Neuroprotective properties and mechanisms of resveratrol in in vitro and in vivo experimental cerebral stroke models

ACS Chemical Neuroscience

Volumn 4, Issue 8, 2013, Pages 1151-1162

  Singh, Nilendra ^a   Agrawal, Megha ^a   Doré, Sylvain ^a  

^a UNIVERSITY OF FLORIDA COLLEGE OF MEDICINE   (United States)

Author keywords

Neurodegenerative disease; neurons; stilbene

Indexed keywords

RESVERATROL;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ANTIINFLAMMATORY ACTIVITY; ANTIOXIDANT ACTIVITY; BRAIN; CEREBROVASCULAR ACCIDENT; DRUG BIOAVAILABILITY; DRUG INDUCED HEADACHE; DRUG METABOLISM; HEART; HUMAN; IN VITRO STUDY; IN VIVO STUDY; MOUSE; NAUSEA; NEUROPROTECTION; NONHUMAN; PRIORITY JOURNAL; REVIEW; SINGLE DRUG DOSE;

ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; APOPTOSIS; BIOLOGICAL AVAILABILITY; BRAIN; DISEASE MODELS, ANIMAL; DRUG EVALUATION, PRECLINICAL; GERBILLINAE; HUMANS; MICE; NEUROPROTECTIVE AGENTS; OXIDATIVE STRESS; RATS; STILBENES; STROKE;

EID: 84883221925     PISSN: None     EISSN: 19487193     Source Type: Journal    
DOI: 10.1021/cn400094w     Document Type: Review

References (146)

1. Albani, D., Polito, L., Signorini, A., and Forloni, G. (2010) Neuroprotective properties of resveratrol in different neurodegenerative disorders Biofactors 36, 370-376
2. Jeandet, P., Douillet-Breuil, A. C., Bessis, R., Debord, S., Sbaghi, M., and Adrian, M. (2002) Phytoalexins from the Vitaceae: Biosynthesis, phytoalexin gene expression in transgenic plants, antifungal activity, and metabolism J. Agric. Food Chem. 50, 2731-2741
3. Ribeiro de Lima, M. T., Waffo-Teguo, P., Teissedre, P. L., Pujolas, A., Vercauteren, J., Cabanis, J. C., and Merillon, J. M. (1999) Determination of stilbenes (trans-astringin, cis- and trans-piceid, and cis- and trans-resveratrol) in Portuguese wines J. Agric. Food Chem. 47, 2666-2670
4. Berzas Nevado, J. J., Contento Salcedo, A. M., and Castaneda Penalvo, G. (1999) Simultaneous determination of cis- and trans-resveratrol in wines by capillary zone electrophoresis Analyst 124, 61-66
5. Ferrieres, J. (2004) The French paradox: Lessons for other countries Heart 90, 107-111
6. Constant, J. (1997) Alcohol, ischemic heart disease, and the French paradox Coron. Artery Dis. 8, 645-649
7. Kopp, P. (1998) Resveratrol, a phytoestrogen found in red wine. A possible explanation for the conundrum of the 'French paradox'? Eur. J. Endocrinol. 138, 619-620
8. Hengst, J. A. and Yun, J. K. (2012) Sphingosine kinase: A key to solving the 'French Paradox'? Br. J. Pharmacol. 166, 1603-1604
9. Udenigwe, C. C., Ramprasath, V. R., Aluko, R. E., and Jones, P. J. (2008) Potential of resveratrol in anticancer and anti-inflammatory therapy Nutr. Rev. 66, 445-454
10. Chen, G., Shan, W., Wu, Y., Ren, L., Dong, J., and Ji, Z. (2005) Synthesis and anti-inflammatory activity of resveratrol analogs Chem. Pharm. Bull. (Tokyo) 53, 1587-1590
11. Nicolini, G., Rigolio, R., Miloso, M., Bertelli, A. A., and Tredici, G. (2001) Anti-apoptotic effect of trans-resveratrol on paclitaxel-induced apoptosis in the human neuroblastoma SH-SY5Y cell line Neurosci. Lett. 302, 41-44
12. Baarine, M., Thandapilly, S. J., Louis, X. L., Mazue, F., Yu, L., Delmas, D., Netticadan, T., Lizard, G., and Latruffe, N. (2011) Pro-apoptotic versus anti-apoptotic properties of dietary resveratrol on tumoral and normal cardiac cells Genes Nutr. 6, 161-169
13. Chang, C. C., Chang, C. Y., Huang, J. P., and Hung, L. M. (2012) Effect of resveratrol on oxidative and inflammatory stress in liver and spleen of streptozotocin-induced type 1 diabetic rats Chin. J. Physiol. 55, 192-201
14. Spanier, G., Xu, H., Xia, N., Tobias, S., Deng, S., Wojnowski, L., Forstermann, U., and Li, H. (2009) Resveratrol reduces endothelial oxidative stress by modulating the gene expression of superoxide dismutase 1 (SOD1), glutathione peroxidase 1 (GPx1) and NADPH oxidase subunit (Nox4) J. Physiol. Pharmacol. 60 (Suppl 4) 111-116
15. Dao, T. M., Waget, A., Klopp, P., Serino, M., Vachoux, C., Pechere, L., Drucker, D. J., Champion, S., Barthelemy, S., Barra, Y., Burcelin, R., and Seree, E. (2011) Resveratrol increases glucose induced GLP-1 secretion in mice: A mechanism which contributes to the glycemic control PLoS One 6 e20700
