Polyphenols’ Effect on Cerebrovascular Health

Luis       Goya; Ricardo    San    Román; Sonia       de Pascual-Teresa
Abstract

Polyphenols are a wide group of plant components that include a high number of individual compounds and are present in foods, dietary supplements, and drugs. Many of them have shown pharmacological effects, are used in cardiovascular disease prevention, and not as many have been assayed in cancer treatment or co-treatment. In the last few years, however, the research on polyphenols' implications in healthy aging, especially in neurodegeneration and cognition improvement, has increased dramatically. Most of the results found in this sense are again related to the capacity of some specific polyphenols to regulate the blood flow, but this time at the cerebral level, and to protect the endothelium at this same level. In this thorough review, we want to concentrate precisely on the effect of polyphenols on cerebrovascular homeostasis, reviewing the mechanisms that underline this effect and the radiological methods and endogenous biomarkers that are used in human trials aimed at showing the beneficial effect of polyphenols or polyphenol rich foods on neuroprotection and cognition function.
Keywords: Polyphenol, cerebral blood flow, neuroprotection, mechanism, biomarker, cerebrovascular.
[1] 
de Pascual-Teresa, S.; Clifford, M.N. Advances in polyphenol research agricultural and food chemistry. J. Agric. Food Chem.,  2017, 65(37), 8093-8095.
[http://dx.doi.org/10.1021/acs.jafc.7b04055] [PMID: 28927282] 
[2] 
Martín, M.A.; Goya, L.; de Pascual-Teresa, S. Effect of cocoa and cocoa products on cognitive performance in young adults. Nutrients,  2020, 12(12), 3691.
[http://dx.doi.org/10.3390/nu12123691] [PMID: 33265948] 
[3] 
Puell, M.C.; de Pascual-Teresa, S. The acute effect of cocoa and red-berries on visual acuity and cone-mediated dark adaptation in healthy eyes. J. Funct. Foods,  2021, 81, 104435.
[http://dx.doi.org/10.1016/j.jff.2021.104435] 
[4] 
Abd El Mohsen, M.M.; Kuhnle, G.; Rechner, A.R.; Schroeter, H.; Rose, S.; Jenner, P.; Rice-Evans, C.A. Uptake and metabolism of epicatechin and its access to the brain after oral ingestion. Free Radic. Biol. Med.,  2002, 33(12), 1693-1702.
[http://dx.doi.org/10.1016/S0891-5849(02)01137-1] [PMID: 12488137] 
[5] 
Cittadini, M.C.; Repossi, G.; Albrecht, C.; Di Paola Naranjo, R.; Miranda, A.R.; de Pascual-Teresa, S.; Soria, E.A. Effects of bioavailable phenolic compounds from Ilex paraguariensis on the brain of mice with lung adenocarcinoma. Phytother. Res.,  2019, 33(4), 1142-1149.
[http://dx.doi.org/10.1002/ptr.6308] [PMID: 30729593] 
[6] 
Spencer, J.P.E. The impact of fruit flavonoids on memory and cognition. Br. J. Nutr.,  2010, 104(Suppl. 3), S40-S47.
[http://dx.doi.org/10.1017/S0007114510003934] [PMID: 20955649] 
[7] 
Ammar, A.; Trabelsi, K.; Boukhris, O.; Bouaziz, B.; Müller, P.; M Glenn, J.; Bott, N.T.; Müller, N.; Chtourou, H.; Driss, T.; Hökelmann, A. Effects of polyphenol-rich interventions on cognition and brain health in healthy young and middle-aged adults: systematic review and meta-analysis. J. Clin. Med.,  2020, 9(5), 1598.
[http://dx.doi.org/10.3390/jcm9051598] [PMID: 32466148] 
[8] 
Cichon, N.; Saluk-Bijak, J.; Gorniak, L.; Przyslo, L.; Bijak, M. Flavonoids as a natural enhancer of neuroplasticity. An overview of the mechanism of neurorestorative action. Antioxidants,  2020, 9(11), 1035.
[http://dx.doi.org/10.3390/antiox9111035] [PMID: 33114058] 
[9] 
Cicero, A.F.G.; Ruscica, M.; Banach, M. Resveratrol and cognitive decline: a clinician perspective. Arch. Med. Sci.,  2019, 15(4), 936-943.
[http://dx.doi.org/10.5114/aoms.2019.85463] [PMID: 31360188] 
[10] 
Ghosh, D.; Scheepens, A. Vascular action of polyphenols. Mol. Nutr. Food Res.,  2009, 53(3), 322-331.
[http://dx.doi.org/10.1002/mnfr.200800182] [PMID: 19051188] 
[11] 
Wightman, E.L. Potential benefits of phytochemicals against Alzheimer’s disease. Proc. Nutr. Soc.,  2017, 76(2), 106-112.
[http://dx.doi.org/10.1017/S0029665116002962] [PMID: 28143625] 
[12] 
Decroix, L.; Tonoli, C.; Soares, D.D.; Tagougui, S.; Heyman, E.; Meeusen, R. Acute cocoa flavanol improves cerebral oxygenation without enhancing executive function at rest or after exercise. Appl. Physiol. Nutr. Metab.,  2016, 41(12), 1225-1232.
[http://dx.doi.org/10.1139/apnm-2016-0245] [PMID: 27849355] 
[13] 
Fantini, S.; Sassaroli, A.; Tgavalekos, K.T.; Kornbluth, J. Cerebral blood flow and autoregulation: current measurement techniques and prospects for noninvasive optical methods. Neurophotonics,  2016, 3(3), 031411.
[http://dx.doi.org/10.1117/1.NPh.3.3.031411] [PMID: 27403447] 
[14] 
D’Andrea, A.; Conte, M.; Scarafile, R.; Riegler, L.; Cocchia, R.; Pezzullo, E.; Cavallaro, M.; Carbone, A.; Natale, F.; Russo, M.G.; Gregorio, G.; Calabrò, R. Transcranial doppler ultrasound: physical principles and principal applications in neurocritical care Unit. J. Cardiovasc. Echogr.,  2016, 26(2), 28-41.
