Bioactive Polyphenols and Neuromodulation: Molecular Mechanisms in Neurodegeneration
The interest in dietary polyphenols in recent years has greatly increased due to their antioxidant bioactivity with preventive properties against chronic diseases. Polyphenols, by modulating different cellular functions, play an important role in neuroprotection and are able to
neutralize the effects of oxidative stress, inflammation, and apoptosis. Interestingly, all these mechanisms are involved in neurodegeneration. Although polyphenols display differences in their effectiveness due to interindividual variability, recent studies indicated that bioactive polyphenols in food and beverages promote health and prevent age-related cognitive decline. Polyphenols have a poor bioavailability and their digestion by gut microbiota produces active metabolites.
In fact, dietary bioactive polyphenols need to be modified by microbiota present in the intestine before being absorbed, and to exert health preventive effects by interacting with cellular signalling pathways. This literature review includes an evaluation of the literature in English up to December 2019 in PubMed and Web of Science databases. A total of 307 studies, consisting of research reports, review articles and articles were examined and 146 were included. The review highlights the role of bioactive polyphenols in neurodegeneration, with a particular mphasis on the cellular and molecular mechanisms that are modulated by polyphenols involved in protection from oxidative stress and apoptosis revention.
Bibliografia:
- Pandey, K.B.; Rizvi, S.I. Plant polyphenols as dietary antioxidants in human health and disease. Oxid. Med.
Cell. Longev. 2009, 2, 270–278.
- Fernandez-Fernandez, L.; Comes, G.; Bolea, I.; Valente, T.; Ruiz, J.; Murtra, P.; Ramirez, B.; Angles, N.;
Reguant, J.; Morello, J.; et al. LMN diet, rich in polyphenols and polyunsaturated fatty acids, improves
mouse cognitive decline associated with aging and Alzheimer’s disease. Behav. Brain Res. 2012, 228, 261–
271.
- Liu, P.; Kemper, L.; Wang, J.; Zahs, K.; Ashe, K.; Pasinetti, G. Grape seed polyphenolic extract specifically
decreases Aβ* 56 in the brains of Tg2576 mice. J. Alzheimers Dis. 2011, 26, 657–666.
- Sandoval-Acuña, C.; Ferreira, J.; Speisky, H. Polyphenols and mitochondria: An update on their
increasingly emerging ROS-scavenging independent actions. Arch. Biochem. Biophys. 2014, 559, 75–90.
- Smolensky, D.; Rhodes, D.; McVey, D.S.; Fawver, Z.; Perumal, R.; Herald, T.; Noronha, L. High-polyphenol
sorghum bran extract inhibits cancer cell growth through ROS induction, cell cycle arrest, and apoptosis. J.
Med. Food 2018, 21, 990–998.
- Mello-Filho, A.C.; Meneghini, R. Iron is the intracellular metal involved in the production of DNA damage
by oxygen radicals. Mutat. Res. 1991, 251, 109–113.
- Gupta, S.; Hastak, K.; Afaq, F.; Ahmad, N.; Mukhtar, H. Essential role of caspases in epigallocatechin-3-
gallate-mediated inhibition of nuclear factor kappa B and induction of apoptosis. Oncogene 2004, 23, 2507–
2522.
- Kinarivala, N.; Patel, R.; Boustany, R.M.; Al-Ahmad, A.; Trippier, P.C. Discovery of aromatic carbamates
that confer neuroprotective activity by enhancing autophagy and inducing the anti-apoptotic protein B-cell
lymphoma 2 (Bcl-2). J. Med. Chem. 2017, 60, 9739–9756.
- Nakaso, K.; Ito, S.; Nakashima, K. Caffeine activates the PI3K/Akt pathway and prevents apoptotic cell
death in a Parkinson’s disease model of SH-SY5Y cells. Neurosci. Lett. 2008, 432, 146–150.
- Vauzour, D.; Vafeiadou, K.; Rice-Evans, C.; Williams, R.J.; Spencer, J.P. Activation of pro-survival Akt and
ERK1/2 signalling pathways underlie the anti-apoptotic effects of flavanones in cortical neurons. J.
Neurochem. 2007, 103, 1355–1367.
- Moosavi, F.; Hosseini, R.; Saso, L.; Firuzi, O. Modulation of neurotrophic signaling pathways by
polyphenols. Drug Des. Devel. 2016, 10, 23–42.
- Di Meo, F.; Donato, S.; Di Pardo, A.; Maglione, V.; Filosa, S.; Crispi, S. New therapeutic drugs from bioactive
natural molecules: The role of gut microbiota metabolism in neurodegenerative diseases. Curr. Drug Metab.
2018, 19, 478–489.
- Filosa, S.; Fico, A.; Paglialunga, F.; Balestrieri, M.; Crooke, A.; Verde, P.; Abrescia, P.; Bautista, J.M.; Martini,
G. Failure to increase glucose consumption through the pentose-phosphate pathway results in the death of
glucose-6-phosphate dehydrogenase gene-deleted mouse embryonic stem cells subjected to oxidative
stress. Biochem. J. 2003, 370, 935–943.
