some food and herbal samples. Food Chem. 100, 699–704.10.1016/j.foodchem.2005.10.028Search in Google Scholar

Wang, L.-F. and Zhang, H.-Y. (2005). A theoretical study of the different radical-scavenging activities of catechin, quercetin, and a rationally designed planar catechin. Bioorg. Chem. 33, 108–115.10.1016/j.bioorg.2005.01.002Search in Google Scholar PubMed

Wang, P., Heber, D., and Henning, S.M. (2012). Quercetin increased bioavailability and decreased methylation of green tea polyphenols in vitro and in vivo. Food Funct. 3, 635–642.10.1039/c2fo10254dSearch in Google Scholar PubMed PubMed Central

Wang, W., Sun, C., Mao, L., Ma, P., Liu, F., Yang, J., and Gao, Y. (2016). The biological activities, chemical stability, metabolism and delivery systems of quercetin: a review. Trends Food Sci. Technol. 56, 21–38.10.1016/j.tifs.2016.07.004Search in Google Scholar

Wohlfart, S., Gelperina, S., and Kreuter, J. (2012). Transport of drugs across the blood–brain barrier by nanoparticles. J. Control. Release 161, 264–273.10.1016/j.jconrel.2011.08.017Search in Google Scholar PubMed

Wong, M.-Y. and Chiu, G.N. (2011). Liposome formulation of co-encapsulated vincristine and quercetin enhanced antitumor activity in a trastuzumab-insensitive breast tumor xenograft model. Nanomedicine 7, 834–840.10.1016/j.nano.2011.02.001Search in Google Scholar PubMed

Wu, S.-K., Chu, P.-C., Chai, W.-Y., Kang, S.-T., Tsai, C.-H., Fan, C.-H., Yeh, C.-K., and Liu, H.-L. (2017). Characterization of different microbubbles in assisting focused ultrasound-induced blood-brain barrier opening. Scientific Rep. 7, 46689.10.1038/srep46689Search in Google Scholar PubMed PubMed Central

Xu, G., Shi, H., Ren, L., Gou, H., Gong, D., Gao, X., and Huang, N. (2015). Enhancing the anti-colon cancer activity of quercetin by self-assembled micelles. Int. J. Nanomedicine 10, 2051–2063.10.2147/IJN.S75550Search in Google Scholar PubMed PubMed Central

Yang, Y., Yang, L.Y., Orban, L., Cuylear, D., Thompson, J., Simon, B., and Yang, Y. (2018). Non-invasive vagus nerve stimulation reduces blood-brain barrier disruption in a rat model of ischemic stroke. Brain Stimul. 11, 689–698.10.1016/j.brs.2018.01.034Search in Google Scholar PubMed PubMed Central

Ye, C.Y., Lei, Y., Tang, X.C., and Zhang, H.Y. (2015). Donepezil attenuates Aβ-associated mitochondrial dysfunction and reduces mitochondrial Aβ accumulation in vivo and in vitro. Neuropharmacology 95, 29–36.10.1016/j.neuropharm.2015.02.020Search in Google Scholar PubMed

Zenaro, E., Piacentino, G., and Constantin, G. (2017). The blood-brain barrier in Alzheimer’s disease. Neurobiol. Dis. 107, 41–56.10.1016/j.nbd.2016.07.007Search in Google Scholar PubMed PubMed Central

Zhang, J., Luo, Y., Zhao, X., Li, X., Li, K., Chen, D., Qiao, M., Hu, H., and Zhao, X. (2016). Co-delivery of doxorubicin and the traditional Chinese medicine quercetin using biotin–PEG2000–DSPE modified liposomes for the treatment of multidrug resistant breast cancer. RSC Advances 6, 113173–113184.10.1039/C6RA24173ESearch in Google Scholar

Zhang, Z., Xu, S., Wang, Y., Yu, Y., Li, F., Zhu, H., Shen, Y., Huang, S., and Guo, S. (2018). Near-infrared triggered co-delivery of doxorubicin and quercetin by using gold nanocages with tetradecanol to maximize anti-tumor effects on MCF-7/ADR cells. J. Colloid Interface Sci. 509, 47–57.10.1016/j.jcis.2017.08.097Search in Google Scholar PubMed

Zhao, L., Shi, Y., Zou, S., Sun, M., Li, L., and Zhai, G. (2011). Formulation and in vitro evaluation of quercetin loaded polymeric micelles composed of pluronic P123 and Da-tocopheryl polyethylene glycol succinate. J. Biomed. Nanotechnol. 7, 358–365.10.1166/jbn.2011.1298Search in Google Scholar PubMed

Zhao, J., Liu, J., Wei, T., Ma, X., Cheng, Q., Huo, S., Zhang, C., Zhang, Y., Duan, X., and Liang, X.-J. (2016). Quercetin-loaded nanomicelles to circumvent human castration-resistant prostate cancer in vitro and in vivo. Nanoscale 8, 5126–5138.10.1039/C5NR08966BSearch in Google Scholar PubMed

Zhao, M.H., Yuan, L., Meng, L.Y., Qiu, J.L., and Wang, C.B. (2017). Quercetin-loaded mixed micelles exhibit enhanced cytotoxic efficacy in non-small cell lung cancer in vitro. Exp. Ther. Med. 14, 5503–5508.10.3892/etm.2017.5230Search in Google Scholar PubMed PubMed Central

Zhao, Y., Du, L., and Liu, Y. (2018). P-347 – Novel nano antioxidant drug delivery systems for the treatment of neurodegenerative diseases. Free Radic. Biol. Med. 120, S150.10.1016/j.freeradbiomed.2018.04.494Search in Google Scholar

Zhou, W., Chen, C., Shi, Y., Wu, Q., Gimple, R.C., Fang, X., Huang, Z., Zhai, K., Ke, S.Q., and Ping, Y.-F. (2017). Targeting glioma stem cell-derived pericytes disrupts the blood-tumor barrier and improves chemotherapeutic efficacy. Cell Stem Cell 21, 591–603.e594.10.1016/j.stem.2017.10.002Search in Google Scholar PubMed PubMed Central

Zhou, Y., Peng, Z., Seven, E.S., and Leblanc, R.M. (2018). Crossing the blood-brain barrier with nanoparticles. J.Control. Release 270, 290–303.10.1016/j.jconrel.2017.12.015Search in Google Scholar PubMed

Zizkova, P., Stefek, M., Rackova, L., Prnova, M., and Lubica, H. (2017). Novel quercetin derivatives: From redox properties to promising treatment of oxidative stress related diseases. Chem. Biol. Interact. 265, 36–46.10.1016/j.cbi.2017.01.019Search in Google Scholar PubMed

Received: 2018-08-01
Accepted: 2018-09-21
Published Online: 2019-02-12
Published in Print: 2019-07-26

©2019 Walter de Gruyter GmbH, Berlin/Boston

Scroll Up Arrow