[http://dx.doi.org/10.4103/2211-4122.183746] [PMID: 28465958] 
[15] 
Purkayastha, S.; Sorond, F. Transcranial doppler ultrasound: technique and application. Semin. Neurol.,  2012, 32(4), 411-420.
[http://dx.doi.org/10.1055/s-0032-1331812] [PMID: 23361485] 
[16] 
Maruyama, J.; Naguro, I.; Takeda, K.; Ichijo, H. Stress-activated MAP kinase cascades in cellular senescence. Curr. Med. Chem.,  2009, 16(10), 1229-1235.
[http://dx.doi.org/10.2174/092986709787846613] [PMID: 19355881] 
[17] 
Ma, X.; Hu, Y. Targeting PI3K/Akt/mTOR cascade: the medicinal potential, updated research highlights and challenges ahead. Curr. Med. Chem.,  2013, 20(24), 2991-3010.
[http://dx.doi.org/10.2174/09298673113209990124] [PMID: 23651303] 
[18] 
Yan, W.; Lakkaniga, N.R.; Carlomagno, F.; Santoro, M.; McDonald, N.Q.; Lv, F.; Gunaganti, N.; Frett, B.; Li, H.Y. antoro, M.; McDonald, N.Q.; Lv, F.; Gunaganti, N.; Frett, B.; Li, H-Y. Insights into current tropomyosin receptor kinase (TRK) inhibitors: development and clinical application. J. Med. Chem.,  2019, 62(4), 1731-1760.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01092] [PMID: 30188734] 
[19] 
Ben Aissa, M.; Lee, S.H.; Bennett, B.M.; Thatcher, G.R.J. Targeting NO/cGMP signaling in the CNS for neurodegeneration and alzheimer’s disease. Curr. Med. Chem.,  2016, 23(24), 2770-2788.
[http://dx.doi.org/10.2174/0929867323666160812145454] [PMID: 27776476] 
[20] 
Shin, W-H.; Park, S-J.; Kim, E-J. Protective effect of anthocyanins in middle cerebral artery occlusion and reperfusion model of cerebral ischemia in rats. Life Sci.,  2006, 79(2), 130-137.
[http://dx.doi.org/10.1016/j.lfs.2005.12.033] [PMID: 16442129] 
[21] 
Baron-Menguy, C.; Bocquet, A.; Guihot, A.L.; Chappard, D.; Amiot, M.J.; Andriantsitohaina, R.; Loufrani, L.; Henrion, D. Effects of red wine polyphenols on postischemic neovascularization model in rats: low doses are proangiogenic, high doses anti-angiogenic. FASEB J.,  2007, 21(13), 3511-3521.
[http://dx.doi.org/10.1096/fj.06-7782com] [PMID: 17595348] 
[22] 
Williams, C.M.; El Mohsen, M.A.; Vauzour, D.; Rendeiro, C.; Butler, L.T.; Ellis, J.A.; Whiteman, M.; Spencer, J.P.E. Blueberry-induced changes in spatial working memory correlate with changes in hippocampal CREB phosphorylation and brain-derived neurotrophic factor (BDNF) levels. Free Radic. Biol. Med.,  2008, 45(3), 295-305.
[http://dx.doi.org/10.1016/j.freeradbiomed.2008.04.008] [PMID: 18457678] 
[23] 
Zhang, J.; Wu, J.; Liu, F.; Tong, L.; Chen, Z.; Chen, J.; He, H.; Xu, R.; Ma, Y.; Huang, C. Neuroprotective effects of anthocyanins and its major component cyanidin-3-O-glucoside (C3G) in the central nervous system: an outlined review. Eur. J. Pharmacol.,  2019, 858, 172500.
[http://dx.doi.org/10.1016/j.ejphar.2019.172500] [PMID: 31238064] 
[24] 
Shan, X.; Chen, J.; Dai, S.; Wang, J.; Huang, Z.; Lv, Z.; Wang, Q.; Wu, Q. Cyanidin-related antidepressant-like efficacy requires PI3K/AKT/FoxG1/FGF-2 pathway modulated enhancement of neuronal differentiation and dendritic maturation. Phytomedicine,  2020, 76, 153269.
[http://dx.doi.org/10.1016/j.phymed.2020.153269] [PMID: 32593103] 
[25] 
Gray, N.E.; Alcazar Magana, A.; Lak, P.; Wright, K.M.; Quinn, J.; Stevens, J.F.; Maier, C.S.; Soumyanath, A. Centella asiatica - Phytochemistry and mechanisms of neuroprotection and cognitive enhancement. Phytochem. Rev.,  2018, 17(1), 161-194.
[http://dx.doi.org/10.1007/s11101-017-9528-y] [PMID: 31736679] 
[26] 
Zou, H.; Long, J.; Zhang, Q.; Zhao, H.; Bian, B.; Wang, Y.; Zhang, J.; Zhao, H.; Wang, L. Induced cortical neurogenesis after focal cerebral ischemia-Three active components from Huang-Lian-Jie-Du Decoction. J. Ethnopharmacol.,  2016, 178, 115-124.
[http://dx.doi.org/10.1016/j.jep.2015.12.001] [PMID: 26657578] 
[27] 
Martín, M.A.; Goya, L.; Ramos, S. Preventive effects of cocoa and cocoa antioxidants in colon cancer. Diseases,  2016, 4(1), 6.
[http://dx.doi.org/10.3390/diseases4010006] [PMID: 28933386] 
[28] 
van Praag, H.; Lucero, M.J.; Yeo, G.W.; Stecker, K.; Heivand, N.; Zhao, C.; Yip, E.; Afanador, M.; Schroeter, H.; Hammerstone, J.; Gage, F.H. Plant-derived flavanol (-)epicatechin enhances angiogenesis and retention of spatial memory in mice. J. Neurosci.,  2007, 27(22), 5869-5878.