16. Berardi, V., Ricci, F., Castelli, M., Galati, G., and Risuleo, G. (2009) Resveratrol exhibits a strong cytotoxic activity in cultured cells and has an antiviral action against polyomavirus: potential clinical use J. Exp. Clin. Cancer Res. 28, 96
17. Clouser, C. L., Chauhan, J., Bess, M. A., Oploo, J. L., Zhou, D., Dimick-Gray, S., Mansky, L. M., and Patterson, S. E. (2012) Anti-HIV-1 activity of resveratrol derivatives and synergistic inhibition of HIV-1 by the combination of resveratrol and decitabine Bioorg. Med. Chem. Lett. 22, 6642-6646
18. Wang, Z., Zou, J., Cao, K., Hsieh, T. C., Huang, Y., and Wu, J. M. (2005) Dealcoholized red wine containing known amounts of resveratrol suppresses atherosclerosis in hypercholesterolemic rabbits without affecting plasma lipid levels Int. J. Mol. Med. 16, 533-540
19. Szmitko, P. E. and Verma, S. (2005) Cardiology patient pages. Red wine and your heart Circulation 111, e10-11
20. Dirnagl, U., Iadecola, C., and Moskowitz, M. A. (1999) Pathobiology of ischaemic stroke: An integrated view Trends Neurosci. 22, 391-397
21. Doré, S. (2010) Potential efficacy and mechanism of action of the flavanol (-)-epicatechin in acute brain trauma Nutr., Trauma, Brain 1-15
22. Mohamad, O., Drury-Stewart, D., Song, M., Faulkner, B., Chen, D., Yu, S. P., and Wei, L. (2013) Vector-free and transgene-free human iPS cells differentiate into functional neurons and enhance functional recovery after ischemic stroke in mice PloS One 8 e64160
23. Libert, S., Cohen, D., and Guarente, L. (2008) Neurogenesis directed by Sirt1 Nat. Cell Biol. 10, 373-374
24. Saharan, S., Jhaveri, D. J., and Bartlett, P. F. (2013) SIRT1 regulates the neurogenic potential of neural precursors in the adult subventricular zone and hippocampus J. Neurosci. Res. 91, 642-659
25. de Santi, C., Pietrabissa, A., Mosca, F., and Pacifici, G. M. (2000) Glucuronidation of resveratrol, a natural product present in grape and wine, in the human liver Xenobiotica 30, 1047-1054
26. De Santi, C., Pietrabissa, A., Spisni, R., Mosca, F., and Pacifici, G. M. (2000) Sulphation of resveratrol, a natural compound present in wine, and its inhibition by natural flavonoids Xenobiotica 30, 857-866
27. Wen, X. and Walle, T. (2006) Methylated flavonoids have greatly improved intestinal absorption and metabolic stability Drug Metab. Dispos. 34, 1786-1792
28. Walle, T., Hsieh, F., DeLegge, M. H., Oatis, J. E., Jr., and Walle, U. K. (2004) High absorption but very low bioavailability of oral resveratrol in humans Drug Metab. Dispos. 32, 1377-1382
29. Schwedhelm, E., Maas, R., Troost, R., and Boger, R. H. (2003) Clinical pharmacokinetics of antioxidants and their impact on systemic oxidative stress Clin. Pharmacokinet. 42, 437-459
30. Walle, T. (2011) Bioavailability of resveratrol Ann. N.Y. Acad. Sci. 1215, 9-15
31. Waterhouse, A. L. (2009) Resveratrol metabolites in urine as biomarker of wine intake in free-living subjects: The PREDIMED Study Free Radical Biol. Med. 46, 1561
32. Zamora-Ros, R., Urpi-Sarda, M., Lamuela-Raventos, R. M., Estruch, R., Martinez-Gonzalez, M. A., Bullo, M., Aros, F., Cherubini, A., and Andres-Lacueva, C. (2009) Resveratrol metabolites in urine as a biomarker of wine intake in free-living subjects: The PREDIMED Study Free Radical Biol. Med. 46, 1562-1566
33. Almeida, L., Vaz-da-Silva, M., Falcao, A., Soares, E., Costa, R., Loureiro, A. I., Fernandes-Lopes, C., Rocha, J. F., Nunes, T., Wright, L., and Soares-da-Silva, P. (2009) Pharmacokinetic and safety profile of trans-resveratrol in a rising multiple-dose study in healthy volunteers Mol. Nutr. Food Res. 53 (Suppl 1) S7-15
34. Pervaiz, S. and Holme, A. L. (2009) Resveratrol: Its biologic targets and functional activity Antioxid. Redox Signaling 11, 2851-2897
35. Andres-Lacueva, C., Macarulla, M. T., Rotches-Ribalta, M., Boto-Ordonez, M., Urpi-Sarda, M., Rodriguez, V. M., and Portillo, M. P. (2012) Distribution of resveratrol metabolites in liver, adipose tissue, and skeletal muscle in rats fed different doses of this polyphenol J. Agric. Food Chem. 60, 4833-4840
36. Clark, D., Tuor, U. I., Thompson, R., Institoris, A., Kulynych, A., Zhang, X., Kinniburgh, D. W., Bari, F., Busija, D. W., and Barber, P. A. (2012) Protection against recurrent stroke with resveratrol: Endothelial protection PLoS One 7 e47792