- Fico, A.; Paglialunga, F.; Cigliano, L.; Abrescia, P.; Verde, P.; Martini, G.; Iaccarino, I.; Filosa, S. Glucose-6-
phosphate dehydrogenase plays a crucialrole in protection from redox-stress-induced apoptosis. Cell Death
Differ. 2004, 11, 823–831-
- Redza-Dutordoir, M.; Averill-Bates, D.A. Activation of apoptosis signalling pathways by reactive oxygen
species. Biochim. Biophys. Acta 2016, 1863, 2977–2992.
- Martindale, J.L.; Holbrook, N.J. Cellular response to oxidative stress: Signaling for suicide and survival. J.
Cell Physiol. 2002, 192, 1–15.
- Young, I.S.; Woodside, J.V. Antioxidants in health and disease. J. Clin. Pathol. 2001, 54, 176–186.
- Halliwell, B. Antioxidant characterization. Methodology and mechanism. Biochem. Pharm. 1995, 49, 1341–
1348.
- Ward, R.J.; Dexter, D.T.; Crichton, R.R. Ageing, neuroinflammation and neurodegeneration. Front. Biosci.
2015, 7, 189–204.
- Matés, J.M. Effects of antioxidant enzymes in the molecular control of reactive oxygen species toxicology.
Toxicology 2000, 153, 83–104.
- Qin, S.; Hou, D.X. Multiple regulations of Keap1/Nrf2 system by dietary phytochemicals. Mol. Nutr. Food
Res. 2016, 60, 1731–1755.
- Zhang, Y.J.; Gan, R.Y.; Li, S.; Zhou, Y.; Li, A.N.; Xu, D.P.; Li, H.B. Antioxidant phytochemicals for the
prevention and treatment of chronic diseases. Molecules 2015, 20, 21138–21156.
- Pisoschi, A.M.; Pop, A. The role of antioxidants in the chemistry of oxidative stress: A review. Eur. J. Med.
Chem. 2015, 97, 55–74.
- Kurutas, E.B. The importance of antioxidants which play the role in cellular response against
oxidative/nitrosative stress: Current state. Nutr. J. 2016, 15, 71.
- Shan, B.; Cai, Y.Z.; Sun, M.; Corke, H. Antioxidant capacity of 26 spice extracts and characterization of their
phenolic constituents. J. Agric. Food Chem. 2005, 53, 7749–7759.
- LĂĽ, J.M.; Lin, P.H.; Yao, Q.; Chen, C. Chemical and molecular mechanisms of antioxidants: Experimental
approaches and model systems. J. Cell Mol. Med. 2010, 14, 840–860.
- Gheldof, N.; Engeseth, N.J. Antioxidant capacity of honeys from various floral sources based on the
determination of oxygen radical absorbance capacity and inhibition of in vitro lipoprotein oxidation in
human serum samples. J. Agric. Food Chem. 2002, 50, 3050–3055.
- del Bano, M.J.; Lorente, J.; Castillo, J.; Benavente-Garcia, O.; del Rio, J.A.; Ortuno, A.; Quirin, K.W.; Gerard,
D. Phenolic diterpenes, flavones, and rosmarinic acid distribution during the development of leaves,
flowers, stems, and roots of Rosmarinus officinalis. Antioxid. Act. J. Agric. Food Chem. 2003, 51, 4247–4253.
- Amorati, R.; Foti, M.C.; Valgimigli, L. Antioxidant activity of essential oils. J. Agric. Food Chem. 2013, 61,
10835–10847.
- Tungmunnithum, D.; Thongboonyou, A.; Pholboon, A.; Yangsabai, A. Flavonoids and other phenolic
compounds from medicinal plants for pharmaceutical and medical aspects: An overview. Medicines 2018,
5, 93.
- Ak, T.; Gülçin, I. Antioxidant and radical scavenging properties of curcumin. Chem. Biol. Interact. 2008, 174,
27–37.
- Foley, T.D. Reductive reprogramming: A not-so-radical hypothesis of neurodegeneration linking redox
perturbations to neuroinflammation and excitotoxicity. Cell Mol. Neurobiol. 2019, 39, 577–590.
- Cui, K.; Luo, X.; Xu, K.; Ven Murthy, M.R. Role of oxidative stress in neurodegeneration: Recent
developments in assay methods for oxidative stress and nutraceutical antioxidants. Prog.
Neuropsychopharmacol. Biol. Psychiatry. 2004, 28, 771–799.
- Andersen, J.K. Oxidative stress in neurodegeneration: Cause or consequence? Nat. Med. 2004, 10, S18–S25.
- Mattson, M.P.; Magnus, T. Ageing and neuronal vulnerability. Nat. Rev. Neurosci. 2006, 7, 278–294.
- Lim, H.J.; Lee, K.S.; Lee, S.; Park, J.H.; Choi, H.E.; Go, S.H.; Kwak, H.J.; Park, H.Y. 15d-PGJ2 stimulates HO1 expression through p38 MAP kinase and Nrf-2 pathway in rat vascular smooth muscle cells. Toxicol. Appl.
Pharm. 2007, 223, 20–27.
- Kim, S.J.; Son, T.G.; Park, H.R.; Park, M.; Kim, M.S.; Kim, H.S.; Chung, H.Y.; Mattson, M.P.; Lee, J. Curcumin
stimulates proliferation of embryonic neural progenitor cells and neurogenesis in the adult hippocampus.