[http://dx.doi.org/10.1523/JNEUROSCI.0914-07.2007] [PMID: 17537957] 
[29] 
Ding, M.L.; Ma, H.; Man, Y.G.; Lv, H.Y. Protective effects of a green tea polyphenol, epigallocatechin-3-gallate, against sevoflurane-induced neuronal apoptosis involve regulation of CREB/BDNF/TrkB and PI3K/Akt/mTOR signalling pathways in neonatal mice. Can. J. Physiol. Pharmacol.,  2017, 95(12), 1396-1405.
[http://dx.doi.org/10.1139/cjpp-2016-0333] [PMID: 28679060] 
[30] 
Nan, W.; Zhonghang, X.; Keyan, C.; Tongtong, L.; Wanshu, G.; Zhongxin, X. Epigallocatechin-3-gallate reduces neuronal apoptosis in rats after middle cerebral artery occlusion injury via PI3K/AKT/eNOS signaling pathway. BioMed Res. Int.,  2018, 2018, 6473580.
[http://dx.doi.org/10.1155/2018/6473580] [PMID: 29770336] 
[31] 
Shin, J.A.; Lee, K.E.; Kim, H.S.; Park, E.M. Acute resveratrol treatment modulates multiple signaling pathways in the ischemic brain. Neurochem. Res.,  2012, 37(12), 2686-2696.
[http://dx.doi.org/10.1007/s11064-012-0858-2] [PMID: 22878646] 
[32] 
Simão, F.; Matté, A.; Pagnussat, A.S.; Netto, C.A.; Salbego, C.G. Resveratrol prevents CA1 neurons against ischemic injury by parallel modulation of both GSK-3β and CREB through PI3-K/Akt pathways. Eur. J. Neurosci.,  2012, 36(7), 2899-2905.
[http://dx.doi.org/10.1111/j.1460-9568.2012.08229.x] [PMID: 22817531] 
[33] 
Simão, F.; Pagnussat, A.S.; Seo, J.H.; Navaratna, D.; Leung, W.; Lok, J.; Guo, S.; Waeber, C.; Salbego, C.G.; Lo, E.H. Pro-angiogenic effects of resveratrol in brain endothelial cells: nitric oxide-mediated regulation of vascular endothelial growth factor and metalloproteinases. J. Cereb. Blood Flow Metab.,  2012, 32(5), 884-895.
[http://dx.doi.org/10.1038/jcbfm.2012.2] [PMID: 22314268] 
[34] 
Bastianetto, S.; Ménard, C.; Quirion, R. Neuroprotective action of resveratrol. Biochim. Biophys. Acta,  2015, 1852(6), 1195-1201.
[http://dx.doi.org/10.1016/j.bbadis.2014.09.011] [PMID: 25281824] 
[35] 
Farzaei, M.H.; Rahimi, R.; Nikfar, S.; Abdollahi, M. Effect of resveratrol on cognitive and memory performance and mood: A meta-analysis of 225 patients. Pharmacol. Res.,  2018, 128, 338-344.
[http://dx.doi.org/10.1016/j.phrs.2017.08.009] [PMID: 28844841] 
[36] 
Wu, W.Y.; Wu, Y.Y.; Huang, H.; He, C.; Li, W.Z.; Wang, H.L.; Chen, H.Q.; Yin, Y.Y. Biochanin A attenuates LPS-induced pro-inflammatory responses and inhibits the activation of the MAPK pathway in BV2 microglial cells. Int. J. Mol. Med.,  2015, 35(2), 391-398.
[http://dx.doi.org/10.3892/ijmm.2014.2020] [PMID: 25483920] 
[37] 
Subedi, L.; Ji, E.; Shin, D.; Jin, J.; Yeo, J.H.; Kim, S.Y. Equol, a dietary daidzein gut metabolite attenuates microglial activation and potentiates neuroprotection in vitro. Nutrients,  2017, 9(3), 207-222.
[http://dx.doi.org/10.3390/nu9030207] [PMID: 28264445] 
[38] 
Ha, S.K.; Lee, P.; Park, J.A.; Oh, H.R.; Lee, S.Y.; Park, J.H.; Lee, E.H.; Ryu, J.H.; Lee, K.R.; Kim, S.Y. Apigenin inhibits the production of NO and PGE2 in microglia and inhibits neuronal cell death in a middle cerebral artery occlusion-induced focal ischemia mice model. Neurochem. Int.,  2008, 52(4-5), 878-886.
[http://dx.doi.org/10.1016/j.neuint.2007.10.005] [PMID: 18037535] 
[39] 
Drouin, A.; Bolduc, V.; Thorin-Trescases, N.; Bélanger, É.; Fernandes, P.; Baraghis, E.; Lesage, F.; Gillis, M.A.; Villeneuve, L.; Hamel, E.; Ferland, G.; Thorin, E. Catechin treatment improves cerebrovascular flow-mediated dilation and learning abilities in atherosclerotic mice. Am. J. Physiol. Heart Circ. Physiol.,  2011, 300(3), H1032-H1043.
[http://dx.doi.org/10.1152/ajpheart.00410.2010] [PMID: 21186270] 
[40] 
Jin, F.; Gong, Q.H.; Xu, Y.S.; Wang, L.N.; Jin, H.; Li, F.; Li, L.S.; Ma, Y.M.; Shi, J.S. Icariin, a phosphodiesterase-5 inhibitor, improves learning and memory in APP/PS1 transgenic mice by stimulation of NO/cGMP signalling. Int. J. Neuropsychopharmacol.,  2014, 17(6), 871-881.
[http://dx.doi.org/10.1017/S1461145713001533] [PMID: 24513083] 
[41] 
Lapi, D.; Vagnani, S.; Pignataro, G.; Esposito, E.; Paterni, M.; Colantuoni, A. Protective effects of quercetin on rat pial microvascular changes during transient bilateral common carotid artery occlusion and reperfusion. Front. Physiol.,  2012, 3, 32.
