A dietary polyphenol resveratrol acts to provide neuroprotection in recurrent stroke models by reducing energy requirements during ischemia

Volume 1, Issue 1, October 2016     |     PP. 12-37      |     PDF (389 K)    |     Pub. Date: October 14, 2016
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houjun Zheng, Faculty of Medicine, ZheJiang Ocean University, ZhouShan, ZheJiang 316004, P.R.China
Ke Ma, Department of reconstructive microsurgery, WeiFang Medical University, ShanDong Province, China.
Xiao-Ji Wang, School of Pharmacy, Jiangxi Science and Technology Normal University, Nan Chang 330013, Jiangxi Province, China.
Li-Mei Wang, Department of Neurobiology, School of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China.

Polyphenol resveratrol (RSV) has been associated with Silent Information Regulator T1 (SIRT1) and AMP-activated protein kinase (AMPK) metabolic stress sensors and probably responds to the intracellular energy status. Our purpose is to investigate the neuroprotective effects of RSV and the association with SIRT1 and AMPK signaling in recurrent ischemia models. In this study, elderly male Wistar rats received a combination of two mild transient Middle Cerebral Artery Occlusions (tMCAO) as in vivo recurrent ischemic model. Primary cultured cortical neuronal cells subjected to combined oxygen–glucose deprivation (OGD) were used as in vitro recurrent ischemic model. RSV administration significantly reduced infarct volumes, improved behavioral deficits and protected neuronal cells from cell death in recurrent ischemic stroke models in vivo and in vitro. RSV treatments significantly increased the intracellular NAD+/NADH ratio, AMPK and SIRT1activities, decreased energy assumption and restored cell energy ATP level. SIRT1 and AMPK inhibitors and specific siRNA for SIRT1 and AMPK significantly abrogated the neuroprotection induced by RSV. AMPK-siRNA and inhibitor decreased SIRT1 activities; however, SIRT1-siRNA and inhibitor had no impact on p-AMPK levels. These results indicated that the neuroprotective effects of RSV increased the intracellular NAD+/NADH ratio as well as AMPK and SIRT1 activities, thereby reducing energy ATP requirements during ischemia. SIRT1 is a downstream target of p-AMPK signaling induced by RSV in the recurrent ischemic stroke model.

RSV NeuroprotectionRecurrent Stroke ModelSIRT1 and AMPK signalingIntracellular NAD+/NADH ratio Intracellular ATP level

Cite this paper
houjun Zheng, Ke Ma, Xiao-Ji Wang, Li-Mei Wang, A dietary polyphenol resveratrol acts to provide neuroprotection in recurrent stroke models by reducing energy requirements during ischemia , SCIREA Journal of Clinical Medicine. Volume 1, Issue 1, October 2016 | PP. 12-37.


[ 1 ] Baur, J.A, Sinclair, D.A. (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat. Rev. Drug Disco., 5, 493–506.
[ 2 ] Benjelloun N, Renolleau S, Represa A, Ben-Ari Y, Charriaut-Marlangue C. (1999) Inflammatory responses in the cerebral cortex after ischemia in the P7 neonatal Rat. Stroke., 30, 1916-23.
[ 3 ] Borra MT, Smith BC, Denu JM. (2005) Mechanism of human SIRT1 activation by resveratrol. J Biol Chem., 280, 17187-17195.
[ 4 ] Bradamante S, Barenghi L, Piccinini F, Bertelli AA, De Jonge R, Beemster P, De Jong JW. (2003) Resveratrol provides late-phase cardioprotection by means of a nitric oxide- and adenosine-mediated mechanism. Eur J Pharmacol., 465, 115-123
[ 5 ] Cantó C, Gerhart-Hines Z, Feige JN, Lagouge M, Noriega L, Milne JC, Elliott PJ, Puigserver P, Auwerx J. (2009) AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature., 23, 1056-60.
[ 6 ] Carling, D. (2004) The AMP-activated protein kinase cascade—a unifying system for energy control. Trends Biochem. Sci., 29, 18–24.