J. Biol. Chem. 2008, 283, 14497–14505.
- Bhakkiyalakshmi, E.; Dineshkumar, K.; Karthik, S.; Sireesh, D.; Hopper, W.; Paulmurugan, R.; Ramkumar,
K.M. Pterostilbene-mediated Nrf2 activation: Mechanistic insights on Keap1: Nrf2 interface. Bioorg. Med.
Chem. 2016, 24, 3378–3386.
- Lu, B.; Chow, A. Neurotrophins and hippocampal synaptic transmission and plasticity. J. Neurosci. Res.
1999, 58, 76–87.
- Chao, M.V.; Rajagopal, R.; Lee, F.S. Neurotrophin signalling in health and disease. Clin. Sci. 2006, 110, 167–
173.
- Sariola, H.; Saarma, M. Novel functions and signalling pathways for GDNF. J. Cell Sci. 2003, 116, 3855–3862.
- Nakajima, K.; Niisato, N.; Marunaka, Y. Quercetin stimulates NGF-induced neurite outgrowth in PC12
cells via activation of Na(+)/K(+)/2Cl(−) cotransporter. Cell Physiol. Biochem. 2011, 28, 147–156.
- Nakajima, K.; Niisato, N.; Marunaka, Y. Genistein enhances the NGF-induced neurite outgrowth. Biomed.
Res. 2011, 32, 351–356.
- Zhang, F.; Wang, Y.Y.; Liu, H.; Lu, Y.F.; Wu, Q.; Liu, J.; Shi, J.S. Resveratrol produces neurotrophic effects
on cultured dopaminergic neurons through prompting astroglial BDNF and GDNF release. Evid. Based
Complement. Altern. Med 2012, 2012, 937605.
- Yuan, H.; Zhang, J.; Liu, H.; Li, Z. The protective effects of resveratrol on Schwann cells with toxicity
induced by ethanol in vitro. Neurochem. Int. 2013, 63, 146–153.
- Huang, E.J.; Reichardt, L.F. TRK receptors: Roles in neuronal signal transduction. Annu. Rev. Biochem. 2003,
72, 609–642.
- Liu, C.; Chan, C.B.; Ye, K. 7,8-dihydroxyflavone, a small molecular TrkB agonist, is useful for treating
various BDNF-implicated human disorders. Transl. Neurodegener. 2016, 5, 2.
- Jang, S.W.; Liu, X.; Yepes, M.; Shepherd, K.R.; Miller, G.W.; Liu, Y.; Wilson, W.D.; Xiao, G.; Blanchi, B.; Sun,
Y.E.; et al. A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proc. Natl.
Acad. Sci. USA 2010, 107, 2687–2692.
- Guo, Z.; Liu, Y.; Cheng, M. Resveratrol protects bupivacaine-induced neuro-apoptosis in dorsal root
ganglion neurons via activation on tropomyosin receptor kinase A. Biomed. Pharm. 2018, 103, 1545–1551.
- Spencer, J.P.; Vafeiadou, K.; Williams, R.J.; Vauzour, D. Neuroinflammation: modulation by flavonoids and
mechanisms of action. Mol. Asp. Med. 2012, 33, 83–97.
- Si, T.L.; Liu, Q.; Ren, Y.F.; Li, H.; Xu, X.Y.; Li, E.H.; Pan, S.Y.; Zhang, J.L.; Wang, K.X. Enhanced antiinflammatory effects of DHA and quercetin in lipopolysaccharide-induced RAW264.7 macrophages by
inhibiting NF-κB and MAPK activation. Mol. Med. Rep. 2016, 14, 499–508.
- Baur, J.A.; Pearson, K.J.; Price, N.L.; Jamieson, H.A.; Lerin, C.; Kalra, A.; Prabhu, V.V.; Allard, J.S.; LopezLluch, G.; Lewis, K.; et al. Resveratrol improves health and survival of mice on a high-calorie diet. Nature
2006, 444, 337–342.
- Zhu, X.; Raina, A.K.; Lee, H.G.; Casadesus, G.; Smith, M.A.; Perry, G. Oxidative stress signalling in
Alzheimer’s disease. Brain Res. 2004, 1000, 32–39.
- Di Pardo, A.; Amico, E.; Scalabrì, F.; Pepe, G.; Castaldo, S.; Elifani, F.; Capocci, L.; De Sanctis, C.; Comerci,
L.; Pompeo, F.; et al. Impairment of blood-brain barrier is an early event in R6/2 mouse model of
Huntington’s disease. Sci. Rep. 2017, 7, 41316.
- Knutson, M.D.; Leeuwenburgh, C. Resveratrol and novel potent activators of SIRT1: Effects on aging and
age-related diseases. Nutr. Rev. 2008, 66, 591–596.
- Polivka, J.; Janku, F. Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway. Pharmacol.
Therap. 2014, 142, 164–175.
- Alexander, G.E. Biology of Parkinson’s disease: Pathogenesis and pathophysiology of a multisystem
neurodegenerative disorder. Dialogues Clin. Neurosci. 2004, 6, 259–280.
- Miller, R.L.; James-Kracke, M.; Sun, G.Y.; Sun, A.Y. Oxidative and inflammatory pathways in Parkinson’s
disease. Neurochem. Res. 2009, 34, 55–65.