37. Lancon, A., Delmas, D., Osman, H., Thenot, J. P., Jannin, B., and Latruffe, N. (2004) Human hepatic cell uptake of resveratrol: involvement of both passive diffusion and carrier-mediated process Biochem. Biophys. Res. Commun. 316, 1132-1137
38. Lancon, A., Hanet, N., Jannin, B., Delmas, D., Heydel, J. M., Lizard, G., Chagnon, M. C., Artur, Y., and Latruffe, N. (2007) Resveratrol in human hepatoma HepG2 cells: metabolism and inducibility of detoxifying enzymes Drug Metab. Dispos. 35, 699-703
39. Burkon, A. and Somoza, V. (2008) Quantification of free and protein-bound trans-resveratrol metabolites and identification of trans-resveratrol-C/O- conjugated diglucuronides-two novel resveratrol metabolites in human plasma Mol. Nutr. Food Res. 52, 549-557
40. Jannin, B., Menzel, M., Berlot, J. P., Delmas, D., Lancon, A., and Latruffe, N. (2004) Transport of resveratrol, a cancer chemopreventive agent, to cellular targets: Plasmatic protein binding and cell uptake Biochem. Pharmacol. 68, 1113-1118
41. Lu, Z., Zhang, Y., Liu, H., Yuan, J., Zheng, Z., and Zou, G. (2007) Transport of a cancer chemopreventive polyphenol, resveratrol: Interaction with serum albumin and hemoglobin J. Fluoresc. 17, 580-587
42. Boocock, D. J., Faust, G. E., Patel, K. R., Schinas, A. M., Brown, V. A., Ducharme, M. P., Booth, T. D., Crowell, J. A., Perloff, M., Gescher, A. J., Steward, W. P., and Brenner, D. E. (2007) Phase I dose escalation pharmacokinetic study in healthy volunteers of resveratrol, a potential cancer chemopreventive agent Cancer Epidemiol., Biomarkers Prev. 16, 1246-1252
43. Boocock, D. J., Patel, K. R., Faust, G. E., Normolle, D. P., Marczylo, T. H., Crowell, J. A., Brenner, D. E., Booth, T. D., Gescher, A., and Steward, W. P. (2007) Quantitation of trans-resveratrol and detection of its metabolites in human plasma and urine by high performance liquid chromatography J. Chromatogr., B: Anal. Technol. Biomed. Life Sci. 848, 182-187
44. Brown, V. A., Patel, K. R., Viskaduraki, M., Crowell, J. A., Perloff, M., Booth, T. D., Vasilinin, G., Sen, A., Schinas, A. M., Piccirilli, G., Brown, K., Steward, W. P., Gescher, A. J., and Brenner, D. E. (2010) Repeat dose study of the cancer chemopreventive agent resveratrol in healthy volunteers: Safety, pharmacokinetics, and effect on the insulin-like growth factor axis Cancer Res. 70, 9003-9011
45. Cottart, C. H., Nivet-Antoine, V., Laguillier-Morizot, C., and Beaudeux, J. L. (2010) Resveratrol bioavailability and toxicity in humans Mol. Nutr. Food Res. 54, 7-16
46. Patel, K. R., Brown, V. A., Jones, D. J., Britton, R. G., Hemingway, D., Miller, A. S., West, K. P., Booth, T. D., Perloff, M., Crowell, J. A., Brenner, D. E., Steward, W. P., Gescher, A. J., and Brown, K. (2010) Clinical pharmacology of resveratrol and its metabolites in colorectal cancer patients Cancer Res. 70, 7392-7399
47. Zamin, L. L., Dillenburg-Pilla, P., Argenta-Comiran, R., Horn, A. P., Simao, F., Nassif, M., Gerhardt, D., Frozza, R. L., and Salbego, C. (2006) Protective effect of resveratrol against oxygen-glucose deprivation in organotypic hippocampal slice cultures: Involvement of PI3-K pathway Neurobiol. Dis. 24, 170-182
48. Zhang, H., Schools, G. P., Lei, T., Wang, W., Kimelberg, H. K., and Zhou, M. (2008) Resveratrol attenuates early pyramidal neuron excitability impairment and death in acute rat hippocampal slices caused by oxygen-glucose deprivation Exp. Neurol. 212, 44-52
49. Agrawal, M., Kumar, V., Singh, A. K., Kashyap, M. P., Khanna, V. K., Siddiqui, M. A., and Pant, A. B. (2013) trans-Resveratrol protects ischemic PC12 Cells by inhibiting the hypoxia associated transcription factors and increasing the levels of antioxidant defense enzymes ACS Chem. Neurosci. 4, 285-294
50. Lanzillotta, A., Pignataro, G., Branca, C., Cuomo, O., Sarnico, I., Benarese, M., Annunziato, L., Spano, P., and Pizzi, M. (2012) Targeted acetylation of NF-kappaB/RelA and histones by epigenetic drugs reduces post-ischemic brain injury in mice with an extended therapeutic window Neurobiol. Dis. 49, 177-189
51. Chanvitayapongs, S., Draczynska-Lusiak, B., and Sun, A. Y. (1997) Amelioration of oxidative stress by antioxidants and resveratrol in PC12 cells Neuroreport 8, 1499-1502