[ 7 ] Chandratheva A, Mehta Z, Geraghty OC, Marquardt L, Rothwell PM. (2009) Population-based study of risk and predictors of stroke in the first few hours after a TIA. Neurology., 72, 1941–1947.
[ 8 ] Correia M, Silva MR, Magalhaes R, Guimaraes L, Silva MC. (2006) Transient ischemic attacks in rural and urban northern Portugal: incidence and short-term prognosis. Stroke., 37, 50-55
[ 9 ] Dal-Pan A, Terrien J, Pifferi F, Botalla R, Hardy I, Marchal J, Zahariev A, Chery I, Zizzari P, Perret M, Picq JL, Epelbaum J, Blanc S, Aujard F. (2011) Caloric restriction or resveratrol supplementation and ageing in a non-human primate: first-year outcome of the RESTRIKAL study in Microcebus murinus. Age (Dordr)., 33, 15-31.
[ 10 ] Das M, Das DK. 2010. Resveratrol and cardiovascular health. Mol Aspects Med.31:503-512.
[ 11 ] Dasgupta B, Milbrandt J. (2007) Resveratrol stimulates AMP kinase activity in neurons. Proc Natl Acad Sci.,104, 7217-7122.
[ 12 ] Della-Mortem D, Dave KR, DeFazio RA, Bao YC, Raval AP, Perez-Pinzon MA. (2009) Resveratrol pretreatment protects rat brain from cerebral ischemic damage via a sirtuin 1-uncoupling protein 2 pathway. Neuroscience., 159, 993-1002.
[ 13 ] Domoki F, Kis B, Gáspár T, Snipes JA, Parks JS, Bari F, Busija DW. (2009) Rosuvastatin induces delayed preconditioning against oxygen-glucose deprivation in cultured cortical neurons. Am J Physiol Cell Physiol., 296, 97-105.
[ 14 ] Dong W, Li N, Gao D, Zhen H, Zhang X, 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
[ 15 ] Dudley J, Das S, Mukherjee S, Das DK. J Nutr Biochem. (2012) 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., 23, 852
[ 16 ] Ferrara N, Rinaldi B, Corbi G, Conti V, Stiuso P, Boccuti S, Rengo G, Rossi F, Filippelli A. (2008) Exercise training promotes SIRT1 activity in aged rats. Rejuvenation Res., 11, 139-150.
[ 17 ] Finkel T, Deng CX, Mostoslavsky R. (2009) Recent progress in the biology and physiology of sirtuins. Nature., 460, 587–591.
[ 18 ] Guarani V, Deflorian G, Franco CA, Krüger M, Phng LK, Bentley K, Toussaint L, Dequiedt F, Mostoslavsky R, Schmidt MH, Zimmermann B, Brandes RP, Mione M, Westphal CH, Braun T, Zeiher AM, Gerhardt H, Dimmeler S, Potente M. (2011) Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase. Nature., 473, 234-8.
[ 19 ] Hardie DG. (2007) AMP-activated/SNF1 protein kinases: conserved energy. Nat. Rev. Mol. Cell. Biol., 8, 774–785.
[ 20 ] Huang, S.S, Tsai, M.C, Chih, C.L, Hung, L.M, Tsai, S.K. (2001) Resveratrol reduction of infarct size in Long–Evans rats subjected to focal cerebral ischemia. Life Sci., 69, 1057–65.
[ 21 ] Jäger S, Handschin C, St-Pierre J, Spiegelman BM. (2007) AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A., 17, 12017-22.
[ 22 ] Johnston DC, Hill MD. (2004) The patient with transient cerebral ischemia: a golden opportunity for stroke prevention. CMAJ., 170, 1134-1137.
[ 23 ] Kopp, P. Resveratrol, a phytoestrogen found in red wine. (1998) A possible explanation for the conundrum of the ‘French paradox’? Eur. J. Endocrinol., 138, 619–20.