- Miller, R.L.; Sun, G.Y.; Sun, A.Y. Cytotoxicity of paraquat in microglial cells: Involvement of PKCδ- and
ERK1/2-dependent NADPH oxidase. Brain Res. 2007, 1167, 129–139.
- Weinreb, O.; Mandel, S.; Amit, T.; Youdim, M.B. Neurological mechanisms of green tea polyphenols in
Alzheimer’s and Parkinson’s diseases. J. Nutr. Biochem. 2004, 15, 506–516.
- Mercer, L.D.; Kelly, B.L.; Horne, M.K.; Beart, P.M. Dietary polyphenols protect dopamine neurons from
oxidative insults and apoptosis: Investigations in primary rat mesencephalic cultures. Biochem Pharm. 2005,
69, 339–345.
- Masuda, M.; Suzuki, N.; Taniguchi, S.; Oikawa, T.; Nonaka, T.; Iwatsubo, T.; Hisanaga, S.; Goedert, M.;
Hasegawa, M. Small molecule inhibitors of alpha-synuclein filament assembly. Biochemistry 2006, 45, 6085–
6094.
- Andrieu, S.; Coley, N.; Lovestone, S.; Aisen, P.S.; Vellas, B. Prevention of sporadic Alzheimer’s disease:
Lessons learned from clinical trials and future directions. Lancet Neurol. 2015, 14, 926–944.
- Haass, C.; Selkoe, D.J. Soluble protein oligomers in neurodegeneration: Lessons from the Alzheimer’s
amyloid beta-peptide. Nat. Rev. Mol. Cell Biol. 2007, 8, 101–112.
- Querfurth, H.W.; LaFerla, F.M. Alzheimer’s disease. N. Engl. J. Med. 2010, 362, 329–344.
- Selkoe, D.J. Alzheimer’s disease: Genes, proteins, and therapy. Physiol. Rev. 2001, 81, 741–766.
- Selkoe, D.J. Alzheimer’s disease results from the cerebral accumulation and cytotoxicity of amyloid betaprotein. J. Alzheimers Dis. 2001, 3, 75–80.
- Snyder, E.M.; Nong, Y.; Almeida, C.G.; Paul, S.; Moran, T.; Choi, E.Y.; Nairn, A.C.; Salter, M.W.; Lombroso,
P.J.; Gouras, G.K.; et al. Regulation of NMDA receptor trafficking by amyloid-beta. Nat. Neurosci. 2005, 8,
1051–1058.
- Flanagan, E.; MĂĽller, M.; Hornberger, M.; Vauzour, D. Impact of flavonoids on cellular and molecular
mechanisms underlying age-related cognitive decline and neurodegeneration. Curr. Nutr. Rep. 2018, 7, 49–
57.
- Wang, R.; Li, Y.H.; Xu, Y.; Li, Y.B.; Wu, H.L.; Guo, H.; Zhang, J.Z.; Zhang, J.J.; Pan, X.Y.; Li, X.J. Curcumin
produces neuroprotective effects via activating brain-derived neurotrophic factor/TrkB-dependent MAPK
and PI-3K cascades in rodent cortical neurons. Prog. Neuropsychopharmacol. Biol. Psychiatry 2010, 34, 147–
153.
- Zhang, L.; Fang, Y.; Xu, Y.; Lian, Y.; Xie, N.; Wu, T.; Zhang, H.; Sun, L.; Zhang, R.; Wang, Z. Curcumin
improves amyloid β-peptide (1–42) induced spatial memory deficits through BDNF-ERK signaling
pathway. PLoS ONE 2015, 10, e0131525.
- Zheng, K.; Dai, X.; Xiao, N.; Wu, X.; Wei, Z.; Fang, W.; Zhu, Y.; Zhang, J.; Chen, X. Curcumin ameliorates
memory decline via inhibiting BACE1 expression and β-amyloid pathology in 5 Ă— FAD transgenic mice.
Mol. Neurobiol. 2017, 54, 1967–1977.
- Zhao, Y.N.; Li, W.F.; Li, F.; Zhang, Z.; Dai, Y.D.; Xu, A.L.; Qi, C.; Gao, J.M.; Gao, J. Resveratrol improves
learning and memory in normally aged mice through microRNA-CREB pathway. Biochem. Biophys. Res.
Commun. 2013, 435, 597–602.
- Fu, Z.; Yang, J.; Wei, Y.; Li, J. Effects of piceatannol and pterostilbene against β-amyloid-induced apoptosis
on the PI3K/Akt/Bad signaling pathway in PC12 cells. Food Funct. 2016, 7, 1014–1023.
- Donmez, G.; Outeiro, T.F. SIRT1 and SIRT2: Emerging targets in neurodegeneration. EMBO Mol. Med. 2013,
5, 344–352.
- Karuppagounder, S.S.; Pinto, J.T.; Xu, H.; Chen, H.L.; Beal, M.F.; Gibson, G.E. Dietary supplementation
with resveratrol reduces plaque pathology in a transgenic model of Alzheimer’s disease. Neurochem. Int.
2009, 54, 111–118.
- Wang, R.; Zhang, Y.; Li, J.; Zhang, C. Resveratrol ameliorates spatial learning memory impairment induced
by Aβ. Neuroscience 2017, 344, 39–47.
