Tyrosol as a Neuroprotector: Strong Effects of a “Weak” Antioxidant

Mark    B.    Plotnikov; Tatiana    M.    Plotnikova
Abstract

The use of neuroprotective agents for stroke is pathogenetically justified, but the translation of the results of preclinical studies of neuroprotectors into clinical practice has been a noticeable failure. One of the leading reasons for these failures is the one-target mechanism of their activity. p-Tyrosol (Tyr), a biophenol, is present in a variety of natural sources, mainly in foods, such as olive oil and wine. Tyr has a wide spectrum of biological activity: antioxidant, stress-protective, anti-inflammatory, anticancer, cardioprotective, neuroprotective and many others. This review analyzes data on the neuroprotective, antioxidant, anti-inflammatory, anti-apoptotic and other kinds of Tyr activity as well as data on the pharmacokinetics of the substance. The data presented in the review substantiate the acceptability of tyr as the basis for the development of a new neuroprotective drug with multitarget activity for the treatment of ischemic stroke. Tyr is a promising molecule for the development of an effective neuroprotective agent for use in ischemic stroke.
Keywords: Ischemic stroke, p-tyrosol, neuroprotective activity, antioxidant activity, anti-inflammatory activity, anti-apoptotic activity, pharmacokinetics.
Graphical Abstract

[1] 
Hachinski, V.; Donnan, G.A.; Gorelick, P.B.; Hacke, W.; Cramer, S.C.; Kaste, M.; Fisher, M.; Brainin, M.; Buchan, A.M.; Lo, E.H.; Skolnick, B.E.; Furie, K.L.; Hankey, G.J.; Kivipelto, M.; Morris, J.; Rothwell, P.M.; Sacco, R.L.; Smith, S.C., Jr; Wang, Y.; Bryer, A.; Ford, G.A.; Iadecola, C.; Martins, S.C.; Saver, J.; Skvortsova, V.; Bayley, M.; Bednar, M.M.; Duncan, P.; Enney, L.; Finklestein, S.; Jones, T.A.; Kalra, L.; Kleim, J.; Nitkin, R.; Teasell, R.; Weiller, C.; Desai, B.; Goldberg, M.P.; Heiss, W.D.; Saarelma, O.; Schwamm, L.H.; Shinohara, Y.; Trivedi, B.; Wahlgren, N.; Wong, L.K.; Hakim, A.; Norrving, B.; Prudhomme, S.; Bornstein, N.M.; Davis, S.M.; Goldstein, L.B.; Leys, D. Tuomilehto, J. Stroke: working toward a prioritized world agenda. Stroke,  2010, 41(6), 1084-1099.
[http://dx.doi.org/10.1161/STROKEAHA.110.586156] [PMID:  20498453] 
[2] 
Brouns, R.; De Deyn, P.P. The complexity of neurobiological processes in acute ischemic stroke. Clin. Neurol. Neurosurg.,  2009, 111(6), 483-495.
[http://dx.doi.org/10.1016/j.clineuro.2009.04.001] [PMID:  19446389] 
[3] 
Neuhaus, A.A.; Couch, Y.; Hadley, G.; Buchan, A.M. Neuroprotection in stroke: the importance of collaboration and reproducibility. Brain,  2017, 140(8), 2079-2092.
[http://dx.doi.org/10.1093/brain/awx126] [PMID:  28641383] 
[4] 
Sarwal, A.; Hussain, M.S.; Shuaib, A. Neuroprotection in stroke. Translational Stroke Research, Springer Series in Translational Stroke Research; Lapchak, P; Zhang, J., Ed.; Springer: New York, 2012, pp. 79-90.
[5] 
Rajah, G.B.; Ding, Y. Experimental neuroprotection in ischemic stroke: a concise review. Neurosurg. Focus,  2017, 42(4)E2
[http://dx.doi.org/10.3171/2017.1.FOCUS16497]] [PMID:  28366067] 
[6] 
Rogalewski, A.; Schneider, A.; Ringelstein, E.B.; Schäbitz, W.R. Toward a multimodal neuroprotective treatment of stroke. Stroke,  2006, 37(4), 1129-1136.
[http://dx.doi.org/10.1161/01.STR.0000209330.73175.34] [PMID:  16527996] 
[7] 
Lapchak, P.A.; Araujo, D.M. Advances in ischemic stroke treatment: neuroprotective and combination therapies. Expert Opin. Emerg. Drugs,  2007, 12(1), 97-112.
[http://dx.doi.org/10.1517/14728214.12.1.97] [PMID:  17355216] 
[8] 
Fisher, M. New approaches to neuroprotective drug development. Stroke,  2011, 42(1)(Suppl.), S24-S27.
[http://dx.doi.org/10.1161/STROKEAHA.110.592394] [PMID:  21164111] 
[9] 
Panossian, A.; Nikoyan, N.; Ohanyan, N.; Hovhannisyan, A.; Abrahamyan, H.; Gabrielyan, E.; Wikman, G. Comparative study of rhodiola preparations on behavioral despair of rats. Phytomedicine,  2008, 15(1-2), 84-91.
[http://dx.doi.org/10.1016/j.phymed.2007.10.003] [PMID:  18054474] 
[10] 
Saratikov, A.S.; Krasnov, E.A. Rhodiola Rosea (Golden Root): A Valuable Medicinal PlantTomsk University Press.: Tomsk: Russain, , 2004. 
[11] 
Torić, J.; Marković, A.K.; Brala, C.J.; Barbarić, M. Anticancer effects of olive oil polyphenols and their combinations with anticancer drugs. Acta Pharm.,  2019, 69(4), 461-482.
[http://dx.doi.org/10.2478/acph-2019-0052] [PMID:  31639094] 
[12] 
Moskalev, A.; Chernyagina, E.; Tsvetkov, V.; Fedintsev, A.; Shaposhnikov, M.; Krut’ko, V.; Zhavoronkov, A.; Kennedy, B.K. Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic. Aging Cell,  2016, 15(3), 407-415.
[http://dx.doi.org/10.1111/acel.12463] [PMID:  26970234] 
[13] 
Samuel, S.M.; Thirunavukkarasu, M.; Penumathsa, S.V.; Paul, D.; Maulik, N. Akt/FOXO3a/SIRT1-mediated cardioprotection by n-tyrosol against ischemic stress in rat in vivo model of myocardial infarction: switching gears toward survival and longevity. J. Agric. Food Chem.,  2008, 56(20), 9692-9698.
[http://dx.doi.org/10.1021/jf802050h] [PMID:  18826227] 
[14] 
Chernyshova, G.A.; Plotnikov, M.B.; Smol’yakova, V.I.; Golubeva, I.V.; Aliev, O.I.; Tolstikova, T.G.; Krysin, A.P.; Sorokina, I.V. Antiarrhythmic activity of n-tyrosol during acute myocardial ischemia and reperfusion. Bull. Exp. Biol. Med.,  2007, 143(6), 689-691.
[http://dx.doi.org/10.1007/s10517-007-0215-7] [PMID:  18239802] 
[15] 
Plotnikov, M.B.; Chernysheva, G.A.; Smol’yakova, V.I.; Plotnikova, T.M.; Sysolyatin, S.V.; Kryukov, Y.A. Anti-ischemic activity of p-tyrosol under conditions of repeated transient myocardial ischemia in rats. Bull. Exp. Biol. Med.,  2018, 165(5), 625-628.