[ 24 ] La-Morte D, Dave KR, DeFazio RA, Bao YC, Raval AP, Perez-Pinzon MA. (2009) Resveratrol pretreatment protects rat brain from cerebral ischemic damage via a sirtuin 1-uncoupling protein 2 pathway. Neuroscience., 159, 993-1002
[ 25 ] Li C, Yan Z, Yang J, Chen H, Li H, Jiang Y, 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.
[ 26 ] Lin TN, He YY, Wu G, Khan M, Hsu CY. (1993) Effect of brain edema on infarct volume in a focal cerebral ischemia model in rats. Stroke., 24, 117–21.
[ 27 ] Liu C, Liang B, Wang Q, Wu J, Zou MH. (2010) Activation of AMP-activated protein kinase alpha1 alleviates endothelial cell apoptosis by increasing the expression of anti-apoptotic proteins Bcl-2 and survivin. J Biol Chem., 285, 15346-55.
[ 28 ] MacDougall NJ, Amarasinghe S, Muir KW. (2009) Secondary prevention of stroke. Expert Rev Cardiovasc Ther., 7, 1103-1115.
[ 29 ] Murayama A, Ohmori K, Fujimura A, Minami H, Yasuzawa-Tanaka K, Kuroda T, Oie S, Daitoku H, Okuwaki M, Nagata K, Fukamizu A, Kimura K, Shimizu T, Yanagisawa J. (2008) Epigenetic control of rDNA loci in response to intracellular energy status. Cell., 133, 627-39.
[ 30 ] Nakano A, Kato H, Watanabe T, Min KD, Yamazaki S, Asano Y, Seguchi O, Higo S, Shintani Y, Asanuma H, Asakura M, Minamino T, Kaibuchi K, Mochizuki N, Kitakaze M, Takashima S. (2010) AMPK controls the speed of microtubule polymerization and directional cell migration through CLIP-170 phosphorylation. Nat Cell Biol., 12, 583-90.
[ 31 ] Pallàs M, Casadesús G, Smith MA, Coto-Montes A, Pelegri C, Vilaplana J, Camins A. (2009) Resveratrol and neurodegenerative diseases: activation of SIRT1 as the potential pathway towards neuroprotection. Curr Neurovasc Res., 6, 70-81.
[ 32 ] Pallàs M, Pizarro JG, Gutierrez-Cuesta J, Crespo-Biel N, Alvira D, Tajes M, Yeste-Velasco M, Folch J, Canudas AM, Sureda FX, Ferrer I, Camins A. (2008) Modulation of SIRT1 expression in different neurodegenerative models and human pathologies. Neuroscience., 154: 1388-97.
[ 33 ] Paolucci S, Antonucci G, Troisi E, Bragoni M, Coiro P, De AD. (2003) Aging and stroke rehabilitation. a case-comparison study. Cerebrovasc Dis., 15, 98-105.
[ 34 ] Penumathsa SV, Maulik N. (2009) Resveratrol: a promising agent in promoting cardioprotection against coronary heart disease. Can J Physiol Pharmacol., 87, 275-86.
[ 35 ] Qiao M, Zhao Z, Barber PA, Foniok T, Sun S, Tuor UI. (2009) Development of a model of recurrent stroke consisting of a mild transient stroke followed by a second moderate stroke in rats. J Neurosci Method., 184, 244-50.
[ 36 ] Qiao M, Meng S, Foniok T, Tuor UI. (2009) Mild cerebral hypoxia-ischemia produces a sub-acute transient inflammatory response that is less selective and prolonged after a substantial insult. Int J Dev Neurosci., 27, 691-700.
[ 37 ] Raval AP, Dave KR, Pérez-Pinzón MA. (2006) Resveratrol mimics ischemic preconditioning in the brain. J Cereb Blood Flow Metab., 26,1141–7.
[ 38 ] Rothwell PM, Warlow CP. (2005) Timing of TIAs preceding stroke: time window for prevention is very short. Neurology., 64, 817-20.