- Rezai-Zadeh, K.; Arendash, G.W.; Hou, H.; Fernandez, F.; Jensen, M.; Runfeldt, M.; Shytle, R.D.; Tan, J.
Green tea epigallocatechin-3-gallate (EGCG) reduces beta-amyloid mediated cognitive impairment and
modulates tau pathology in Alzheimer’s transgenic mice. Brain Res. 2008, 1214, 177–187.
- Evin, G.; Barakat, A.; Masters, C.L. BACE: Therapeutic target and potential biomarker for Alzheimer’s
disease. Int. J. Biochem. Cell Biol. 2010, 42, 1923–1926.
- Ortiz-LĂłpez, L.; Márquez-Valadez, B.; GĂłmez-Sánchez, A.; Silva-Lucero, M.D.; Torres-PĂ©rez, M.; TĂ©llezBallesteros, R.I.; Ichwan, M.; Meraz-RĂos, M.A.; Kempermann, G.; RamĂrez-RodrĂguez, G.B. Green tea
compound epigallo-catechin-3-gallate (EGCG) increases neuronal survival in adult hippocampal
neurogenesis in vivo and in vitro. Neuroscience 2016, 322, 208–220.
- Li, Y.; Zhou, S.; Li, J.; Sun, Y.; Hasimu, H.; Liu, R.; Zhang, T. Quercetin protects human brain microvascular
endothelial cells from fibrillar β-amyloid1–40-induced toxicity. Acta Pharm. Sin. B 2015, 5, 47–54.
- Zhang, X.; Hu, J.; Zhong, L.; Wang, N.; Yang, L.; Liu, C.C.; Li, H.; Wang, X.; Zhou, Y.; Zhang, Y.; et al.
Quercetin stabilizes apolipoprotein E and reduces brain Aβ levels in amyloid model mice.
Neuropharmacology 2016, 108, 179–192.
- Sabogal-Guáqueta, A.M.; Muñoz-Manco, J.I.; RamĂrez-Pineda, J.R.; Lamprea-Rodriguez, M.; Osorio, E.;
Cardona-Gómez, G.P. The flavonoid quercetin ameliorates Alzheimer’s disease pathology and protects
cognitive and emotional function in aged triple transgenic Alzheimer’s disease model mice.
Neuropharmacology 2015, 93, 134–145.
- Lu, Y.; Liu, Q.; Yu, Q. Quercetin enrich diet during the early-middle not middle-late stage of Alzheimer’s
disease ameliorates cognitive dysfunction. Am. J. Transl. Res. 2018, 10, 1237–1246.
- Kong, Y.; Li, K.; Fu, T.; Wan, C.; Zhang, D.; Song, H.; Zhang, Y.; Liu, N.; Gan, Z.; Yuan, L. Quercetin
ameliorates Aβ toxicity in Drosophila AD model by modulating cell cycle-related protein expression.
Oncotarget 2016, 7, 67716–67731.
- Cui, Q.; Li, X.; Zhu, H. Curcumin ameliorates dopaminergic neuronal oxidative damage via activation of
the Akt/Nrf2 pathway. Mol. Med. Rep. 2016, 13, 1381–1388.
- Wu, J.; Li, Q.; Wang, X.; Yu, S.; Li, L.; Wu, X.; Chen, Y.; Zhao, J.; Zhao, Y. Neuroprotection by curcumin in
ischemic brain injury involves the Akt/Nrf2 pathway. PLoS ONE 2013, 8, e59843.
- Ramkumar, M.; Rajasankar, S.; Swaminathan Johnson, W.M.; Prabu, K.; Venkatesh Gobi, V.
Demethoxycurcumin ameliorates rotenone-induced toxicity in rats. Front. Biosci. 2019, 11, 1–11.
- Dauer, W.; Przedborski, S. Parkinson’s disease: Mechanisms and models. Neuron 2003, 39, 889–909.
- Wang, Y.L.; Ju, B.; Zhang, Y.Z.; Yin, H.L.; Liu, Y.J.; Wang, S.S.; Zeng, Z.L.; Yang, X.P.; Wang, H.T.; Li, J.F.
Protective Effect of Curcumin Against Oxidative Stress-Induced Injury in Rats with Parkinson's Disease
Through the Wnt/ β-Catenin Signaling Pathway. Cell Physiol Biochem 2017, 43, 2226-2241,
doi:10.1159/000484302.
- Yu, S.; Wang, X.; He, X.; Wang, Y.; Gao, S.; Ren, L.; Shi, Y. Curcumin exerts anti-inflammatory and
antioxidative properties in 1-methyl-4-phenylpyridinium ion (MPP(+))-stimulated mesencephalic
astrocytes by interference with TLR4 and downstream signaling pathway. Cell Stress. Chaperones. 2016, 21,
697–705.
- Potdar, S.; Parmar, M.S.; Ray, S.D.; Cavanaugh, J.E. Protective effects of the resveratrol analog piceid in
dopaminergic SH-SY5Y cells. Arch. Toxicol. 2018, 92, 669–677.
- Zeng, W.; Zhang, W.; Lu, F.; Gao, L.; Gao, G. Resveratrol attenuates MPP. Neurosci. Lett. 2017, 637, 50–56.