[http://dx.doi.org/10.1007/s10517-018-4228-1] [PMID:  30225710] 
[16] 
Marrugat, J.; Covas, M.I.; Fitó, M.; Schröder, H.; Miró-Casas, E.; Gimeno, E.; López-Sabater, M.C.; de la Torre, R.; Farré, M. SOLOS Investigators. Effects of differing phenolic content in dietary olive oils on lipids and LDL oxidation--a randomized controlled trial. Eur. J. Nutr.,  2004, 43(3), 140-147.
[http://dx.doi.org/10.1007/s00394-004-0452-8] [PMID:  15168036] 
[17] 
Turner, R.; Etienne, N.; Alonso, M.G.; de Pascual-Teresa, S.; Minihane, A.M.; Weinberg, P.D.; Rimbach, G. Antioxidant and anti-atherogenic activities of olive oil phenolics. Int. J. Vitam. Nutr. Res.,  2005, 75(1), 61-70.
[http://dx.doi.org/10.1024/0300-9831.75.1.61] [PMID:  15830923] 
[18] 
Anter, J.; Tasset, I.; Demyda-Peyrás, S.; Ranchal, I.; Moreno-Millán, M.; Romero-Jimenez, M.; Muntané, J.; Luque de Castro, M.D.; Muñoz-Serrano, A.; Alonso-Moraga, Á. Evaluation of potential antigenotoxic, cytotoxic and proapoptotic effects of the olive oil by-product “alperujo”, hydroxytyrosol, tyrosol and verbascoside. Mutat. Res. Genet. Toxicol. Environ. Mutagen.,  2014, 772, 25-33.
[http://dx.doi.org/10.1016/j.mrgentox.2014.07.002] [PMID:  25308544] 
[19] 
Fragopoulou, E.; Nomikos, T.; Karantonis, H.C.; Apostolakis, C.; Pliakis, E.; Samiotaki, M.; Panayotou, G.; Antonopoulou, S. Biological activity of acetylated phenolic compounds. J. Agric. Food Chem.,  2007, 55(1), 80-89.
[http://dx.doi.org/10.1021/jf0627221] [PMID:  17199317] 
[20] 
Plotnikov, M.B.; Chernysheva, G.A.; Smol’yakova, V.I.; Maslov, M.Y.; Cherkashina, I.V.; Krysin, A.P.; Sorokina, I.V.; Tolstikova, T.G. Effect of n-tyrosol on blood viscosity and platelet aggregation. Bull. Exp. Biol. Med.,  2007, 143(1), 61-63.
[http://dx.doi.org/10.1007/s10517-007-0017-y] [PMID:  18019014] 
[21] 
Panossian, A.; Wikman, G.; Sarris, J. Rosenroot (Rhodiola rosea): traditional use, chemical composition, pharmacology and clinical efficacy. Phytomedicine,  2010, 17(7), 481-493.
[http://dx.doi.org/10.1016/j.phymed.2010.02.002] [PMID:  20378318] 
[22] 
Gris, E.F.; Mattivi, F.; Ferreira, E.A.; Vrhovsek, U.; Filho, D.W.; Pedrosa, R.C.; Bordignon-Luiz, M.T. Stilbenes and tyrosol as target compounds in the assessment of antioxidant and hypolipidemic activity of Vitis vinifera red wines from southern Brazil. J. Agric. Food Chem.,  2011, 59(14), 7954-7961.
[http://dx.doi.org/10.1021/jf2008056] [PMID:  21718033] 
[23] 
Tuck, K.L.; Hayball, P.J. Major phenolic compounds in olive oil: metabolism and health effects. J. Nutr. Biochem.,  2002, 13(11), 636-644.
[http://dx.doi.org/10.1016/S0955-2863(02)00229-2] [PMID:  12550060] 
[24] 
Wang, S-J.; Lee, H-J.; Cho, J-Y.; Park, K-H.; Moon, J-H. Isolation and identification of antioxidant from makgeolli. Korean J. Food Sci. Technol.,  2012, 44, 14-20.
[http://dx.doi.org/10.9721/KJFST.2012.44.1.014] 
[25] 
Owen, R.W.; Giacosa, A.; Hull, W.E.; Haubner, R.; Würtele, G.; Spiegelhalder, B.; Bartsch, H. Olive-oil consumption and health: the possible role of antioxidants. Lancet Oncol.,  2000, 1, 107-112.
[http://dx.doi.org/10.1016/S1470-2045(00)00015-2] [PMID:  11905662] 
[26] 
Bayram, B.; Ozcelik, B.; Schultheiss, G.; Frank, J.; Rimbach, G. A validated method for the determination of selected phenolics in olive oil using high-performance liquid chromatography with coulometric electrochemical detection and a fused-core column. Food Chem.,  2013, 138(2-3), 1663-1669.
[http://dx.doi.org/10.1016/j.foodchem.2012.11.122] [PMID:  23411296] 
[27] 
Bevilacqua, L.; Buiarelli, F.; Coccioli, F.; Jasionowska, R. Identification of compounds in wine by HPLC-tandem mass spectrometry. Ann. Chim.,  2004, 94(9-10), 679-689.
[http://dx.doi.org/10.1002/adic.200490085] [PMID:  15506618] 
[28] 
Sysolyatin, S.V.; Kryukov, Yu.A.; Malykhin, V.V.; Muradov, K.K.; Chernysheva, G.A.; Aliev, O.I.; Smol’yakova, V.I.; Anishchenko, A.M.; Sidekhmenova, A.V.; Shamanaev, A.Yu.; Plotnikov, M.B. p-Tyrosol: a new synthetic method and new types of pharmacological activity. Russ. Chem. Bull.,  2015, 64, 2210-2214.
[http://dx.doi.org/10.1007/s11172-015-1140-y] 
[29] 
Martín, S.; González-Burgos, E.; Carretero, M.E.; Gómez-Serranillos, M.P. Neuroprotective properties of Spanish red wine and its isolated polyphenols on astrocytes. Food Chem.,  2011, 128(1), 40-48.
[http://dx.doi.org/10.1016/j.foodchem.2011.02.074] [PMID:  25214327] 
[30] 
Vauzour, D.; Corona, G.; Spencer, J.P. Caffeic acid, tyrosol and p-coumaric acid are potent inhibitors of 5-S-cysteinyl-dopamine induced neurotoxicity. Arch. Biochem. Biophys.,  2010, 501(1), 106-111.
[http://dx.doi.org/10.1016/j.abb.2010.03.016] [PMID:  20361927] 
[31] 
Vauzour, D.; Vafeiadou, K.; Corona, G.; Pollard, S.E.; Tzounis, X.; Spencer, J.P. Champagne wine polyphenols protect primary cortical neurons against peroxynitrite-induced injury. J. Agric. Food Chem.,  2007, 55(8), 2854-2860.
[http://dx.doi.org/10.1021/jf063304z] [PMID:  17381112] 
[32] 
Hornedo-Ortega, R.; Cerezo, A.B.; Troncoso, A.M.; Garcia-Parrilla, M.C. Corrigendum to “Protective effects of hydroxytyrosol against α-synuclein toxicity on PC12 cells and fibril formation” Food Chem. Toxicol. 120 (2018) 41-49. Food Chem. Toxicol.,  2018, 121, 719.