52. Okawara, M., Katsuki, H., Kurimoto, E., Shibata, H., Kume, T., and Akaike, A. (2007) Resveratrol protects dopaminergic neurons in midbrain slice culture from multiple insults Biochem. Pharmacol. 73, 550-560
53. Bournival, J., Quessy, P., and Martinoli, M. G. (2009) Protective effects of resveratrol and quercetin against MPP+ -induced oxidative stress act by modulating markers of apoptotic death in dopaminergic neurons Cell. Mol. Neurobiol. 29, 1169-1180
54. Lee, M. K., Kang, S. J., Poncz, M., Song, K. J., and Park, K. S. (2007) Resveratrol protects SH-SY5Y neuroblastoma cells from apoptosis induced by dopamine Exp. Mol. Med. 39, 376-384
55. Fukui, M., Choi, H. J., and Zhu, B. T. (2010) Mechanism for the protective effect of resveratrol against oxidative stress-induced neuronal death Free Radical Biol. Med. 49, 800-813
56. Wang, Q., Yu, S., Simonyi, A., Rottinghaus, G., Sun, G. Y., and Sun, A. Y. (2004) Resveratrol protects against neurotoxicity induced by kainic acid Neurochem. Res. 29, 2105-2112
57. Ban, J. Y., Cho, S. O., Choi, S. H., Ju, H. S., Kim, J. Y., Bae, K., Song, K. S., and Seong, Y. H. (2008) Neuroprotective effect of Smilacis chinae rhizome on NMDA-induced neurotoxicity in vitro and focal cerebral ischemia in vivo J. Pharmacol. Sci. 106, 68-77
58. Utreras, E., Terse, A., Keller, J., Iadarola, M. J., and Kulkarni, A. B. (2011) Resveratrol inhibits Cdk5 activity through regulation of p35 expression Mol. Pain 7, 49
59. Kim, D. W., Kim, Y. M., Kang, S. D., Han, Y. M., and Pae, H. O. (2012) Effects of resveratrol and trans-3,5,4'-trimethoxystilbene on glutamate-induced cytotoxicity, heme oxygenase-1, and sirtuin 1 in HT22 neuronal cells Biomol. Ther. 20, 306-312
60. Son, Y., Byun, S. J., and Pae, H. O. (2013) Involvement of heme oxygenase-1 expression in neuroprotection by piceatannol, a natural analog and a metabolite of resveratrol, against glutamate-mediated oxidative injury in HT22 neuronal cells Amino Acids 10.1007/s00726-013-1518-9
61. Sakata, Y., Zhuang, H., Kwansa, H., Koehler, R. C., and Doré, S. (2010) Resveratrol protects against experimental stroke: putative neuroprotective role of heme oxygenase 1 Exp. Neurol. 224, 325-329
62. Chen, C. Y., Jang, J. H., Li, M. H., and Surh, Y. J. (2005) Resveratrol upregulates heme oxygenase-1 expression via activation of NF-E2-related factor 2 in PC12 cells Biochem. Biophys. Res. Commun. 331, 993-1000
63. Yousuf, S., Atif, F., Ahmad, M., Hoda, N., Ishrat, T., Khan, B., and Islam, F. (2009) Resveratrol exerts its neuroprotective effect by modulating mitochondrial dysfunctions and associated cell death during cerebral ischemia Brain Res. 1250, 242-253
64. Andrabi, S. A., Spina, M. G., Lorenz, P., Ebmeyer, U., Wolf, G., and Horn, T. F. (2004) Oxyresveratrol (trans-2,3′,4,5′- tetrahydroxystilbene) is neuroprotective and inhibits the apoptotic cell death in transient cerebral ischemia Brain Res. 1017, 98-107
65. Shin, J. A., Lee, K. E., Kim, H. S., and Park, E. M. (2012) Acute resveratrol treatment modulates multiple signaling pathways in the ischemic brain Neurochem. Res. 37, 2686-2696
66. Ren, J., Fan, C., Chen, N., Huang, J., and Yang, Q. (2011) Resveratrol pretreatment attenuates cerebral ischemic injury by upregulating expression of transcription factor Nrf2 and HO-1 in rats Neurochem. Res. 36, 2352-2362
67. Della-Morte, D., Dave, K. R., DeFazio, R. A., Bao, Y. C., Raval, A. P., and Perez-Pinzon, M. A. (2009) Resveratrol pretreatment protects rat brain from cerebral ischemic damage via a sirtuin 1-uncoupling protein 2 pathway Neuroscience 159, 993-1002
68. Wang, Q., Xu, J., Rottinghaus, G. E., Simonyi, A., Lubahn, D., Sun, G. Y., and Sun, A. Y. (2002) Resveratrol protects against global cerebral ischemic injury in gerbils Brain Res. 958, 439-447
69. Gao, D., Zhang, X., Jiang, X., Peng, Y., Huang, W., Cheng, G., and Song, L. (2006) Resveratrol reduces the elevated level of MMP-9 induced by cerebral ischemia-reperfusion in mice Life Sci. 78, 2564-2570
70. Dong, W., Li, N., Gao, D., Zhen, H., Zhang, X., and Li, F. (2008) Resveratrol attenuates ischemic brain damage in the delayed phase after stroke and induces messenger RNA and protein express for angiogenic factors J. Vasc. Surg. 48, 709-714
71. Sinha, K., Chaudhary, G., and Gupta, Y. K. (2002) Protective effect of resveratrol against oxidative stress in middle cerebral artery occlusion model of stroke in rats Life Sci. 71, 655-665