- Gaballah, H.H.; Zakaria, S.S.; Elbatsh, M.M.; Tahoon, N.M. Modulatory effects of resveratrol on
endoplasmic reticulum stress-associated apoptosis and oxido-inflammatory markers in a rat model of
rotenone-induced Parkinson’s disease. Chem. Biol. Interact. 2016, 251, 10–16.
- Karuppagounder, S.S.; Madathil, S.K.; Pandey, M.; Haobam, R.; Rajamma, U.; Mohanakumar, K.P.
Quercetin up-regulates mitochondrial complex-I activity to protect against programmed cell death in
rotenone model of Parkinson’s disease in rats. Neuroscience 2013, 236, 136–148.
- Choi, J.Y.; Park, C.S.; Kim, D.J.; Cho, M.H.; Jin, B.K.; Pie, J.E.; Chung, W.G. Prevention of nitric oxidemediated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson’s disease in mice by tea
phenolic epigallocatechin 3-gallate. Neurotoxicology 2002, 23, 367–374.
- Levites, Y.; Weinreb, O.; Maor, G.; Youdim, M.B.; Mandel, S. Green tea polyphenol(−)-epigallocatechin-3-
gallate prevents N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic
neurodegeneration. J. Neurochem. 2001, 78, 1073–1082.
- Walker, F.O. Huntington's Disease. Semin Neurol 2007, 27, 143-150, doi:10.1055/s-2007-971176.
- Strong, T.V.; Tagle, D.A.; Valdes, J.M.; Elmer, L.W.; Boehm, K.; Swaroop, M.; Kaatz, K.W.; Collins, F.S.;
Albin, R.L. Widespread expression of the human and rat Huntington’s disease gene in brain and nonneural
tissues. Nat. Genet. 1993, 5, 259–265.
- Sciacca, S.; Favellato, M.; Madonna, M.; Metro, D.; Marano, M.; Squitieri, F. Early enteric neuron
dysfunction in mouse and human Huntington’s disease. Parkinsonism Relat. Disord. 2017, 34, 73–74.
- Siddiqui, A.; Rivera-Sánchez, S.; Castro, M.e.R.; Acevedo-Torres, K.; Rane, A.; Torres-Ramos, C.A.;
Nicholls, D.G.; Andersen, J.K.; Ayala-Torres, S. Mitochondrial DNA damage is associated with reduced
mitochondrial bioenergetics in Huntington’s disease. Free Radic Biol Med 2012, 53, 1478–1488.
- Xun, Z.; Rivera-Sánchez, S.; Ayala-Peña, S.; Lim, J.; Budworth, H.; Skoda, E.M.; Robbins, P.D.;
Niedernhofer, L.J.; Wipf, P.; McMurray, C.T. Targeting of XJB-5–131 to mitochondria suppresses oxidative
DNA damage and motor decline in a mouse model of Huntington’s disease. Cell Rep. 2012, 2, 1137–1142.
- Naia, L.; Rosenstock, T.R.; Oliveira, A.M.; Oliveira-Sousa, S.I.; Caldeira, G.L.; Carmo, C.; Laço, M.N.;
Hayden, M.R.; Oliveira, C.R.; Rego, A.C. Comparative mitochondrial-based protective effects ofresveratrol
and nicotinamide in Huntington’s disease models. Mol Neurobiol. 2017, 54, 5385–5399.
- Sandhir, R.; Yadav, A.; Mehrotra, A.; Sunkaria, A.; Singh, A.; Sharma, S. Curcumin nanoparticles attenuate
neurochemical and neurobehavioral deficits in experimental model of Huntington’s disease.
Neuromolecular. Med. 2014, 16, 106–118.
- Chongtham, A.; Agrawal, N. Curcumin modulates cell death and is protective in Huntington’s disease
model. Sci. Rep. 2016, 6, 18736.
- Elifani, F.; Amico, E.; Pepe, G.; Capocci, L.; Castaldo, S.; Rosa, P.; Montano, E.; Pollice, A.; Madonna, M.;
Filosa, S.; et al. Curcumin dietary supplementation ameliorates disease phenotype in an animal model of
Huntington’s disease. Hum Mol Genet 2019, 28, 4012–4021.
- Sandhir, R.; Mehrotra, A. Quercetin supplementation is effective in improving mitochondrial dysfunctions
induced by 3-nitropropionic acid: Implications in Huntington’s disease. Biochim. Biophys. Acta 2013, 1832,
421–430.
- Chakraborty, J.; Singh, R.; Dutta, D.; Naskar, A.; Rajamma, U.; Mohanakumar, K.P. Quercetin improves
behavioral deficiencies, restores astrocytes and microglia, and reduces serotonin metabolism in 3-
nitropropionic acid-induced rat model of Huntington’s disease. CNS Neurosci. 2014, 20, 10–19.
- Jellinger, K.A. The enigma of vascular cognitive disorder and vascular dementia. Acta Neuropathol. 2007,
113, 349–388.
- Molino, S.; Dossena, M.; Buonocore, D.; Ferrari, F.; Venturini, L.; Ricevuti, G.; Verri, M. Polyphenols in
dementia: From molecular basis to clinical trials. Life Sci. 2016, 161, 69–77.