[http://dx.doi.org/10.1016/j.fct.2018.09.037] [PMID:  30253891] 
[33] 
Ma, C.J.; Kim, Y.C.; Sung, S.H. Compounds with neuroprotective activity from the medicinal plant Machilus thunbergii. J. Enzyme Inhib. Med. Chem.,  2009, 24(5), 1117-1121.
[http://dx.doi.org/10.1080/14756360802632971] [PMID:  19555186] 
[34] 
De La Cruz, J.P.; Ruiz-Moreno, M.I.; Guerrero, A.; Reyes, J.J.; Benitez-Guerrero, A.; Espartero, J.L.; González-Correa, J.A. Differences in the neuroprotective effect of orally administered virgin olive oil (Olea europaea) polyphenols tyrosol and hydroxytyrosol in rats. J. Agric. Food Chem.,  2015, 63(25), 5957-5963.
[http://dx.doi.org/10.1021/acs.jafc.5b00627] [PMID:  26066316] 
[35] 
Bu, Y.; Rho, S.; Kim, J.; Kim, M.Y.; Lee, D.H.; Kim, S.Y.; Choi, H.; Kim, H. Neuroprotective effect of tyrosol on transient focal cerebral ischemia in rats. Neurosci. Lett.,  2007, 414(3), 218-221.
[http://dx.doi.org/10.1016/j.neulet.2006.08.094] [PMID:  17316989] 
[36] 
Atochin, D.N.; Chernysheva, G.A.; Smolyakova, V.I.; Osipenko, A.N.; Logvinov, S.V.; Zhdankina, A.A.; Sysolyatin, S.V.; Kryukov, Y.A.; Anfinogenova, Y.; Plotnikova, T.M.; Plotnikov, M.B. Neuroprotective effects of p-tyrosol after the global cerebral ischemia in rats. Phytomedicine,  2016, 23(7), 784-792.
[http://dx.doi.org/10.1016/j.phymed.2016.03.015] [PMID:  27180226] 
[37] 
Panossian, A.; Hovhannisyan, A.; Abrahamyan, H.; Gabrielyan, E.; Wikman, G. Pharmacokynetics of active constituents of Rhodiola rosea SHR-5 extract Comprehensive Bioactive Natural Products. In: Efficacy, Safety and Clinical Evaluation; Gupta, V.K., Ed.; I. Stadium Press: LLC: Texas, USA,; , 2010; 2, pp. pp 307-329.
[38] 
Guo, N.; Zhu, M.; Han, X.; Sui, D.; Wang, Y.; Yang, Q. The metabolism of salidroside to its aglycone p-tyrosol in rats following the administration of salidroside. PLoS One,  2014, 9(8)e103648
[http://dx.doi.org/10.1371/journal.pone.0103648]] [PMID:  25101641] 
[39] 
Han, T. Effects of salidroside pretreatment on expression of tumor necrosis factor-alpha and permeability of blood brain barrier in rat model of focal cerebral ischemia-reperfusion injury. Asian Pac. J. Trop. Med.,  2013, 6(2), 156-158.
[http://dx.doi.org/10.1016/S1995-7645(13)60014-0] [PMID:  23339921] 
[40] 
Shi, T.Y.; Feng, S.F.; Xing, J.H.; Wu, Y.M.; Li, X.Q.; Zhang, N.; Tian, Z.; Liu, S.B.; Zhao, M.G. Neuroprotective effects of Salidroside and its analogue tyrosol galactoside against focal cerebral ischemia in vivo and H2O2-induced neurotoxicity in vitro. Neurotox. Res.,  2012, 21(4), 358-367.
[http://dx.doi.org/10.1007/s12640-011-9290-7] [PMID:  22095090] 
[41] 
Zou, Y.Q.; Cai, Z.Y.; Mao, Y.F.; Li, J.B.; Deng, X.M. Effects of salidroside-pretreatment on neuroethology of rats after global cerebral ischemia-reperfusion. J. Chin. Integr. Med.,  2009, 7(2), 130-134.
[http://dx.doi.org/10.3736/jcim20090207] [PMID:  19216855] 
[42] 
Han, J.; Xiao, Q.; Lin, Y.H.; Zheng, Z.Z.; He, Z.D.; Hu, J.; Chen, L.D. Neuroprotective effects of salidroside on focal cerebral ischemia/reperfusion injury involve the nuclear erythroid 2-related factor 2 pathway. Neural Regen. Res.,  2015, 10(12), 1989-1996.
[http://dx.doi.org/10.4103/1673-5374.172317] [PMID:  26889188] 
[43] 
Gage, F.H. Neurogenesis in the adult brain. J. Neurosci.,  2002, 22(3), 612-613.
[http://dx.doi.org/10.1523/JNEUROSCI.22-03-00612.2002] [PMID:  11826087] 
[44] 
Koh, S.H.; Park, H.H. Neurogenesis in stroke recovery. Transl. Stroke Res.,  2017, 8(1), 3-13.
[http://dx.doi.org/10.1007/s12975-016-0460-z] [PMID:  26987852] 
[45] 
Khodanovich, M.Y.; Kisel’, A.A.; Chernysheva, G.A.; Smol’yakova, V.I.; Kudabaeva, M.S.; Krutenkova, E.P.; Tyumentseva, Y.A.; Plotnikov, M.B. p-Tyrosol enhances production of new neurons in the hippocampal CA1 field after transient global cerebral ischemia in rats. Bull. Exp. Biol. Med.,  2019, 168(2), 224-228.
[http://dx.doi.org/10.1007/s10517-019-04679-7] [PMID:  31776958] 
[46] 
St-Laurent-Thibault, C.; Arseneault, M.; Longpré, F.; Ramassamy, C. Tyrosol and hydroxytyrosol, two main components of olive oil, protect N2a cells against amyloid-β-induced toxicity. Involvement of the NF-κB signaling. Curr. Alzheimer Res.,  2011, 8(5), 543-551.
[http://dx.doi.org/10.2174/156720511796391845] [PMID:  21605049] 
[47] 
Chen, J.; Zhou, Y.; Mueller-Steiner, S.; Chen, L.F.; Kwon, H.; Yi, S.; Mucke, L.; Gan, L. SIRT1 protects against microglia-dependent amyloid-beta toxicity through inhibiting NF-kappaB signaling. J. Biol. Chem.,  2005, 280(48), 40364-40374.
[http://dx.doi.org/10.1074/jbc.M509329200] [PMID:  16183991] 
[48] 
Dewapriya, P.; Himaya, S.W.; Li, Y.X.; Kim, S.K. Tyrosol exerts a protective effect against dopaminergic neuronal cell death in in vitro model of Parkinson’s disease. Food Chem.,  2013, 141(2), 1147-1157.
[http://dx.doi.org/10.1016/j.foodchem.2013.04.004] [PMID:  23790897] 
[49] 
Taniguchi, K.; Yamamoto, F.; Arai, T.; Yang, J.; Sakai, Y.; Itoh, M.; Mamada, N.; Sekiguchi, M.; Yamada, D.; Saitoh, A.; Kametani, F.; Tamaoka, A.; Araki, Y.M.; Wada, K.; Mizusawa, H.; Araki, W. Tyrosol reduces amyloid-β oligomer neurotoxicity and alleviates synaptic, oxidative, and cognitive disturbances in Alzheimer’s disease model mice. J. Alzheimers Dis.,  2019, 70(3), 937-952.