72. Karalis, F., Soubasi, V., Georgiou, T., Nakas, C. T., Simeonidou, C., Guiba-Tziampiri, O., and Spandou, E. (2011) Resveratrol ameliorates hypoxia/ischemia-induced behavioral deficits and brain injury in the neonatal rat brain Brain Res. 1425, 98-110
73. Huang, X., Zhou, Q., Gu, L., Liu, D., Li, Z., Liu, Q., and Zhu, D. (2010) [Protective effects of resveratrol on neonatal rat cardiomyocyte lesion induced by hypoxia] Zhongguo Zhong Yao Za Zhi 35, 94-98
74. West, T., Atzeva, M., and Holtzman, D. M. (2007) Pomegranate polyphenols and resveratrol protect the neonatal brain against hypoxic-ischemic injury Dev. Neurosci. 29, 363-372
75. Singleton, R. H., Yan, H. Q., Fellows-Mayle, W., and Dixon, C. E. (2010) Resveratrol attenuates behavioral impairments and reduces cortical and hippocampal loss in a rat controlled cortical impact model of traumatic brain injury J. Neurotrauma 27, 1091-1099
76. Kwon, K. J., Kim, J. N., Kim, M. K., Lee, J., Ignarro, L. J., Kim, H. J., Shin, C. Y., and Han, S. H. (2011) Melatonin synergistically increases resveratrol-induced heme oxygenase-1 expression through the inhibition of ubiquitin-dependent proteasome pathway: a possible role in neuroprotection J. Pineal Res. 50, 110-123
77. Karaoglan, A., Akdemir, O., Barut, S., Kokturk, S., Uzun, H., Tasyurekli, M., and Colak, A. (2008) The effects of resveratrol on vasospasm after experimental subarachnoidal hemorrhage in rats Surg. Neurol. 70, 337-343
78. Shin, J. A., Lee, H., Lim, Y. K., Koh, Y., Choi, J. H., and Park, E. M. (2010) Therapeutic effects of resveratrol during acute periods following experimental ischemic stroke J. Neuroimmunol. 227, 93-100
79. Sun, A. Y., Wang, Q., Simonyi, A., and Sun, G. Y. (2010) Resveratrol as a therapeutic agent for neurodegenerative diseases Mol. Neurobiol. 41, 375-383
80. Mizutani, K., Ikeda, K., Kawai, Y., and Yamori, Y. (2001) Protective effect of resveratrol on oxidative damage in male and female stroke-prone spontaneously hypertensive rats Clin. Exp. Pharmacol. Physiol. 28, 55-59
81. Wang, C. X., Wheeler, C. T., Alberico, T., Sun, X. P., Seeberger, J., Laslo, M., Spangler, E., Kern, B., de Cabo, R., and Zou, S. G. (2013) The effect of resveratrol on lifespan depends on both gender and dietary nutrient composition in Drosophila melanogaster Age 35, 69-81
82. Renolleau, S., Fau, S., Goyenvalle, C., Joly, L. M., Chauvier, D., Jacotot, E., Mariani, J., and Charriaut-Marlangue, C. (2007) Specific caspase inhibitor Q-VD-OPh prevents neonatal stroke in P7 rat: A role for gender J. Neurochem. 100, 1062-1071
83. Di Liberto, V., Makela, J., Korhonen, L., Olivieri, M., Tselykh, T., Malkia, A., Do Thi, H., Belluardo, N., Lindholm, D., and Mudo, G. (2012) Involvement of estrogen receptors in the resveratrol-mediated increase in dopamine transporter in human dopaminergic neurons and in striatum of female mice Neuropharmacology 62, 1011-1018
84. Culmsee, C., Zhu, C., Landshamer, S., Becattini, B., Wagner, E., Pellecchia, M., Blomgren, K., and Plesnila, N. (2005) Apoptosis-inducing factor triggered by poly(ADP-ribose) polymerase and Bid mediates neuronal cell death after oxygen-glucose deprivation and focal cerebral ischemia J. Neurosci. 25, 10262-10272
85. Yu, S. W., Wang, H., Poitras, M. F., Coombs, C., Bowers, W. J., Federoff, H. J., Poirier, G. G., Dawson, T. M., and Dawson, V. L. (2002) Mediation of poly(ADP-ribose) polymerase-1-dependent cell death by apoptosis-inducing factor Science 297, 259-263
86. Liu, F., Li, Z., Li, J., Siegel, C., Yuan, R., and McCullough, L. D. (2009) Sex differences in caspase activation after stroke Stroke 40, 1842-1848
87. Gong, Q. H., Wang, Q., Shi, J. S., Huang, X. N., Liu, Q., and Ma, H. (2007) Inhibition of caspases and intracellular free Ca2+ concentrations are involved in resveratrol protection against apoptosis in rat primary neuron cultures Acta Pharmacol. Sin. 28, 1724-1730
88. Shin, S., Jeon, J. H., Park, D., Jang, M. J., Choi, J. H., Choi, B. H., Joo, S. S., Nahm, S. S., Kim, J. C., and Kim, Y. B. (2008) trans-Resveratrol relaxes the corpus cavernosum ex vivo and enhances testosterone levels and sperm quality in vivo Arch. Pharm. Res. 31, 83-87