- Awasthi, H.; Tota, S.; Hanif, K.; Nath, C.; Shukla, R. Protective effect of curcumin against intracerebral
streptozotocin induced impairment in memory and cerebral blood flow. Life Sci. 2010, 86, 87–94.
- Anastácio, J.R.; Netto, C.A.; Castro, C.C.; Sanches, E.F.; Ferreira, D.C.; Noschang, C.; Krolow, R.; Dalmaz,
C.; Pagnussat, A. Resveratrol treatment has neuroprotective effects and prevents cognitive impairment
after chronic cerebral hypoperfusion. Neurol. Res. 2014, 36, 627–633.
- Shen, D.; Tian, X.; Sang, W.; Song, R. Effect of melatonin and resveratrol against memory impairment and
hippocampal damage in a rat model of vascular dementia. Neuroimmunomodulation 2016, 23, 318–331.
- Tota, S.; Awasthi, H.; Kamat, P.K.; Nath, C.; Hanif, K. Protective effect of quercetin against intracerebral
streptozotocin induced reduction in cerebral blood flow and impairment of memory in mice. Behav. Brain
Res. 2010, 209, 73–79.
- Jayaraj, R.; Elangovan, N.; Manigandan, K.; Singh, S.; Shukla, S. CNB-001 a novel curcumin derivative,
guards dopamine neurons in MPTP model of Parkinson’s disease. BioMed Res. Int. 2014,
doi:10.1155/2014/236182.
- Selma, M.V.; EspĂn, J.C.; Tomás-Barberán, F.A. Interaction between phenolics and gut microbiota: Role in
human health. J. Agric. Food Chem. 2009, 57, 6485–6501.
- Aura, A. Microbial metabolism of dietary phenolic compounds in the colon. Phytochem. Rev. 2008, 7, 407–
429.
- Deprez, S.; Mila, I.; Huneau, J.F.; Tome, D.; Scalbert, A. Transport of proanthocyanidin dimer, trimer, and
polymer across monolayers of human intestinal epithelial Caco-2 cells. Antioxid. Redox. Signal. 2001, 3, 957–
967.
- Kang, S.M.; Lee, S.H.; Heo, S.J.; Kim, K.N.; Jeon, Y.J. Evaluation of antioxidant properties of a new
compound, pyrogallol-phloroglucinol-6,6’-bieckol isolated from brown algae, Ecklonia cava. Nutr. Res.
Pract. 2011, 5, 495–502.
- Deng, H.; Fang, Y. The three catecholics benserazide, catechol and pyrogallol are GPR35 agonists.
Pharmaceuticals 2013, 6, 500–509.
- Di Giovanni, S.; Eleuteri, S.; Paleologou, K.E.; Yin, G.; Zweckstetter, M.; Carrupt, P.A.; Lashuel, H.A.
Entacapone and tolcapone, two catechol O-methyltransferase inhibitors, block fibril formation of alphasynuclein and beta-amyloid and protect against amyloid-induced toxicity. J. Biol. Chem. 2010, 285, 14941–
14954.
- Di Meo, F.; Margarucci, S.; Galderisi, U.; Crispi, S.; Peluso, G. Curcumin, gut microbiota, and
neuroprotection. Nutrients 2019, 11, 2426.
- Basholli-Salihu, M.; Schuster, R.; Mulla, D.; Praznik, W.; Viernstein, H.; Mueller, M. Bioconversion of piceid
to resveratrol by selected probiotic cell extracts. Bioprocess. Biosyst. Eng. 2016, 39, 1879–1885.
- Bode, L.M.; Bunzel, D.; Huch, M.; Cho, G.S.; Ruhland, D.; Bunzel, M.; Bub, A.; Franz, C.M.; Kulling, S.E. In
vivo and in vitro metabolism of trans-resveratrol by human gut microbiota. Am. J. Clin. Nutr. 2013, 97, 295–
309.
- Blaut, M.; Schoefer, L.; Braune, A. Transformation of flavonoids by intestinal microorganisms. Int. J. Vitam.
Nutr. Res. 2003, 73, 79–87.
- Zheng, C.J.; Liu, R.; Xue, B.; Luo, J.; Gao, L.; Wang, Y.; Ou, S.; Li, S.; Peng, X. Impact and consequences of
polyphenols and fructooligosaccharide interplay on gut microbiota in rats. Food Funct. 2017, 8, 1925–1932.
- Angelino, D.; Carregosa, D.; Domenech-Coca, C.; Savi, M.; Figueira, I.; Brindani, N.; Jang, S.; Lakshman, S.;
Molokin, A.; Urban, J.F.; et al. 5-(hydroxyphenyl)-γ-valerolactone-sulfate, a key microbial metabolite of
flavan-3-ols, is able to reach the brain: Evidence from different in. Nutrients 2019, 11, 2678.
- Johnson, S.L.; Kirk, R.D.; DaSilva, N.A.; Ma, H.; Seeram, N.P.; Bertin, M.J. Polyphenol microbial metabolites
exhibit gut and blood-brain barrier permeability and protect murine microglia against LPS-induced
inflammation. Metabolites 2019, 9, 78.