[http://dx.doi.org/10.3233/JAD-190098] [PMID:  31227651] 
[50] 
García-Moreno, J.C.; Porta de la Riva, M.; Martínez-Lara, E.; Siles, E.; Cañuelo, A. Tyrosol, a simple phenol from EVOO, targets multiple pathogenic mechanisms of neurodegeneration in a C. elegans model of Parkinson’s disease. Neurobiol. Aging,  2019, 82, 60-68.
[http://dx.doi.org/10.1016/j.neurobiolaging.2019.07.003] [PMID:  31404721] 
[51] 
Qu, Z.Q.; Zhou, Y.; Zeng, Y.S.; Lin, Y.K.; Li, Y.; Zhong, Z.Q.; Chan, W.Y. Protective effects of a Rhodiola crenulata extract and salidroside on hippocampal neurogenesis against streptozotocin-induced neural injury in the rat. PLoS One,  2012, 7(1)e29641
[http://dx.doi.org/10.1371/journal.pone.0029641]] [PMID:  22235318] 
[52] 
Vissers, M.N.; Zock, P.L.; Katan, M.B. Bioavailability and antioxidant effects of olive oil phenols in humans: a review. Eur. J. Clin. Nutr.,  2004, 58(6), 955-965.
[http://dx.doi.org/10.1038/sj.ejcn.1601917] [PMID:  15164117] 
[53] 
Covas, M.I.; Miró-Casas, E.; Fitó, M.; Farré-Albadalejo, M.; Gimeno, E.; Marrugat, J.; De La Torre, R. Bioavailability of tyrosol, an antioxidant phenolic compound present in wine and olive oil, in humans. Drugs Exp. Clin. Res.,  2003, 29(5-6), 203-206.
[PMID: 15134375] 
[54] 
Soldevila-Domenech, N.; Boronat, A.; Mateus, J.; Diaz-Pellicer, P.; Matilla, I.; Pérez-Otero, M.; Aldea-Perona, A.; de la Torre, R. Generation of the antioxidant hydroxytyrosol from tyrosol present in beer and red wine in a randomized clinical trial. Nutrients,  2019, 11(9)E2241
[http://dx.doi.org/10.3390/nu11092241]] [PMID:  31540384] 
[55] 
Pérez-Mañá, C.; Farré, M.; Rodríguez-Morató, J.; Papaseit, E.; Pujadas, M.; Fitó, M.; Robledo, P.; Covas, M.I.; Cheynier, V.; Meudec, E.; Escudier, J.L.; de la Torre, R. Moderate consumption of wine, through both its phenolic compounds and alcohol content, promotes hydroxytyrosol endogenous generation in humans. A randomized controlled trial. Mol. Nutr. Food Res.,  2015, 59(6), 1213-1216.
[http://dx.doi.org/10.1002/mnfr.201400842] [PMID:  25712532] 
[56] 
Boronat, A.; Martínez-Huélamo, M.; Cobos, A.; de la Torre, R. Wine and olive oil phenolic compounds interaction in humans. Diseases,  2018, 6(3)E76
[http://dx.doi.org/10.3390/diseases6030076]] [PMID:  30200425] 
[57] 
Chernysheva, G.A.; Smol’niakova, V.I.; Cherkashina, I.V.; Plotnikov, M.B.; Tolstikova, T.G.; Krysin, A.P.; Sorokina, I.V. The main pharmacokinetic parameters of p-tyrosol upon intravenous injection in rats. Eksp. Klin. Farmakol.,  2005, 68(6), 43-44.
[PMID: 16405034] 
[58] 
Guo, N.; Hu, Z.; Fan, X.; Zheng, J.; Zhang, D.; Xu, T.; Yu, T.; Wang, Y.; Li, H. Simultaneous determination of salidroside and its aglycone metabolite p-tyrosol in rat plasma by liquid chromatography-tandem mass spectrometry. Molecules,  2012, 17(4), 4733-4754.
[http://dx.doi.org/10.3390/molecules17044733] [PMID:  22525439] 
[59] 
Chernysheva, G.A.; Smol’niakova, V.I.; Cherkashina, I.V.; Tolstikova, T.G.; Krysin, A.P.; Sorokina, I.V. Pharmacokinetics of p-tyrosol when administered orally. Pharmacy (Basel),  2007, 5, 34-35.
[60] 
Chernyshova, G.A.; Plotnikov, M.B.; Smol’iakova, V.I.; Krasnov, E.A. Main pharmacokinetic parameters of p-tyrosol after intravenous injection in rats. Part III: Distribution of p-tyrosol in rat. Eksp. Klin. Farmakol.,  2011, 74(7), 27-29.
[PMID: 21894765] 
[61] 
D’Antuono, I.; Garbetta, A.; Ciasca, B.; Linsalata, V.; Minervini, F.; Lattanzio, V.M.; Logrieco, A.F.; Cardinali, A. Biophenols from Table Olive cv Bella di Cerignola: chemical characterization, bioaccessibility, and intestinal absorption. J. Agric. Food Chem.,  2016, 64(28), 5671-5678.
[http://dx.doi.org/10.1021/acs.jafc.6b01642] [PMID:  27355793] 
[62] 
Ginsberg, M.D. Life after cerovive: a personal perspective on ischemic neuroprotection in the post-NXY-059 era. Stroke,  2007, 38(6), 1967-1972.
[http://dx.doi.org/10.1161/STROKEAHA.106.479170] [PMID:  17478741] 
[63] 
van der Worp, H.B.; Kappelle, L.J.; Algra, A.; Bär, P.R.; Orgogozo, J.M.; Ringelstein, E.B.; Bath, P.M.; van Gijn, J. TESS Investigators. TESS II Investigators. The effect of tirilazad mesylate on infarct volume of patients with acute ischemic stroke. Neurology,  2002, 58(1), 133-135.
[http://dx.doi.org/10.1212/WNL.58.1.133] [PMID:  11781420] 
[64] 
Zafra-Gómez, A.; Luzón-Toro, B.; Jiménez-Diaz, I.; Ballesteros, O.; Navalón, A. Quantification of phenolic antioxidants in rat cerebrospinal fluid by GC-MS after oral administration of compounds. J. Pharm. Biomed. Anal.,  2010, 53(1), 103-108.
[http://dx.doi.org/10.1016/j.jpba.2010.03.003] [PMID:  20363576] 
[65] 
Tuck, K.L.; Freeman, M.P.; Hayball, P.J.; Stretch, G.L.; Stupans, I. The in vivo fate of hydroxytyrosol and tyrosol, antioxidant phenolic constituents of olive oil, after intravenous and oral dosing of labeled compounds to rats. J. Nutr.,  2001, 131(7), 1993-1996.
[http://dx.doi.org/10.1093/jn/131.7.1993] [PMID:  11435519] 
[66] 
Rodríguez-Morató, J.; Robledo, P.; Tanner, J.A.; Boronat, A.; Pérez-Mañá, C.; Oliver, C.C.Y.; Tyndale, R.F.; de la Torre, R. CYP2D6 and CYP2A6 biotransform dietary tyrosol into hydroxytyrosol. Food Chem.,  2017, 217, 716-725.
[http://dx.doi.org/10.1016/j.foodchem.2016.09.026] [PMID:  27664690] 
[67] 
Boronat, A.; Mateus, J.; Soldevila-Domenech, N.; Guerra, M.; Rodríguez-Morató, J.; Varon, C.; Muñoz, D.; Barbosa, F.; Morales, J.C.; Gaedigk, A.; Langohr, K.; Covas, M.I.; Pérez-Mañá, C.; Fitó, M.; Tyndale, R.F.; de la Torre, R. Cardiovascular benefits of tyrosol and its endogenous conversion into hydroxytyrosol in humans. A randomized, controlled trial. Free Radic. Biol. Med.,  2019, 143, 471-481.