89. Chao, J., Li, H., Cheng, K. W., Yu, M. S., Chang, R. C., and Wang, M. (2010) Protective effects of pinostilbene, a resveratrol methylated derivative, against 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y cells J. Nutr. Biochem. 21, 482-489
90. Agrawal, M., Kumar, V., Kashyap, M. P., Khanna, V. K., Randhawa, G. S., and Pant, A. B. (2011) Ischemic insult induced apoptotic changes in PC12 cells: protection by trans resveratrol Eur. J. Pharmacol. 666, 5-11
91. Zini, R., Morin, C., Bertelli, A., Bertelli, A. A., and Tillement, J. P. (1999) Effects of resveratrol on the rat brain respiratory chain Drugs Exp. Clin. Res. 25, 87-97
92. Dudley, J., Das, S., Mukherjee, S., and Das, D. K. (2009) Resveratrol, a unique phytoalexin present in red wine, delivers either survival signal or death signal to the ischemic myocardium depending on dose J. Nutr. Biochem. 20, 443-452
93. 1 Bax interaction after transient global ischemia J. Cereb. Blood Flow Metab. 18, 882-886
94. Li, Z., Pang, L., Fang, F., Zhang, G., Zhang, J., Xie, M., and Wang, L. (2012) Resveratrol attenuates brain damage in a rat model of focal cerebral ischemia via up-regulation of hippocampal Bcl-2 Brain Res. 1450, 116-124
95. Block, M. L. and Hong, J. S. (2007) Chronic microglial activation and progressive dopaminergic neurotoxicity Biochem. Soc. Trans. 35, 1127-1132
96. Gao, H. M., Liu, B., Zhang, W., and Hong, J. S. (2003) Novel anti-inflammatory therapy for Parkinson's disease Trends Pharmacol. Sci. 24, 395-401
97. Ransohoff, R. M. and Perry, V. H. (2009) Microglial physiology: Unique stimuli, specialized responses Annu. Rev. Immunol. 27, 119-145
98. Zhang, F., Liu, J., and Shi, J. S. (2010) Anti-inflammatory activities of resveratrol in the brain: role of resveratrol in microglial activation Eur. J. Pharmacol. 636, 1-7
99. Candelario-Jalil, E., de Oliveira, A. C., Graf, S., Bhatia, H. S., Hull, M., Munoz, E., and Fiebich, B. L. (2007) Resveratrol potently reduces prostaglandin E2 production and free radical formation in lipopolysaccharide- activated primary rat microglia J. Neuroinflammation 4, 25
100. Lorenz, P., Roychowdhury, S., Engelmann, M., Wolf, G., and Horn, T. F. (2003) Oxyresveratrol and resveratrol are potent antioxidants and free radical scavengers: Effect on nitrosative and oxidative stress derived from microglial cells Nitric Oxide 9, 64-76
101. Bi, X. L., Yang, J. Y., Dong, Y. X., Wang, J. M., Cui, Y. H., Ikeshima, T., Zhao, Y. Q., and Wu, C. F. (2005) Resveratrol inhibits nitric oxide and TNF-alpha production by lipopolysaccharide-activated microglia Int. Immunopharmacol. 5, 185-193
102. Kim, Y. A., Kim, G. Y., Park, K. Y., and Choi, Y. H. (2007) Resveratrol inhibits nitric oxide and prostaglandin E2 production by lipopolysaccharide- activated C6 microglia J. Med. Food 10, 218-224
103. Blanchet, J., Longpre, F., Bureau, G., Morissette, M., DiPaolo, T., Bronchti, G., and Martinoli, M. G. (2008) Resveratrol, a red wine polyphenol, protects dopaminergic neurons in MPTP-treated mice Prog. Neuro-Psychopharmacol. 32, 1243-1250
104. Wang, M. J., Huang, H. M., Hsieh, S. J., Jeng, K. C., and Kuo, J. S. (2001) Resveratrol inhibits interleukin-6 production in cortical mixed glial cells under hypoxia/hypoglycemia followed by reoxygenation J. Neuroimmunol. 112, 28-34
105. Wang, Q., Tang, X. N., and Yenari, M. A. (2007) The inflammatory response in stroke J. Neuroimmunol. 184, 53-68
106. Inoue, H., Jiang, X. F., Katayama, T., Osada, S., Umesono, K., and Namura, S. (2003) Brain protection by resveratrol and fenofibrate against stroke requires peroxisome proliferator-activated receptor alpha in mice Neurosci. Lett. 352, 203-206
107. Bureau, G., Longpre, F., and Martinoli, M. G. (2008) Resveratrol and quercetin, two natural polyphenols, reduce apoptotic neuronal cell death induced by neuroinflammation J. Neurosci. Res. 86, 403-410
108. Lee, M., Hyun, D., Jenner, P., and Halliwell, B. (2001) Effect of overexpression of wild-type and mutant Cu/Zn-superoxide dismutases on oxidative damage and antioxidant defences: relevance to Down's syndrome and familial amyotrophic lateral sclerosis J. Neurochem. 76, 957-965
109. Marklund, S. L., Westman, N. G., Lundgren, E., and Roos, G. (1982) Copper- and zinc-containing superoxide dismutase, manganese-containing superoxide dismutase, catalase, and glutathione peroxidase in normal and neoplastic human cell lines and normal human tissues Cancer Res. 42, 1955-1961