- Figueira, I.; Garcia, G.; PimpĂŁo, R.C.; Terrasso, A.P.; Costa, I.; Almeida, A.F.; Tavares, L.; Pais, T.F.; Pinto,
P.; Ventura, M.R.; et al. Polyphenols journey through blood-brain barrier towards neuronal protection. Sci.
Rep. 2017, 7, 11456.
- Youdim, K.A.; Qaiser, M.Z.; Begley, D.J.; Rice-Evans, C.A.; Abbott, N.J. Flavonoid permeability across an
in situ model of the blood-brain barrier. Free Radic. Biol. Med. 2004, 36, 592–604.
- Filosa, S.; Di Meo, F.; Crispi, S. Polyphenols-gut microbiota interplay and brain neuromodulation. Neural.
Regen. Res. 2018, 13, 2055–2059.
- Bird, J.K.; Raederstorff, D.; Weber, P.; Steinert, R.E. Cardiovascular and antiobesity effects of resveratrol
mediated through the gut microbiota. Adv. Nutr. 2017, 8, 839–849.
- Arakawa, H.; Maeda, M.; Okubo, S.; Shimamura, T. Role of hydrogen peroxide in bactericidal action of
catechin. Biol. Pharm. Bull. 2004, 27, 277–281.
- Tzounis, X.; Vulevic, J.; Kuhnle, G.G.; George, T.; Leonczak, J.; Gibson, G.R.; Kwik-Uribe, C.; Spencer, J.P.
Flavanol monomer-induced changes to the human faecal microflora. Br. J. Nutr. 2008, 99, 782–792.
- Yamakoshi, J.; Tokutake, S.; Kikuchi, M.; Kubota, Y.; Konishi, H.; Mitsuoka, T. Effect of ProanthocyanidinRich Extract from Grape Seeds on Human Fecal Flora and Fecal Odor. Microbial Ecology in Health and Disease
2001, 13, 25-31.
- GarcĂa-Mediavilla, M.V.; Sánchez-Campos, S.; Tuñón, M.J. Fruit polyphenols, immunity and inflammation.
Br. J. Nutr. 2010, 104, S15–S27.
- Tzounis, X.; Rodriguez-Mateos, A.; Vulevic, J.; Gibson, G.R.; Kwik-Uribe, C.; Spencer, J.P. Prebiotic
evaluation of cocoa-derived flavanols in healthy humans by using a randomized, controlled, double-blind,
crossover intervention study. Am. J. Clin. Nutr. 2011, 93, 62–72.
- Queipo-Ortuño, M.I.; Boto-Ordóñez, M.; Murri, M.; Gomez-Zumaquero, J.M.; Clemente-Postigo, M.;
Estruch, R.; Cardona Diaz, F.; Andrés-Lacueva, C.; Tinahones, F.J. Influence of red wine polyphenols and
ethanol on the gut microbiota ecology and biochemical biomarkers. Am. J. Clin. Nutr. 2012, 95, 1323–1334.
- Brasili, E.; Hassimotto, N.M.A.; Del Chierico, F.; Marini, F.; Quagliariello, A.; Sciubba, F.; Miccheli, A.;
Putignani, L.; Lajolo, F. Daily consumption of orange juice from Citrus sinensis L. Osbeck cv. Cara Cara and
cv. Bahia differently affects gut microbiota profiling as unveiled by an integrated meta-omics approach. J.
Agric. Food Chem. 2019, 67, 1381–1391.
- Gerhardt, S.; Mohajeri, M.H. Changes of colonic bacterial composition in Parkinson’s disease and other
neurodegenerative diseases. Nutrients 2018, 10, 708.
- Sun, M.F.; Shen, Y.Q. Dysbiosis of gut microbiota and microbial metabolites in Parkinson’s disease. Ageing
Res. Rev. 2018, 45, 53–61.
- Hsiao, E.Y.; McBride, S.W.; Hsien, S.; Sharon, G.; Hyde, E.R.; McCue, T.; Codelli, J.A.; Chow, J.; Reisman,
S.E.; Petrosino, J.F.; et al. Microbiota modulate behavioral and physiological abnormalities associated with
neurodevelopmental disorders. Cell 2013, 155, 1451–1463.
- Lyte, M. Probiotics function mechanistically as delivery vehicles for neuroactive compounds: Microbial
endocrinology in the design and use of probiotics. Bioessays 2011, 33, 574–581.
- Nzakizwanayo, J.; Dedi, C.; Standen, G.; Macfarlane, W.M.; Patel, B.A.; Jones, B.V. Escherichia coli Nissle
1917 enhances bioavailability of serotonin in gut tissues through modulation of synthesis and clearance.
Sci. Rep. 2015, 5, 17324.
- O’Mahony, S.M.; Clarke, G.; Borre, Y.E.; Dinan, T.G.; Cryan, J.F. Serotonin, tryptophan metabolism and the
brain-gut-microbiome axis. Behav. Brain Res. 2015, 277, 32–48.
- Yunes, R.A.; Poluektova, E.U.; Dyachkova, M.S.; Klimina, K.M.; Kovtun, A.S.; Averina, O.V.; Orlova, V.S.;
Danilenko, V.N. GABA production and structure of gadB/gadC genes in Lactobacillus and Bifidobacterium
strains from human microbiota. Anaerobe 2016, 42, 197–204.