[http://dx.doi.org/10.1016/j.freeradbiomed.2019.08.032] [PMID:  31479717] 
[68] 
Young, J.; Wahle, K.W.; Boyle, S.P. Cytoprotective effects of phenolic antioxidants and essential fatty acids in human blood monocyte and neuroblastoma cell lines: surrogates for neurological damage in vivo. Prostaglandins Leukot. Essent. Fatty Acids,  2008, 78(1), 45-59.
[http://dx.doi.org/10.1016/j.plefa.2007.10.005] [PMID:  18036798] 
[69] 
Atzeri, A.; Lucas, R.; Incani, A.; Peñalver, P.; Zafra-Gómez, A.; Melis, M.P.; Pizzala, R.; Morales, J.C.; Deiana, M. Hydroxytyrosol and tyrosol sulfate metabolites protect against the oxidized cholesterol pro-oxidant effect in Caco-2 human enterocyte-like cells. Food Funct.,  2016, 7(1), 337-346.
[http://dx.doi.org/10.1039/C5FO00074B] [PMID:  26488801] 
[70] 
Muriana, F.J.G.; Montserrat-de la Paz, S.; Lucas, R.; Bermudez, B.; Jaramillo, S.; Morales, J.C.; Abia, R.; Lopez, S. Tyrosol and its metabolites as antioxidative and anti-inflammatory molecules in human endothelial cells. Food Funct.,  2017, 8(8), 2905-2914.
[http://dx.doi.org/10.1039/C7FO00641A] [PMID:  28740975] 
[71] 
Serreli, G.; Deiana, M. Biological relevance of extra virgin olive oil polyphenols metabolites. Antioxidants,  2018, 7(12)E170
[http://dx.doi.org/10.3390/antiox7120170]] [PMID:  30469520] 
[72] 
Roleira, F.M.F.; Tavares-da-Silva, E.J.; Garrido, J.; Borges, F. Antioxidants and stroke: success and pitfalls. Translational Stroke Research, Springer Series in Translational Stroke Research; Lapchak, P; Zhang, J., Ed.; Springer: New York, 2012, pp. 117-143.
[73] 
Barber, P.A.; Demchuk, A.M.; Hirt, L.; Buchan, A.M. Biochemistry of ischemic stroke. Adv. Neurol.,  2003, 92, 151-164.
[PMID: 12760178] 
[74] 
Sanderson, T.H.; Reynolds, C.A.; Kumar, R.; Przyklenk, K.; Hüttemann, M. Molecular mechanisms of ischemia-reperfusion injury in brain: pivotal role of the mitochondrial membrane potential in reactive oxygen species generation. Mol. Neurobiol.,  2013, 47(1), 9-23.
[http://dx.doi.org/10.1007/s12035-012-8344-z] [PMID:  23011809] 
[75] 
Chamorro, Á.; Dirnagl, U.; Urra, X.; Planas, A.M. Neuroprotection in acute stroke: targeting excitotoxicity, oxidative and nitrosative stress, and inflammation. Lancet Neurol.,  2016, 15(8), 869-881.
[http://dx.doi.org/10.1016/S1474-4422(16)00114-9] [PMID:  27180033] 
[76] 
Margaill, I.; Plotkine, M.; Lerouet, D. Antioxidant strategies in the treatment of stroke. Free Radic. Biol. Med.,  2005, 39(4), 429-443.
[http://dx.doi.org/10.1016/j.freeradbiomed.2005.05.003] [PMID:  16043015] 
[77] 
Wang, C.X.; Shuaib, A. Neuroprotective effects of free radical scavengers in stroke. Drugs Aging,  2007, 24(7), 537-546.
[http://dx.doi.org/10.2165/00002512-200724070-00002] [PMID:  17658905] 
[78] 
Cerretani, L.; Bendini, A. Tyrosol is inferior to other simple phenols and polyphenols in antiradical/antioxidant activity when different non-cellular systems are used to evaluate this activityOlives and Olive Oil in Health and Disease Prevention; Preedy, V; Watson, R., Ed.; Academic Press: Amsterdam, 2010, pp. 625-635.
[79] 
Mateos, R.; Domínguez, M.M.; Espartero, J.L.; Cert, A. Antioxidant effect of phenolic compounds, alpha-tocopherol, and other minor components in virgin olive oil. J. Agric. Food Chem.,  2003, 51(24), 7170-7175.
[http://dx.doi.org/10.1021/jf034415q] [PMID:  14611189] 
[80] 
Khymenets, O.; Fitó, M.; Touriño, S.; Muñoz-Aguayo, D.; Pujadas, M.; Torres, J.L.; Joglar, J.; Farré, M.; Covas, M.I.; de la Torre, R. Antioxidant activities of hydroxytyrosol main metabolites do not contribute to beneficial health effects after olive oil ingestion. Drug Metab. Dispos.,  2010, 38(9), 1417-1421.
[http://dx.doi.org/10.1124/dmd.110.032821] [PMID:  20516254] 
[81] 
Le Tutour, B.; Guedon, D. Antioxidative activities of Olea europaea leaves and related phenolic compounds. Phytochemistry,  1992, 31, 1173-1178.
[http://dx.doi.org/10.1016/0031-9422(92)80255-D] 
[82] 
Fusi, J.; Bianchi, S.; Daniele, S.; Pellegrini, S.; Martini, C.; Galetta, F.; Giovannini, L.; Franzoni, F. An in vitro comparative study of the antioxidant activity and SIRT1 modulation of natural compounds. Biomed. Pharmacother.,  2018, 101, 805-819.
[http://dx.doi.org/10.1016/j.biopha.2018.03.006] [PMID:  29525677] 
[83] 
de la Puerta, R.; Martínez Domínguez, M.E.; Ruíz-Gutíerrez, V.; Flavill, J.A.; Hoult, J.R. Effects of virgin olive oil phenolics on scavenging of reactive nitrogen species and upon nitrergic neurotransmission. Life Sci.,  2001, 69(10), 1213-1222.
[http://dx.doi.org/10.1016/S0024-3205(01)01218-8] [PMID:  11508353] 
[84] 
Drummen, G.P.; Makkinje, M.; Verkleij, A.J.; Op den Kamp, J.A.; Post, J.A. Attenuation of lipid peroxidation by antioxidants in rat-1 fibroblasts: comparison of the lipid peroxidation reporter molecules cis-parinaric acid and C11-BODIPY(581/591) in a biological setting. Biochim. Biophys. Acta,  2004, 1636(2-3), 136-150.
[http://dx.doi.org/10.1016/j.bbalip.2003.10.013] [PMID:  15164761] 
[85] 
Vlachogianni, I.C.; Fragopoulou, E.; Kostakis, I.K.; Antonopoulou, S. In vitro assessment of antioxidant activity of tyrosol, resveratrol and their acetylated derivatives. Food Chem.,  2015, 177, 165-173.
[http://dx.doi.org/10.1016/j.foodchem.2014.12.092] [PMID:  25660873] 
[86] 
Pérez-Bonilla, M.; Salido, S.; van Beek, T.A.; Linares-Palomino, P.J.; Altarejos, J.; Nogueras, M.; Sánchez, A. Isolation and identification of radical scavengers in olive tree (Olea europaea) wood. J. Chromatogr. A,  2006, 1112(1-2), 311-318.