110. Moi, P., Chan, K., Asunis, I., Cao, A., and Kan, Y. W. (1994) Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region Proc. Natl. Acad. Sci. U. S. A. 91, 9926-9930
111. Innamorato, N. G., Rojo, A. I., Garcia-Yague, A. J., Yamamoto, M., de Ceballos, M. L., and Cuadrado, A. (2008) The transcription factor Nrf2 is a therapeutic target against brain inflammation J. Immunol. 181, 680-689
112. Shah, Z. A., Li, R. C., Thimmulappa, R. K., Kensler, T. W., Yamamoto, M., Biswal, S., and Doré, S. (2007) Role of reactive oxygen species in modulation of Nrf2 following ischemic reperfusion injury Neuroscience 147, 53-59
113. Rojo, A. I., Innamorato, N. G., Martin-Moreno, A. M., De Ceballos, M. L., Yamamoto, M., and Cuadrado, A. (2010) Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson's disease Glia 58, 588-598
114. Lee, J. M., Shih, A. Y., Murphy, T. H., and Johnson, J. A. (2003) NF-E2-related factor-2 mediates neuroprotection against mitochondrial complex I inhibitors and increased concentrations of intracellular calcium in primary cortical neurons J. Biol. Chem. 278, 37948-37956
115. Vargas, M. R. and Johnson, J. A. (2009) The Nrf2-ARE cytoprotective pathway in astrocytes Expert Rev. Mol. Med. 11 e17
116. Liverman, C. S., Cui, L., Yong, C., Choudhuri, R., Klein, R. M., Welch, K. M. A., and Berman, N. E. J. (2004) Response of the brain to oligemia: Gene expression, c-Fos, and Nrf2 localization Mol. Brain Res. 126, 57-66
117. Srivastava, S., Alfieri, A., Siow, R. C., Mann, G. E., and Fraser, P. A. (2013) Temporal and spatial distribution of Nrf2 in rat brain following stroke: Quantitation of nuclear to cytoplasmic Nrf2 content using a novel immunohistochemical technique J. Physiol. 10.1113/jphysiol.2013.257964
118. Chan, K., Han, X. D., and Kan, Y. W. (2001) An important function of Nrf2 in combating oxidative stress: detoxification of acetaminophen Proc. Natl. Acad. Sci. U. S. A. 98, 4611-4616
119. Wang, J., Fields, J., Zhao, C., Langer, J., Thimmulappa, R. K., Kensler, T. W., Yamamoto, M., Biswal, S., and Doré, S. (2007) Role of Nrf2 in protection against intracerebral hemorrhage injury in mice Free Radical Biol. Med. 43, 408-414
120. Wang, B., Cao, W., Biswal, S., and Dore, S. (2011) Carbon monoxide-activated Nrf2 pathway leads to protection against permanent focal cerebral ischemia Stroke 42, 2605-2610
121. Leonardo, C. C. and Doré, S. (2011) Dietary flavonoids are neuroprotective through Nrf2-coordinated induction of endogenous cytoprotective proteins Nutr Neurosci. 14, 226-236
122. Shah, Z. A., Li, R. C., Ahmad, A. S., Kensler, T. W., Yamamoto, M., Biswal, S., and Doré, S. (2010) The flavanol (-)-epicatechin prevents stroke damage through the Nrf2/HO1 pathway J. Cereb. Blood Flow Metab. 30, 1951-1961
123. Kwak, M. K., Itoh, K., Yamamoto, M., and Kensler, T. W. (2002) Enhanced expression of the transcription factor Nrf2 by cancer chemopreventive agents: role of antioxidant response element-like sequences in the nrf2 promoter Mol. Cell. Biol. 22, 2883-2892
124. Baur, J. A., Pearson, K. J., Price, N. L., Jamieson, H. A., Lerin, C., Kalra, A., Prabhu, V. V., Allard, J. S., Lopez-Lluch, G., Lewis, K., Pistell, P. J., Poosala, S., Becker, K. G., Boss, O., Gwinn, D., Wang, M., Ramaswamy, S., Fishbein, K. W., Spencer, R. G., Lakatta, E. G., Le Couteur, D., Shaw, R. J., Navas, P., Puigserver, P., Ingram, D. K., de Cabo, R., and Sinclair, D. A. (2006) Resveratrol improves health and survival of mice on a high-calorie diet Nature 444, 337-342
125. Park, S. J., Ahmad, F., Philp, A., Baar, K., Williams, T., Luo, H., Ke, H., Rehmann, H., Taussig, R., Brown, A. L., Kim, M. K., Beaven, M. A., Burgin, A. B., Manganiello, V., and Chung, J. H. (2012) Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases Cell 148, 421-433
126. Leonard, S. S., Xia, C., Jiang, B. H., Stinefelt, B., Klandorf, H., Harris, G. K., and Shi, X. (2003) Resveratrol scavenges reactive oxygen species and effects radical-induced cellular responses Biochem. Biophys. Res. Commun. 309, 1017-1026
127. Zhang, F., Shi, J. S., Zhou, H., Wilson, B., Hong, J. S., and Gao, H. M. (2010) Resveratrol protects dopamine neurons against lipopolysaccharide-induced neurotoxicity through its anti-inflammatory actions Mol. Pharmacol. 78, 466-477