[http://dx.doi.org/10.3389/fphys.2012.00032] [PMID: 22403549] 
[42] 
Lapi, D.; Stornaiuolo, M.; Sabatino, L.; Sommella, E.; Tenore, G.; Daglia, M.; Scuri, R.; Di Maro, M.; Colantuoni, A.; Novellino, E. The pomace extract Taurisolo protects rat brain from ischemia-reperfusion injury. Front. Cell. Neurosci.,  2020, 14, 3.
[http://dx.doi.org/10.3389/fncel.2020.00003] [PMID: 32063837] 
[43] 
Di Giacomo, C.; Acquaviva, R.; Santangelo, R.; Sorrenti, V.; Vanella, L.; Li Volti, G.; D’Orazio, N.; Vanella, A.; Galvano, F. Effect of treatment with cyanidin-3-O-β-D-glucoside on rat ischemic/reperfusion brain damage. Evid. Based Complement. Alternat. Med.,  2012, 2012, 285750.
[http://dx.doi.org/10.1155/2012/285750] [PMID: 23008739] 
[44] 
Mastantuono, T.; Di Maro, M.; Chiurazzi, M.; Battiloro, L.; Muscariello, E.; Nasti, G.; Starita, N.; Colantuoni, A.; Lapi, D. Rat pial microvascular changes during cerebral blood flow decrease and recovery: effects of cyanidin administration. Front. Physiol.,  2018, 9, 540.
[http://dx.doi.org/10.3389/fphys.2018.00540] [PMID: 29867577] 
[45] 
Kiziltepe, U.; Turan, N.N.; Han, U.; Ulus, A.T.; Akar, F. Resveratrol, a red wine polyphenol, protects spinal cord from ischemia-reperfusion injury. J. Vasc. Surg.,  2004, 40(1), 138-145.
[http://dx.doi.org/10.1016/j.jvs.2004.03.032] [PMID: 15218474] 
[46] 
Xia, N.; Förstermann, U.; Li, H. Resveratrol and endothelial nitric oxide. Molecules,  2014, 19(10), 16102-16121.
[http://dx.doi.org/10.3390/molecules191016102] [PMID: 25302702] 
[47] 
Sokoya, E. Resveratrol protects endothelial cells from rapid stretch injury and hypoxia in vitro. Curr. Drug Ther.,  2015, 10, 56-64.
[http://dx.doi.org/10.2174/157488551001150825100709] 
[48] 
Tu, X.K.; Yang, W.Z.; Shi, S.S.; Chen, Y.; Wang, C.H.; Chen, C.M.; Chen, Z. Baicalin inhibits TLR2/4 signaling pathway in rat brain following permanent cerebral ischemia. Inflammation,  2011, 34(5), 463-470.
[http://dx.doi.org/10.1007/s10753-010-9254-8] [PMID: 20859668] 
[49] 
Hanke, M.L.; Kielian, T. Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin. Sci. (Lond.),  2011, 121(9), 367-387.
[http://dx.doi.org/10.1042/CS20110164] [PMID: 21745188] 
[50] 
Kauppinen, A.; Suuronen, T.; Ojala, J.; Kaarniranta, K.; Salminen, A. Antagonistic crosstalk between NF-κB and SIRT1 in the regulation of inflammation and metabolic disorders. Cell. Signal.,  2013, 25(10), 1939-1948.
[http://dx.doi.org/10.1016/j.cellsig.2013.06.007] [PMID: 23770291] 
[51] 
Zheng, M.; Qu, L.; Lou, Y. Effects of icariin combined with Panax notoginseng saponins on ischemia reperfusion-induced cognitive impairments related with oxidative stress and CA1 of hippocampal neurons in rat. Phytother. Res.,  2008, 22(5), 597-604.
[http://dx.doi.org/10.1002/ptr.2276] [PMID: 18398927] 
[52] 
Zhu, H.R.; Wang, Z.Y.; Zhu, X.L.; Wu, X.X.; Li, E.G.; Xu, Y. Icariin protects against brain injury by enhancing SIRT1-dependent PGC-1alpha expression in experimental stroke. Neuropharmacology,  2010, 59(1-2), 70-76.
[http://dx.doi.org/10.1016/j.neuropharm.2010.03.017] [PMID: 20381504] 
[53] 
Zhang, T.; Su, J.; Guo, B.; Wang, K.; Li, X.; Liang, G. Apigenin protects blood-brain barrier and ameliorates early brain injury by inhibiting TLR4-mediated inflammatory pathway in subarachnoid hemorrhage rats. Int. Immunopharmacol.,  2015, 28(1), 79-87.
[http://dx.doi.org/10.1016/j.intimp.2015.05.024] [PMID: 26028151] 
[54] 
Kao, T.K.; Ou, Y.C.; Lin, S.Y.; Pan, H.C.; Song, P.J.; Raung, S.L.; Lai, C.Y.; Liao, S.L.; Lu, H.C.; Chen, C.J. Luteolin inhibits cytokine expression in endotoxin/cytokine-stimulated microglia. J. Nutr. Biochem.,  2011, 22(7), 612-624.
[http://dx.doi.org/10.1016/j.jnutbio.2010.01.011] [PMID: 21036586] 
[55] 
Lu, H.; Shi, J.X.; Zhang, D.M.; Chen, H.L.; Qi, M.; Yin, H.X. Genistein, a soybean isoflavone, reduces the production of pro-inflammatory and adhesion molecules induced by hemolysate in brain microvascular endothelial cells. Acta Neurol. Belg.,  2009, 109(1), 32-37.
[PMID: 19402570] 
[56] 
Wang, W.; Tang, L.; Li, Y.; Wang, Y. Biochanin A protects against focal cerebral ischemia/reperfusion in rats via inhibition of p38-mediated inflammatory responses. J. Neurol. Sci.,  2015, 348(1-2), 121-125.