[http://dx.doi.org/10.1016/j.chroma.2005.12.055] [PMID:  16426626] 
[87] 
Chen, D.; Fan, J.; Wang, P.; Zhu, L.; Jin, Y.; Peng, Y.; Du, S. Isolation, identification and antioxidative capacity of water-soluble phenylpropanoid compounds from Rhodiola crenulata. Food Chem.,  2012, 134(4), 2126-2133.
[http://dx.doi.org/10.1016/j.foodchem.2012.04.011] [PMID:  23442665] 
[88] 
Dávalos, J.Z.; Valderrama-Negrón, A.C.; Barrios, J.R.; Freitas, V.L.S.; Ribeiro da Silva, M.D.M.C. Energetic and structural properties of two phenolic antioxidants: tyrosol and hydroxytyrosol. J. Phys. Chem. A,  2018, 122(16), 4130-4137.
[http://dx.doi.org/10.1021/acs.jpca.8b00457] [PMID:  29616550] 
[89] 
Di Benedetto, R.; Varì, R.; Scazzocchio, B.; Filesi, C.; Santangelo, C.; Giovannini, C.; Matarrese, P.; D’Archivio, M.; Masella, R. Tyrosol, the major extra virgin olive oil compound, restored intracellular antioxidant defences in spite of its weak antioxidative effectiveness. Nutr. Metab. Cardiovasc. Dis.,  2007, 17(7), 535-545.
[http://dx.doi.org/10.1016/j.numecd.2006.03.005] [PMID:  16928436] 
[90] 
Lee, K.M.; Hur, J.; Lee, Y.; Yoon, B-R.; Choi, S.Y. Protective effects of tyrosol against oxidative damage in L6 muscle cells. Food Sci. Technol. Res.,  2018, 24, 943-947.
[http://dx.doi.org/10.3136/fstr.24.943] 
[91] 
Giovannini, C.; Straface, E.; Modesti, D.; Coni, E.; Cantafora, A.; De Vincenzi, M.; Malorni, W.; Masella, R. Tyrosol, the major olive oil biophenol, protects against oxidized-LDL-induced injury in Caco-2 cells. J. Nutr.,  1999, 129(7), 1269-1277.
[http://dx.doi.org/10.1093/jn/129.7.1269] [PMID:  10395586] 
[92] 
Giovannini, C.; Scazzocchio, B.; Matarrese, P.; Varì, R.; D’Archivio, M.; Di Benedetto, R.; Casciani, S.; Dessì, M.R.; Straface, E.; Malorni, W.; Masella, R. Apoptosis induced by oxidized lipids is associated with up-regulation of p66Shc in intestinal Caco-2 cells: protective effects of phenolic compounds. J. Nutr. Biochem.,  2008, 19(2), 118-128.
[http://dx.doi.org/10.1016/j.jnutbio.2007.01.010] [PMID:  17588737] 
[93] 
Deiana, M.; Corona, G.; Incani, A.; Loru, D.; Rosa, A.; Atzeri, A.; Paola Melis, M.; Assunta Dessì, M. Protective effect of simple phenols from extravirgin olive oil against lipid peroxidation in intestinal Caco-2 cells. Food Chem. Toxicol.,  2010, 48(10), 3008-3016.
[http://dx.doi.org/10.1016/j.fct.2010.07.041] [PMID:  20691238] 
[94] 
Moreno, J.J. Effect of olive oil minor components on oxidative stress and arachidonic acid mobilization and metabolism by macrophages RAW 264.7. Free Radic. Biol. Med.,  2003, 35(9), 1073-1081.
[http://dx.doi.org/10.1016/S0891-5849(03)00465-9] [PMID:  14572610] 
[95] 
Chimi, H.; Morel, I.; Lescoat, G.; Pasdeloup, N.; Cillard, P.; Cillard, J. Inhibition of iron toxicity in rat hepatocyte culture by natural phenolic compounds. Toxicol. In Vitro,  1995, 9(5), 695-702.
[http://dx.doi.org/10.1016/0887-2333(95)00060-L] [PMID:  20650146] 
[96] 
Aissa, I.; Bouaziz, M.; Frikha, F.; Ben Mansourc, R.; Gargouri, Y. Synthesized tyrosyl hydroxyphenylacetate, a novel antioxidant, anti-stress and antibacterial compound. Proc Biochem.,  2012, 47, 2356-2364.
[http://dx.doi.org/10.1016/j.procbio.2012.09.016] 
[97] 
Ma, C.J.; Kim, S.R.; Kim, J.; Kim, Y.C. Meso-dihydroguaiaretic acid and licarin A of Machilus thunbergii protect against glutamate-induced toxicity in primary cultures of a rat cortical cells. Br. J. Pharmacol.,  2005, 146(5), 752-759.
[http://dx.doi.org/10.1038/sj.bjp.0706380] [PMID:  16151440] 
[98] 
Salucci, S.; Burattini, S.; Battistelli, M.; Buontempo, F.; Canonico, B.; Martelli, A.M.; Papa, S.; Falcieri, E. Tyrosol prevents apoptosis in irradiated keratinocytes. J. Dermatol. Sci.,  2015, 80(1), 61-68.
[http://dx.doi.org/10.1016/j.jdermsci.2015.07.002] [PMID:  26166167] 
[99] 
Anrather, J.; Iadecola, C. Inflammation and stroke: An overview. Neurotherapeutics,  2016, 13(4), 661-670.
[http://dx.doi.org/10.1007/s13311-016-0483-x] [PMID:  27730544] 
[100] 
Barone, F.C.; Schmidt, D.B.; Hillegass, L.M.; Price, W.J.; White, R.F.; Feuerstein, G.Z.; Clark, R.K.; Lee, E.V.; Griswold, D.E.; Sarau, H.M. Reperfusion increases neutrophils and leukotriene B4 receptor binding in rat focal ischemia. Stroke,  1992, 23(9), 1337-1347.
[http://dx.doi.org/10.1161/01.STR.23.9.1337] [PMID:  1381529] 
[101] 
Feuerstein, G.Z.; Wang, X.; Barone, F.C. Inflammatory gene expression in cerebral ischemia and trauma. Potential new therapeutic targets. Ann. N. Y. Acad. Sci.,  1997, 825, 179-193.
[http://dx.doi.org/10.1111/j.1749-6632.1997.tb48428.x] [PMID:  9369986] 
[102] 
Gehrmann, J.; Bonnekoh, P.; Miyazawa, T.; Hossmann, K.A.; Kreutzberg, G.W. Immunocytochemical study of an early microglial activation in ischemia. J. Cereb. Blood Flow Metab.,  1992, 12(2), 257-269.
[http://dx.doi.org/10.1038/jcbfm.1992.36] [PMID:  1548298] 
[103] 
Liu, J.; Zhang, C.; Tao, W.; Liu, M. Systematic review and meta-analysis of the efficacy of sphingosine-1-phosphate (S1P) receptor agonist FTY720 (fingolimod) in animal models of stroke. Int. J. Neurosci.,  2013, 123(3), 163-169.