[ 39 ] Sakata Y, Zhuang H, Kwansa H, Koehler RC, Doré S. (2010) Resveratrol protects against experimental stroke: putative neuroprotective role of heme oxygenase 1. Exp Neurol., 224, 325-9.
[ 40 ] Shichita T, Muto G, Yoshimura A. (2011) T lymphocyte function in the delayed phase of ischemic brain injury. Inflammation and Regeneration., 31, 102-108.
[ 41 ] Shin JA, Lee H, Lim YK, Koh Y, Choi JH, Park EM. (2010) Therapeutic effects of resveratrol during acute periods following experimental ischemic stroke. J Neuroimmunol., 227, 93-100.
[ 42 ] Sinha K, Chaudhary G, Gupta YK. (2002) Protective effect of resveratrol against oxidative stress in middle cerebral artery occlusion model of stroke in rats. Life Sci.,71, 655–665.
[ 43 ] Smith JM, Lunga P, Story D, Harris N, Le Belle J, James MF, Pickard JD, Fawcett JW. (2007) Inosine promotes recovery of skilled motor function in a model of focal brain injury. Brain.,130, 915-25.
[ 44 ] Spence JD. (2010) Secondary stroke prevention. Nat Rev Neurol., 6, 477-86.
[ 45 ] Suwa M, Nakano H, Higaki Y, Nakamura T, Katsuta S and Kumagai, S. (2003) Increased wheel-running activity in the genetically skeletal muscle fast-twich fiber dominant rats. J. Appl. Physiol., 94, 185–192.
[ 46 ] Turnley AM, Stapleton D, Mann RJ, Witters LA, Kemp BE, Bartlett PF. (1999) Cellular distribution and developmental expression of AMP-activated protein kinase isoforms in mouse central nervous system. J Neurochem.,72,1707–16
[ 47 ] Troyano A, Fernández C, Sancho P, de Blas E, Aller P. (2001) Effect of glutathione depletion on antitumor drug toxicity (apoptosis and necrosis) in U-937 human promonocytic cells. The role of intracellular oxidation. J Biol Chem., 276, 47107-15.
[ 48 ] Tsai SK, Hung LM, Fu YT, Cheng H, Nien MW, Liu HY, Zhang FB, Huang SS. (2007) Resveratrol neuroprotective effects during focal cerebral ischemia injury via nitric oxide mechanism in rats. J Vasc Surg., 46, 346-53.
[ 49 ] Walle T, Hsieh F, DeLegge MH, Oatis JE Jr, Walle UK. (2004) High absorption but very low bioavailability of oral resveratrol in humans. Drug Metab Dispos., 32, 1377-82.
[ 50 ] Wood JG, Rogina B, Lavu S, Howitz K, Helfand SL, Tatar M, Sinclair D. (2004) Sirtuin activators mimic caloric restriction and delay ageing in metazoans. Nature., 430, 686-9.
[ 51 ] Yang J, Liu GY, Lu DL, Dai F, Qian YP, Jin XL, Zhou B. (2010) Hybrid-Increased Radical-Scavenging Activity of Resveratrol Derivatives by Incorporating a Chroman Moiety of Vitamin E. Chemistry., 16,12808-13.
[ 52 ] Yi CO, Jeon BT, Shin HJ, Jeong EA, Chang KC, Lee JE, Lee DH, Kim HJ, Kang SS, Cho GJ, Choi WS, Roh GS. (2011) Resveratrol activates AMPK and suppresses LPS-induced NF-κB-dependent COX-2 activation in RAW 264.7 macrophage cells. Anat Cell Biol., 4,194-203.
[ 53 ] Yousuf S, Atif F, Ahmad M, Hoda N, Ishrat T, Khan B, Islam F. (2009) Resveratrol exerts its neuroprotective effect by modulating mitochondrial dysfunctions and associated cell death during cerebral ischemia. Brain Res., 23, 242-53.
[ 54 ] Zhang F, Liu J, Shi JS. (2011) Anti-inflammatory activities of resveratrol in the brain: role of resveratrol in microglial activation. Eur J Pharmacol., 636,1-7.