[http://dx.doi.org/10.1016/j.jns.2014.11.018] [PMID: 25466482] 
[57] 
Wu, L.Y.; Ye, Z.N.; Zhuang, Z.; Gao, Y.; Tang, C.; Zhou, C.H.; Wang, C.X.; Zhang, X.S.; Xie, G.B.; Liu, J.P.; Zhou, M.L.; Hang, C.H.; Shi, J.X. Biochanin A reduces inflammatory injury and neuronal apoptosis following subarachnoid hemorrhage via suppression of the TLRs/TIRAP/MyD88/NF-κB pathway. Behav. Neurol.,  2018, 2018, 1960106.
[http://dx.doi.org/10.1155/2018/1960106] [PMID: 29971136] 
[58] 
Seong, K.J.; Lee, H.G.; Kook, M.S.; Ko, H.M.; Jung, J.Y.; Kim, W.J. Epigallocatechin-3-gallate rescues LPS-impaired adult hippocampal neurogenesis through suppressing the TLR4-NF-κB signaling pathway in mice. Korean J. Physiol. Pharmacol.,  2016, 20(1), 41-51.
[http://dx.doi.org/10.4196/kjpp.2016.20.1.41] [PMID: 26807022] 
[59] 
Cui, H.X.; Chen, J.H.; Li, J.W.; Cheng, F.R.; Yuan, K. Protection of anthocyanin from Myrica rubra against cerebral ischemia-reperfusion injury via modulation of the TLR4/NF-κB and NLRP3 pathways. Molecules,  2018, 23, 1788-1799.
[http://dx.doi.org/10.3390/molecules23071788] 
[60] 
Clark, D.; Tuor, U.I.; Thompson, R.; Institoris, A.; Kulynych, A.; Zhang, X.; Kinniburgh, D.W.; Bari, F.; Busija, D.W.; Barber, P.A. Protection against recurrent stroke with resveratrol: endothelial protection. PLoS One,  2012, 7(10), e47792.
[http://dx.doi.org/10.1371/journal.pone.0047792] [PMID: 23082218] 
[61] 
Tang, F.; Guo, S.; Liao, H.; Yu, P.; Wang, L.; Song, X.; Chen, J.; Yang, Q. Resveratrol enhances neurite outgrowth and synaptogenesis via sonic hedgehog signaling following oxygen-glucose deprivation/reoxygenation injury. Cell. Physiol. Biochem.,  2017, 43(2), 852-869.
[http://dx.doi.org/10.1159/000481611] [PMID: 28957797] 
[62] 
Cai, J.C.; Liu, W.; Lu, F.; Kong, W.B.; Zhou, X.X.; Miao, P.; Lei, C.X.; Wang, Y. Resveratrol attenuates neurological deficit and neuroinflammation following intracerebral hemorrhage. Exp. Ther. Med.,  2018, 15(5), 4131-4138.
[http://dx.doi.org/10.3892/etm.2018.5938] [PMID: 29725362] 
[63] 
Ramos, S. Effects of dietary flavonoids on apoptotic pathways related to cancer chemoprevention. J. Nutr. Biochem.,  2007, 18(7), 427-442.
[http://dx.doi.org/10.1016/j.jnutbio.2006.11.004] [PMID: 17321735] 
[64] 
Ren, J.; Fan, C.; Chen, N.; Huang, J.; Yang, Q. Resveratrol pretreatment attenuates cerebral ischemic injury by upregulating expression of transcription factor Nrf2 and HO-1 in rats. Neurochem. Res.,  2011, 36(12), 2352-2362.
[http://dx.doi.org/10.1007/s11064-011-0561-8] [PMID: 21850487] 
[65] 
Law, B.N.; Ling, A.P.; Koh, R.Y.; Chye, S.M.; Wong, Y.P. Neuroprotective effects of orientin on hydrogen peroxide-induced apoptosis in SH-SY5Y cells. Mol. Med. Rep.,  2014, 9(3), 947-954.
[http://dx.doi.org/10.3892/mmr.2013.1878] [PMID: 24366367] 
[66] 
Magalingam, K.B.; Radhakrishnan, A.; Ramdas, P.; Haleagrahara, N. Quercetin glycosides induced neuroprotection by changes in the gene expression in a cellular model of Parkinson’s disease. J. Mol. Neurosci.,  2015, 55(3), 609-617.
[http://dx.doi.org/10.1007/s12031-014-0400-x] [PMID: 25129099] 
[67] 
Dong, Y.S.; Wang, J.L.; Feng, D.Y.; Qin, H.Z.; Wen, H.; Yin, Z.M.; Gao, G.D.; Li, C. Protective effect of quercetin against oxidative stress and brain edema in an experimental rat model of subarachnoid hemorrhage. Int. J. Med. Sci.,  2014, 11(3), 282-290.
[http://dx.doi.org/10.7150/ijms.7634] [PMID: 24516353] 
[68] 
Han, Y.; Zhang, T.; Su, J.; Zhao, Y.; Li, X. Apigenin attenuates oxidative stress and neuronal apoptosis in early brain injury following subarachnoid hemorrhage. J. Clin. Neurosci.,  2017, 40, 157-162.
[http://dx.doi.org/10.1016/j.jocn.2017.03.003] [PMID: 28342702] 
[69] 
Mo, Z.T.; Li, W.N.; Zhai, Y.R.; Gong, Q.H. Icariin attenuates OGD/R-induced autophagy via Bcl-2-dependent cross talk between apoptosis and autophagy in PC12 cells. Evid. Based Complement. Alternat. Med.,  2016, 2016, 4343084.
[http://dx.doi.org/10.1155/2016/4343084] [PMID: 27610184] 
[70] 
Wang, Z.H.; Chen, B.H.; Lin, Y.Y.; Xing, J.; Wei, Z.L.; Ren, L. Herbal decoction of Gastrodia, Uncaria, and Curcuma confers neuroprotection against cerebral ischemia in vitro and in vivo. J. Integr. Neurosci.,  2020, 19(3), 513-519.