[http://dx.doi.org/10.3109/00207454.2012.749255] [PMID:  23167788] 
[104] 
Fu, Y.; Zhang, N.; Ren, L.; Yan, Y.; Sun, N.; Li, Y.J.; Han, W.; Xue, R.; Liu, Q.; Hao, J.; Yu, C.; Shi, F.D.; Hao, J.; Yu, C.; Shi, F.D. Impact of an immune modulator fingolimod on acute ischemic stroke. Proc. Natl. Acad. Sci. USA,  2014, 111(51), 18315-18320.
[http://dx.doi.org/10.1073/pnas.1416166111] [PMID:  25489101] 
[105] 
Luo, G.; Huang, Y.; Mo, D.; Ma, N.; Gao, F.; Song, L.; Sun, X.; Xu, X.; Liu, L.; Huo, X.; Wang, B.; Li, X.; Jia, B.; Deng, Y.; Zhang, X.; Fernandez-Escobar, A.; Peng, G.; Miao, Z. Tyrosol attenuates pro-inflammatory cytokines from cultured astrocytes and NF-κB activation in in vitro oxygen glucose deprivation. Neurochem. Int.,  2018, 121, 140-145.
[http://dx.doi.org/10.1016/j.neuint.2018.10.006] [PMID:  30291953] 
[106] 
Lambertsen, K.L.; Biber, K.; Finsen, B. Inflammatory cytokines in experimental and human stroke. J. Cereb. Blood Flow Metab.,  2012, 32(9), 1677-1698.
[http://dx.doi.org/10.1038/jcbfm.2012.88] [PMID:  22739623] 
[107] 
Je, I.G.; Kim, D.S.; Kim, S.W.; Lee, S.; Lee, H.S.; Park, E.K.; Khang, D.; Kim, S.H. Tyrosol suppresses allergic inflammation by inhibiting the activation of phosphoinositide 3-kinase in mast cells. PLoS One,  2015, 10(6)e0129829
[http://dx.doi.org/10.1371/journal.pone.0129829]] [PMID:  26068872] 
[108] 
Giovannini, L.; Migliori, M.; Filippi, C.; Origlia, N.; Panichi, V.; Falchi, M.; Bertelli, A.A.; Bertelli, A. Inhibitory activity of the white wine compounds, tyrosol and caffeic acid, on lipopolysaccharide-induced tumor necrosis factor-alpha release in human peripheral blood mononuclear cells. Int. J. Tissue React.,  2002, 24(2), 53-56.
[PMID:  12182233] 
[109] 
De Stefano, D.; Maiuri, M.C.; Carnuccio, R. Effects of Tyrosol on RAW 264.7 Macrophages activated by interferon-γ and gliadin Olives and Olive Oil in Health and Disease Prevention; Preedy, V.; Watson, R; Carnuccio, R., Ed.; Academic Press: Amsterdam, 2010, pp. 1263-1268.
[110] 
De Stefano, D.; Maiuri, M.C.; Simeon, V.; Grassia, G.; Soscia, A.; Cinelli, M.P.; Carnuccio, R. Lycopene, quercetin and tyrosol prevent macrophage activation induced by gliadin and IFN-gamma. Eur. J. Pharmacol.,  2007, 566(1-3), 192-199.
[http://dx.doi.org/10.1016/j.ejphar.2007.03.051] [PMID:  17477920] 
[111] 
de la Puerta, R.; Ruiz Gutierrez, V.; Hoult, J.R.S. Inhibition of leukocyte 5-lipoxygenase by phenolics from virgin olive oil. Biochem. Pharmacol.,  1999, 57(4), 445-449.
[http://dx.doi.org/10.1016/S0006-2952(98)00320-7] [PMID:  9933033] 
[112] 
Yadav, T.C.; Kumar, N.; Raj, U.; Goel, N.; Vardawaj, P.K.; Prasad, R.; Pruthi, V. Exploration of interaction mechanism of tyrosol as a potent anti-inflammatory agent. J. Biomol. Struct. Dyn.,  2020, 38(2), 382-397.
[http://dx.doi.org/10.1080/07391102.2019.1575283] [PMID:  30887884] 
[113] 
Serreli, G.; Melis, M.P.; Corona, G.; Deiana, M. Modulation of LPS-induced nitric oxide production in intestinal cells by hydroxytyrosol and tyrosol metabolites: Insight into the mechanism of action. Food Chem. Toxicol.,  2019, 125, 520-527.
[http://dx.doi.org/10.1016/j.fct.2019.01.039] [PMID:  30735752] 
[114] 
Chang, C-Y.; Huang, I-T.; Shih, H-J.; Chang, Y-Y.; Kao, M-C.; Shih, P-C.; Huang, C-J. Cluster of differentiation 14 and toll-like receptor 4 are involved in the anti-inflammatory effects of tyrosol. J. Funct. Foods,  2019, 53, 93-104.
[http://dx.doi.org/10.1016/j.jff.2018.12.011] 
[115] 
Carluccio, M.A.; Siculella, L.; Ancora, M.A.; Massaro, M.; Scoditti, E.; Storelli, C.; Visioli, F.; Distante, A.; De Caterina, R. Olive oil and red wine antioxidant polyphenols inhibit endothelial activation: antiatherogenic properties of Mediterranean diet phytochemicals. Arterioscler. Thromb. Vasc. Biol.,  2003, 23(4), 622-629.
[http://dx.doi.org/10.1161/01.ATV.0000062884.69432.A0] [PMID:  12615669] 
[116] 
Manna, C.; Napoli, D.; Cacciapuoti, G.; Porcelli, M.; Zappia, V. Olive oil phenolic compounds inhibit homocysteine-induced endothelial cell adhesion regardless of their different antioxidant activity. J. Agric. Food Chem.,  2009, 57(9), 3478-3482.
[http://dx.doi.org/10.1021/jf8037659] [PMID:  19358606] 
[117] 
Kim, Y.Y.; Lee, S.; Kim, M.J.; Kang, B.C.; Dhakal, H.; Choi, Y.A.; Park, P.H.; Choi, H.; Shin, T.Y.; Choi, H.G.; Kwon, T.K.; Khang, D.; Kim, S.H. Tyrosol attenuates lipopolysaccharide-induced acute lung injury by inhibiting the inflammatory response and maintaining the alveolar capillary barrier. Food Chem. Toxicol.,  2017, 109(Pt 1), 526-533.
[http://dx.doi.org/10.1016/j.fct.2017.09.053] [PMID:  28974441] 
[118] 
Wang, W.C.; Xia, Y.M.; Yang, B.; Su, X.N.; Chen, J.K.; Li, W.; Jiang, T. Protective effects of tyrosol against LPS-induced acute lung injury via inhibiting NF-κB and AP-1 activation and activating the HO-1/Nrf2 pathways. Biol. Pharm. Bull.,  2017, 40(5), 583-593.
[http://dx.doi.org/10.1248/bpb.b16-00756] [PMID:  28190857] 
[119] 
Sato, K.; Mihara, Y.; Kanai, K.; Yamashita, Y.; Kimura, Y.; Itoh, N. Relative potency of tyrosol in the treatment of endotoxin-induced uveitis in rats. J. Vet. Med. Sci.,  2016, 78(10), 1631-1634.
[http://dx.doi.org/10.1292/jvms.16-0254] [PMID:  27350009] 
[120] 
Miles, E.A.; Zoubouli, P.; Calder, P.C. Differential anti-inflammatory effects of phenolic compounds from extra virgin olive oil identified in human whole blood cultures. Nutrition,  2005, 21(3), 389-394.