128. Zhuang, H., Kim, Y. S., Koehler, R. C., and Doré, S. (2003) Potential mechanism by which resveratrol, a red wine constituent, protects neurons Ann. N.Y. Acad. Sci. 993, 276-286
129. Bastianetto, S., Zheng, W. H., and Quirion, R. (2000) Neuroprotective abilities of resveratrol and other red wine constituents against nitric oxide-related toxicity in cultured hippocampal neurons Br. J. Pharmacol. 131, 711-720
130. Ungvari, Z., Orosz, Z., Rivera, A., Labinskyy, N., Xiangmin, Z., Olson, S., Podlutsky, A., and Csiszar, A. (2007) Resveratrol increases vascular oxidative stress resistance Am. J. Physiol.: Heart Circ. Physiol. 292, H2417-2424
131. Ungvari, Z., Labinskyy, N., Mukhopadhyay, P., Pinto, J. T., Bagi, Z., Ballabh, P., Zhang, C., Pacher, P., and Csiszar, A. (2009) Resveratrol attenuates mitochondrial oxidative stress in coronary arterial endothelial cells Am. J. Physiol.: Heart Circ. Physiol. 297, H1876-1881
132. Robb, E. L., Page, M. M., Wiens, B. E., and Stuart, J. A. (2008) Molecular mechanisms of oxidative stress resistance induced by resveratrol: Specific and progressive induction of MnSOD Biochem. Biophys. Res. Commun. 367, 406-412
133. Frombaum, M., Le Clanche, S., Bonnefont-Rousselot, D., and Borderie, D. (2012) Antioxidant effects of resveratrol and other stilbene derivatives on oxidative stress and*NO bioavailability: Potential benefits to cardiovascular diseases Biochimie. 94, 269-276
134. He, X., Wang, L., Szklarz, G., Bi, Y., and Ma, Q. (2012) Resveratrol inhibits paraquat-induced oxidative stress and fibrogenic response by activating the nuclear factor erythroid 2-related factor 2 pathway J. Pharmacol. Exp. Ther. 342, 81-90
135. 2, semiquinones, and quinones Free Radical Biol. Med. 51, 2319-2327
136. Rubiolo, J. A., Mithieux, G., and Vega, F. V. (2008) Resveratrol protects primary rat hepatocytes against oxidative stress damage: activation of the Nrf2 transcription factor and augmented activities of antioxidant enzymes Eur. J. Pharmacol. 591, 66-72
137. Chen, C. Y., Jang, J. H., Li, M. H., and Surh, Y. J. (2005) Resveratrol upregulates heme oxygenase-1 expression via activation of NF-E2-related factor 2 in PC12 cells Biochem. Biophys. Res. Commun. 331, 993-1000
138. Huang, S. S., Tsai, M. C., Chih, C. L., Hung, L. M., and Tsai, S. K. (2001) Resveratrol reduction of infarct size in Long-Evans rats subjected to focal cerebral ischemia Life Sci. 69, 1057-1065
139. Cui, X., Jin, Y., Hofseth, A. B., Pena, E., Habiger, J., Chumanevich, A., Poudyal, D., Nagarkatti, M., Nagarkatti, P. S., Singh, U. P., and Hofseth, L. J. (2010) Resveratrol suppresses colitis and colon cancer associated with colitis Cancer Prev. Res. 3, 549-559
140. Ungvari, Z., Bagi, Z., Feher, A., Recchia, F. A., Sonntag, W. E., Pearson, K., de Cabo, R., and Csiszar, A. (2010) Resveratrol confers endothelial protection via activation of the antioxidant transcription factor Nrf2 Am. J. Physiol.: Heart Circ. Physiol. 299, H18-24
141. Tsai, S. K., Hung, L. M., Fu, Y. T., Cheng, H., Nien, M. W., Liu, H. Y., Zhang, F. B., and Huang, S. S. (2007) Resveratrol neuroprotective effects during focal cerebral ischemia injury via nitric oxide mechanism in rats J. Vasc. Surg. 46, 346-353
142. http://clinicaltrials.gov/ct2/results?term= Resveratrol+physiological+benefits&Search=Search.
143. http://apps.who.int/trialsearch/AdvSearch.aspx.
144. Kennedy, D. O., Wightman, E. L., Reay, J. L., Lietz, G., Okello, E. J., Wilde, A., and Haskell, C. F. (2010) Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans: A double-blind, placebo-controlled, crossover investigation Am. J. Clin. Nutr. 91, 1590-1597
145. Ghanim, H., Sia, C. L., Korzeniewski, K., Lohano, T., Abuaysheh, S., Marumganti, A., Chaudhuri, A., and Dandona, P. (2011) A resveratrol and polyphenol preparation suppresses oxidative and inflammatory stress response to a high-fat, high-carbohydrate meal J. Clin. Endocrinol. Metab. 96, 1409-1414
146. Li, C., Yan, Z., Yang, J., Chen, H., Li, H., Jiang, Y., and Zhang, Z. (2010) Neuroprotective effects of resveratrol on ischemic injury mediated by modulating the release of neurotransmitter and neuromodulator in rats Neurochem. Int. 56, 495-500