[http://dx.doi.org/10.31083/j.jin.2020.03.002] [PMID: 33070532] 
[71] 
Liu, D.; Wang, H.; Zhang, Y.; Zhang, Z. Protective effects of chlorogenic acid on cerebral ischemia/reperfusion injury rats by regulating oxidative stress-related Nrf2 pathway. Drug Des. Devel. Ther.,  2020, 14, 51-60.
[http://dx.doi.org/10.2147/DDDT.S228751] [PMID: 32021091] 
[72] 
Smith, R.E. The effects of dietary supplements that overactivate the Nrf2/ARE system. Curr. Med. Chem.,  2020, 27(13), 2077-2094.
[http://dx.doi.org/10.2174/0929867326666190517113533] [PMID: 31099320] 
[73] 
Brandes, M.S.; Gray, N.E. NRF2 as a therapeutic target in neurodegenerative diseases. ASN Neuro,  2020, 12, 1759091419899782.
[http://dx.doi.org/10.1177/1759091419899782] [PMID: 31964153] 
[74] 
Ma, Y.; Sullivan, J.C.; Schreihofer, D.A. Dietary genistein and equol (4′, 7 isoflavandiol) reduce oxidative stress and protect rats against focal cerebral ischemia. Am. J. Physiol. Regul. Integr. Comp. Physiol.,  2010, 299(3), R871-R877.
[http://dx.doi.org/10.1152/ajpregu.00031.2010] [PMID: 20631292] 
[75] 
Wang, J.; He, C.; Wu, W.Y.; Chen, F.; Wu, Y.Y.; Li, W.Z.; Chen, H.Q.; Yin, Y.Y. Biochanin A protects dopaminergic neurons against lipopolysaccharide-induced damage and oxidative stress in a rat model of Parkinson’s disease. Pharmacol. Biochem. Behav.,  2015, 138, 96-103.
[http://dx.doi.org/10.1016/j.pbb.2015.09.013] [PMID: 26394281] 
[76] 
Shah, Z.A.; Li, R.C.; Ahmad, A.S.; Kensler, T.W.; Yamamoto, M.; Biswal, S.; Doré, S. The flavanol (-)-epicatechin prevents stroke damage through the Nrf2/HO1 pathway. J. Cereb. Blood Flow Metab.,  2010, 30(12), 1951-1961.
[http://dx.doi.org/10.1038/jcbfm.2010.53] [PMID: 20442725] 
[77] 
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(1), 73-79.
[http://dx.doi.org/10.1016/j.bbr.2010.01.017] [PMID: 20096732] 
[78] 
Rodrigo, R.; Fernández-Gajardo, R.; Gutiérrez, R.; Matamala, J.M.; Carrasco, R.; Miranda-Merchak, A.; Feuerhake, W. Oxidative stress and pathophysiology of ischemic stroke: novel therapeutic opportunities. CNS Neurol. Disord. Drug Targets,  2013, 12(5), 698-714.
[http://dx.doi.org/10.2174/1871527311312050015] [PMID: 23469845] 
[79] 
Kong, D.; Yan, Y.; He, X.Y.; Yang, H.; Liang, B.; Wang, J.; He, Y.; Ding, Y.; Yu, H. Effects of resveratrol on the mechanisms of antioxidants and estrogen in Alzheimer’s disease. BioMed Res. Int.,  2019, 2019, 8983752.
[http://dx.doi.org/10.1155/2019/8983752] [PMID: 31016201] 
[80] 
Toth, P.; Tarantini, S.; Tucsek, Z.; Ashpole, N.M.; Sosnowska, D.; Gautam, T.; Ballabh, P.; Koller, A.; Sonntag, W.E.; Csiszar, A.; Ungvari, Z. Resveratrol treatment rescues neurovascular coupling in aged mice: Role of improved cerebromicrovascular endothelial function and downregulation of NADPH oxidase. Am. J. Physiol. Heart Circ. Physiol.,  2014, 306(3), H299-H308.
[http://dx.doi.org/10.1152/ajpheart.00744.2013] [PMID: 24322615] 
[81] 
Liang, G.; Shi, B.; Luo, W.; Yang, J. The protective effect of caffeic acid on global cerebral ischemia-reperfusion injury in rats. Behav. Brain Funct.,  2015, 11, 18-27.
[http://dx.doi.org/10.1186/s12993-015-0064-x] [PMID: 25907417] 
[82] 
Surapaneni, S.; Prakash, T.; Ansari, M.; Manjunath, P.M.; Kotresha, D.; Goli, D. Study on cerebroprotective actions of Clerodendron glandulosumleaves extract against long term bilateral common carotid artery occlusion in rats. Biomed. Pharmacother.,  2016, 80, 87-94.
[http://dx.doi.org/10.1016/j.biopha.2016.02.029] [PMID: 27133043] 
[83] 
Nejad, K.H.; Sarkaki, A.; Dianat, M.; Farbood, Y.; Badavi, M.; Gharib-Naseri, M.K. Preventive effects of ellagic acid on nucleus tractus solitarius electrical activity and oxidative stress altered by cerebral global ischemia/reperfusion in rat. Braz. Arch. Biol. Technol.,  2017, 60, 1-11.
[84] 
Jittiwat, J.; Chonpathompikunlert, P.; Sukketsiri, W. Neuroprotective effects of Apium graveolens against focal cerebral ischemia occur partly via antioxidant, anti-inflammatory, and anti-apoptotic pathways. J. Sci. Food Agric.,  2021, 101(6), 2256-2263.
[http://dx.doi.org/10.1002/jsfa.10846] [PMID: 33006386] 
[85] 
Brivio, P.; Sbrini, G.; Corsini, G.; Paladini, M.S.; Racagni, G.; Molteni, R.; Calabrese, F. Chronic restraint stress inhibits the response to a second hit in adult male rats: a role for BDNF signaling. Int. J. Mol. Sci.,  2020, 21(17), 6261-6272.