[http://dx.doi.org/10.1016/j.nut.2004.06.031] [PMID:  15797683] 
[121] 
Dell’Agli, M.; Fagnani, R.; Galli, G.V.; Maschi, O.; Gilardi, F.; Bellosta, S.; Crestani, M.; Bosisio, E.; De Fabiani, E.; Caruso, D. Olive oil phenols modulate the expression of metalloproteinase 9 in THP-1 cells by acting on nuclear factor-kappaB signaling. J. Agric. Food Chem.,  2010, 58(4), 2246-2252.
[http://dx.doi.org/10.1021/jf9042503] [PMID:  20102205] 
[122] 
Palmerini, C.A.; Carlini, E.; Saccardi, C.; Servili, M.; Montedoro, G.; Arienti, G. Activity of olive oil phenols on lymphomonocyte cytosolic calcium. J. Nutr. Biochem.,  2005, 16(2), 109-113.
[http://dx.doi.org/10.1016/j.jnutbio.2004.10.006] [PMID:  15681170] 
[123] 
Green, D.R.; Reed, J.C. Mitochondria and apoptosis. Science,  1998, 281(5381), 1309-1312.
[http://dx.doi.org/10.1126/science.281.5381.1309] [PMID:  9721092] 
[124] 
Sun, Y.; Liu, W.Z.; Liu, T.; Feng, X.; Yang, N.; Zhou, H.F. Signaling pathway of MAPK/ERK in cell proliferation, differentiation, migration, senescence and apoptosis. J. Recept. Signal Transduct. Res.,  2015, 35(6), 600-604.
[http://dx.doi.org/10.3109/10799893.2015.1030412] [PMID:  26096166] 
[125] 
Mosca, L.; Lendaro, E.; d’Erme, M.; Marcellini, S.; Moretti, S.; Rosei, M.A. 5-S-Cysteinyl-dopamine effect on the human dopaminergic neuroblastoma cell line SH-SY5Y. Neurochem. Int.,  2006, 49(3), 262-269.
[http://dx.doi.org/10.1016/j.neuint.2006.01.023] [PMID:  16549224] 
[126] 
Sun, L.; Isaak, C.K.; Zhou, Y.; Petkau, J.C. O, K.; Liu, Y.; Siow, Y.L. Salidroside and tyrosol from Rhodiola protect H9c2 cells from ischemia/reperfusion-induced apoptosis. Life Sci.,  2012, 91(5-6), 151-158.
[http://dx.doi.org/10.1016/j.lfs.2012.06.026] [PMID:  22771701] 
[127] 
Chen, H.H.; Chen, Y.T.; Huang, Y.W.; Tsai, H.J.; Kuo, C.C. 4-Ketopinoresinol, a novel naturally occurring ARE activator, induces the Nrf2/HO-1 axis and protects against oxidative stress-induced cell injury via activation of PI3K/AKT signaling. Free Radic. Biol. Med.,  2012, 52(6), 1054-1066.
[http://dx.doi.org/10.1016/j.freeradbiomed.2011.12.012] [PMID:  22245092] 
[128] 
Ott, E.O.; Lechner, H.; Aranibar, A. High blood viscosity syndrome in cerebral infarction. Stroke,  1974, 5(3), 330-333.
[http://dx.doi.org/10.1161/01.STR.5.3.330] [PMID:  4836535] 
[129] 
Fisher, M.; Meiselman, H.J. Hemorheological factors in cerebral ischemia. Stroke,  1991, 22(9), 1164-1169.
[http://dx.doi.org/10.1161/01.STR.22.9.1164] [PMID:  1833861] 
[130] 
van Kooten, F.; Ciabattoni, G.; Patrono, C.; Dippel, D.W.; Koudstaal, P.J. Platelet activation and lipid peroxidation in patients with acute ischemic stroke. Stroke,  1997, 28(8), 1557-1563.
[http://dx.doi.org/10.1161/01.STR.28.8.1557] [PMID:  9259748] 
[131] 
McCarty, M.F.; O’Keefe, J.H.; DiNicolantonio, J.J. Pentoxifylline for vascular health: a brief review of the literature. Open Heart,  2016, 3(1)e000365
[http://dx.doi.org/10.1136/openhrt-2015-000365]] [PMID:  26870389] 
[132] 
Karković, M.A.; Torić, J.; Barbarić, M.; Jakobušić, B.C.; Torić, J.; Barbarić, M.; Jakobušić, B.C. Hydroxytyrosol, tyrosol and derivatives and their potential effects on human health. Molecules,  2019, 24(10)E2001
[http://dx.doi.org/10.3390/molecules24102001]] [PMID:  31137753] 
[133] 
Vauzour, D. Dietary polyphenols as modulators of brain functions: biological actions and molecular mechanisms underpinning their beneficial effects. Oxid. Med. Cell. Longev.,  2012, 2012914273
[http://dx.doi.org/10.1155/2012/914273]] [PMID:  22701758] 
[134] 
Obied, H.K.; Prenzler, P.D.; Omar, S.H.; Ismael, R.; Servili, M.; Esposto, S.; Taticchi, A.; Selvaggini, R.; Urbani, S. Pharmacology of olive biophenols. Advances in Molecular Toxicology; Fishbein, J.C., Ed.; Elsevier Science B. V.: Oxford, UK, 2012, Vol. 6, pp. 195-242.
[http://dx.doi.org/10.1016/B978-0-444-59389-4.00006-9] 
[135] 
Angeloni, C.; Malaguti, M.; Barbalace, M.C.; Hrelia, S. Bioactivity of Olive Oil Phenols in Neuroprotection. Int. J. Mol. Sci.,  2017, 18(11)E2230
[http://dx.doi.org/10.3390/ijms18112230]] [PMID:  29068387] 
[136] 
Khoshnam, S.E.; Winlow, W.; Farzaneh, M.; Farbood, Y.; Moghaddam, H.F. Pathogenic mechanisms following ischemic stroke. Neurol. Sci.,  2017, 38(7), 1167-1186.
[http://dx.doi.org/10.1007/s10072-017-2938-1] [PMID:  28417216] 
[137] 
McDonald, S.; Prenzler, P.; Antolovich, M.; Robards, K. Phenolic content and antioxidant activity of olive extracts. Food Chem.,  2001, 73, 73-84.
[http://dx.doi.org/10.1016/S0308-8146(00)00288-0] 
[138] 
Anter, J.; Campos-Sánchez, J.; Hamss, R.E.; Rojas-Molina, M.; Muñoz-Serrano, A.; Analla, M.; Alonso-Moraga, A. Modulation of genotoxicity by extra-virgin olive oil and some of its distinctive components assessed by use of the Drosophila wing-spot test. Mutat. Res.,  2010, 703(2), 137-142.
[http://dx.doi.org/10.1016/j.mrgentox.2010.08.012] [PMID:  20732449] 
[139] 
Nousis, L.; Doulias, P.T.; Aligiannis, N.; Bazios, D.; Agalias, A.; Galaris, D.; Mitakou, S. DNA protecting and genotoxic effects of olive oil related components in cells exposed to hydrogen peroxide. Free Radic. Res.,  2005, 39(7), 787-795.
[http://dx.doi.org/10.1080/10715760500045806] [PMID:  16036359] 
Cite As
Current Neuropharmacology

Tyrosol as a Neuroprotector: Strong Effects of a “Weak” Antioxidant

Abstract

Graphical Abstract