[http://dx.doi.org/10.3390/ijms21176261] [PMID: 32872446] 
[86] 
Liu, R.; Zhang, T.; Yang, H.; Lan, X.; Ying, J.; Du, G. The flavonoid apigenin protects brain neurovascular coupling against amyloid-25-35-induced toxicity in mice. J. Alzheimers Dis.,  2011, 24(1), 85-100.
[http://dx.doi.org/10.3233/JAD-2010-101593] [PMID: 21297270] 
[87] 
Liu, R.; Zhang, T.T.; Zhou, D.; Bai, X.Y.; Zhou, W.L.; Huang, C.; Song, J.K.; Meng, F.R.; Wu, C.X.; Li, L.; Du, G.H. Quercetin protects against the Aβ(25-35)-induced amnesic injury: involvement of inactivation of rage-mediated pathway and conservation of the NVU. Neuropharmacology,  2013, 67, 419-431.
[http://dx.doi.org/10.1016/j.neuropharm.2012.11.018] [PMID: 23231807] 
[88] 
Oh, S.B.; Park, H.R.; Jang, Y.J.; Choi, S.Y.; Son, T.G.; Lee, J. Baicalein attenuates impaired hippocampal neurogenesis and the neurocognitive deficits induced by γ-ray radiation. Br. J. Pharmacol.,  2013, 168(2), 421-431.
[http://dx.doi.org/10.1111/j.1476-5381.2012.02142.x] [PMID: 22891631] 
[89] 
Wiciński, M.; Malinowski, B.; Węclewicz, M.M.; Grześk, E.; Grześk, G. Resveratrol increases ierum BDNF concentrations and reduces vascular smooth muscle cells contractility via a NOS-3-independent mechanism. BioMed Res. Int.,  2017, 2017, 9202954.
[http://dx.doi.org/10.1155/2017/9202954] [PMID: 28261618] 
[90] 
Calahorra, J.; Shenk, J.; Wielenga, V.H.; Verweij, V.; Geenen, B.; Dederen, P.J.; Peinado, M.Á.; Siles, E.; Wiesmann, M.; Kiliaan, A.J. Hydroxytyrosol, the major phenolic compound of olive oil, as an acute therapeutic strategy after ischemic stroke. Nutrients,  2019, 11(10), 1-31.
[http://dx.doi.org/10.3390/nu11102430] [PMID: 31614692] 
[91] 
Sánchez-Rabaneda, F.; Jáuregui, O.; Casals, I.; Andrés-Lacueva, C.; Izquierdo-Pulido, M.; Lamuela-Raventós, R-M. Liquid chromatographic/electrospray ionization tandem mass spectrometric study of the phenolic composition of cocoa (Theobroma cacao). J. Mass Spectrom.,  2003, 38(1), 35-42.
[http://dx.doi.org/10.1002/jms.395] [PMID: 12526004] 
[92] 
Socci, V.; Tempesta, D.; Desideri, G.; De Gennaro, L.; Ferrara, M. Enhancing human cognition with cocoa flavonoids. Front. Nutr.,  2017, 4, 19.
[http://dx.doi.org/10.3389/fnut.2017.00019] [PMID: 28560212] 
[93] 
Haskell-Ramsay, C.F.; Schmitt, J.; Actis-Goretta, L. The impact of epicatechin on human cognition: the role of cerebral blood flow. Nutrients,  2018, 10(8), 986.
[http://dx.doi.org/10.3390/nu10080986] [PMID: 30060538] 
[94] 
Barrera-Reyes, P.K.; de Lara, J.C-F.; González-Soto, M.; Tejero, M.E. Effects of cocoa-derived polyphenols on cognitive function in humans. Systematic review and analysis of methodological aspects. Plant Foods Hum. Nutr.,  2020, 75(1), 1-11.
[http://dx.doi.org/10.1007/s11130-019-00779-x] [PMID: 31933112] 
[95] 
Fisher, N.D.L.; Sorond, F.A.; Hollenberg, N.K. Cocoa flavanols and brain perfusion. J. Cardiovasc. Pharmacol.,  2006, 47, S210-S214.
[http://dx.doi.org/10.1097/00005344-200606001-00017] 
[96] 
Faridi, Z.; Njike, V.Y.; Dutta, S.; Ali, A.; Katz, D.L. Acute dark chocolate and cocoa ingestion and endothelial function: a randomized controlled crossover trial. Am. J. Clin. Nutr.,  2008, 88(1), 58-63.
[http://dx.doi.org/10.1093/ajcn/88.1.58] [PMID: 18614724] 
[97] 
Monahan, K.D.; Feehan, R.P.; Kunselman, A.R.; Preston, A.G.; Miller, D.L.; Lott, M.E. Dose-dependent increases in flow-mediated dilation following acute cocoa ingestion in healthy older adults. J. Appl. Physiol.,  2011, 111(6), 1568-1574.
[http://dx.doi.org/10.1152/japplphysiol.00865.2011] [PMID: 21903881] 
[98] 
Katz, D.L.; Doughty, K.; Ali, A. Cocoa and chocolate in human health and disease. Antioxid. Redox Signal.,  2011, 15(10), 2779-2811.
[http://dx.doi.org/10.1089/ars.2010.3697] [PMID: 21470061] 
[99] 
Massee, L.A.; Ried, K.; Pase, M.; Travica, N.; Yoganathan, J.; Scholey, A.; Macpherson, H.; Kennedy, G.; Sali, A.; Pipingas, A. The acute and sub-chronic effects of cocoa flavanols on mood, cognitive and cardiovascular health in young healthy adults: a randomized, controlled trial. Front. Pharmacol.,  2015, 6, 93.
[http://dx.doi.org/10.3389/fphar.2015.00093] [PMID: 26042037] 
[100] 
Bolduc, V.; Baraghis, E.; Duquette, N.; Thorin-Trescases, N.; Lambert, J.; Lesage, F.; Thorin, E. Catechin prevents severe dyslipidemia-associated changes in wall biomechanics of cerebral arteries in LDLr-/-:hApoB+/+ mice and improves cerebral blood flow. Am. J. Physiol. Heart Circ. Physiol.,  2012, 302(6), H1330-H1339.
[http://dx.doi.org/10.1152/ajpheart.01044.2011] [PMID: 22268108] 
[101] 
Nehlig, A. The neuroprotective effects of cocoa flavanol and its influence on cognitive performance. Br. J. Clin. Pharmacol.,  2013, 75(3), 716-727.
[http://dx.doi.org/10.1111/j.1365-2125.2012.04378.x] [PMID: 22775434] 
[102] 
Wightman, E.L.; Haskell, C.F.; Forster, J.S.; Veasey, R.C.; Kennedy, D.O. Epigallocatechin gallate, cerebral blood flow parameters, cognitive performance and mood in healthy humans: a double-blind, placebo-controlled, crossover investigation. Hum. Psychopharmacol.,  2012, 27(2), 177-186.
[http://dx.doi.org/10.1002/hup.1263] [PMID: 22389082] 
[103] 
Salom, J.B.; Castelló-Ruiz, M.; Pérez-Asensio, F.J.; Burguete, M.C.; Torregrosa, G.; Alborch, E. Acute effects of three isoflavone class phytoestrogens and a mycoestrogen on cerebral microcirculation. Phytomedicine,  2007, 14(7-8), 556-562.
[http://dx.doi.org/10.1016/j.phymed.2006.12.017] [PMID: 17291736] 
[104] 
Gao, Y.; Gu, W.; Chen, L.; Xu, Z.; Li, Y. The role of daidzein-loaded sterically stabilized solid lipid nanoparticles in therapy for cardio-cerebrovascular diseases. Biomaterials,  2008, 29(30), 4129-4136.
[http://dx.doi.org/10.1016/j.biomaterials.2008.07.008] [PMID: 18667234] 
[105] 
Kennedy, D.O.; Wightman, E.L.; Reay, J.L.; Lietz, G.; Okello, E.J.; Wilde, A.; Haskell, C.F. Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans: a double-blind, placebo-controlled, crossover investigation. Am. J. Clin. Nutr.,  2010, 91(6), 1590-1597.
[http://dx.doi.org/10.3945/ajcn.2009.28641] [PMID: 20357044] 
[106] 
Wightman, E.L.; Reay, J.L.; Haskell, C.F.; Williamson, G.; Dew, T.P.; Kennedy, D.O. Effects of resveratrol alone or in combination with piperine on cerebral blood flow parameters and cognitive performance in human subjects: a randomised, double-blind, placebo-controlled, cross-over investigation. Br. J. Nutr.,  2014, 112(2), 203-213.
[http://dx.doi.org/10.1017/S0007114514000737] [PMID: 24804871] 
[107] 
Wightman, E.L.; Haskell-Ramsay, C.F.; Reay, J.L.; Williamson, G.; Dew, T.; Zhang, W.; Kennedy, D.O. The effects of chronic trans-resveratrol supplementation on aspects of cognitive function, mood, sleep, health and cerebral blood flow in healthy, young humans. Br. J. Nutr.,  2015, 114(9), 1427-1437.
[http://dx.doi.org/10.1017/S0007114515003037] [PMID: 26344014] 
[108] 
Evans, H.M.; Howe, P.R.C.; Wong, R.H. Clinical evaluation of effects of chronic resveratrol supplementation on cerebrovascular function, cognition, mood, physical function and general well-being in Postmenopausal Women. Rationale and study design. Nutrients,  2016, 8(3), 150-163.
[http://dx.doi.org/10.3390/nu8030150] [PMID: 27005658] 
[109] 
Chan, S.L.; Capdeville-Atkinson, C.; Atkinson, J. Red wine polyphenols improve endothelium-dependent dilation in rat cerebral arterioles. J. Cardiovasc. Pharmacol.,  2008, 51(6), 553-558.
[http://dx.doi.org/10.1097/FJC.0b013e3181760fa5] [PMID: 18496148] 
[110] 
Chan, S.L.; Tabellion, A.; Bagrel, D.; Perrin-Sarrado, C.; Capdeville-Atkinson, C.; Atkinson, J. Impact of chronic treatment with red wine polyphenols (RWP) on cerebral arterioles in the spontaneous hypertensive rat. J. Cardiovasc. Pharmacol.,  2008, 51(3), 304-310.
[http://dx.doi.org/10.1097/FJC.0b013e318163a946] [PMID: 18356696] 
[111] 
Haskell-Ramsay, C.F.; Stuart, R.C.; Okello, E.J.; Watson, A.W. Cognitive and mood improvements following acute supplementation with purple grape juice in healthy young adults. Eur. J. Nutr.,  2017, 56(8), 2621-2631.
[http://dx.doi.org/10.1007/s00394-017-1454-7] [PMID: 28429081] 
[112] 
Jackson, P.A.; Wightman, E.L.; Veasey, R.; Forster, J.; Khan, J.; Saunders, C.; Mitchell, S.; Haskell-Ramsay, C.F.; Kennedy, D.O. A randomized, crossover study of the acute cognitive and cerebral blood flow effects of phenolic, nitrate and botanical beverages in young, healthy humans. Nutrients,  2020, 12(8), 2254-2269.
[http://dx.doi.org/10.3390/nu12082254] [PMID: 32731478] 
[113] 
Wightman, E.L.; Jackson, P.A.; Khan, J.; Forster, J.; Heiner, F.; Feistel, B.; Suarez, C.G.; Pischel, I.; Kennedy, D.O. The acute and chronic cognitive and cerebral blood flow effects of a Sideritis scardica (Greek mountain tea) extract: a double blind, randomized, placebo controlled, parallel groups study in healthy humans. Nutrients,  2018, 10(8), 955-977.
[http://dx.doi.org/10.3390/nu10080955] [PMID: 30042362] 
Cite As
Current Medicinal Chemistry

Polyphenols’ Effect on Cerebrovascular Health

Abstract
