Abstract
Astroglial cells are key modulators of neuropathology events. Resveratrol, a redox-active compound present in grapes and wine, has a wide range of biological effects. The aim of this study was to investigate whether resveratrol is able to prevent hydrogen peroxide (H2O2)-induced oxidative damage in C6 astroglial cells. We found that following a short oxidative insult (Model I—1 mM H2O2/30 min), resveratrol increased glutamate uptake (60%), glutamine synthetase (GS) (139%), glutathione (GSH) (120%), and S100B secretion (24%); and attenuated DCFH oxidation (34%) as compared to H2O2 values. Under less intense (0.1 mM H2O2), but lasting (6 h) insult (Model II), resveratrol had an opposite effect, potentiating the H2O2-induced decrease in glutamate uptake (from 34 to 63%), in GS (from 22 to 50%), in GSH (from 22 to 54%), and also potentiating DCFH oxidation (from 24 to 38%). The transcription factor, NF-κB, was activated in both models. Cell morphology alterations were also observed in the presence of H2O2 with process-bearing cells, accompanied by cell body retraction and actin reorganization. This effect was not prevented by resveratrol, but was prevented by lysophosphatidic acid (LPA), a specific upstream positive regulator of Rho A. In summary, these findings showed that resveratrol, a redox-active compound, was able to modulate important neurotrophic function of astroglial cells under different oxidative conditions.
Similar content being viewed by others
References
Atten MJ, Godoy-Romero E, Attar BM, Milson T, Zopel M, Holian O (2005) Resveratrol regulates cellular PKC alpha and delta to inhibit growth and induce apoptosis in gastric cancer cells. Invest New Drugs 23:111–119
Bak LK, Schousboe A, Waagepetersen HS (2006) The glutamate/GABA-glutamine cycle: aspects of transport, neurotransmitter homeostasis and ammonia transfer. J Neurochem 98:641–653
Ballard DW, Walker WH, Doerre S, Sista P, Molitor JA, Dixon EP, Peffer NJ, Hannink M, Greene WC (1990) The v-rel oncogene encodes a kappa B enhancer binding protein that inhibits NF-kappa B function. Cell 63:803–814
Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5:493–506
Baur JA et al (2006) Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444:337–342
Benda P, Lightbody J, Sato G, Levine L, Sweet W (1968) Differentiated rat glial cell strain in tissue culture. Science 161:370–371
Browne RW, Armstrong D (1998) Reduced glutathione and glutathione disulfide. Methods Mol Biol 108:347–352
Bull ND, Wood JP, Osborne NN, Barnett NL (2007) Protein kinase C-mediated modulation of glutamate transporter activity in rat retina. Curr Eye Res 32:123–131
Castagne V, Gautschi M, Lefevre K, Posada A, Clarke PG (1999) Relationships between neuronal death and the cellular redox status. Focus on the developing nervous system. Prog Neurobiol 59:397–423
Cechin SR, Gottfried C, Prestes CC, Andrighetti L, Wofchuk ST, Rodnight R (2002) Astrocyte stellation in saline media lacking bicarbonate: possible relation to intracellular pH and tyrosine phosphorylation. Brain Res 946:12–23
Czyz M (2005) Specificity and selectivity of the NFkappaB response. Postepy Biochem 51:60–68
de Almeida LM, Pineiro CC, Leite MC, Brolese G, Tramontina F, Feoli AM, Gottfried C, Goncalves CA (2007) Resveratrol increases glutamate uptake, glutathione content, and S100B secretion in cortical astrocyte cultures. Cell Mol Neurobiol 27:661–668
De la Lastra CA, Villegas I (2007) Resveratrol as an antioxidant and pro-oxidant agent: mechanisms and clinical implications. Biochem Soc Trans 35:1156–1160
de Souza DF, Leite MC, Quincozes-Santos A, Nardin P, Tortorelli LS, Rigo MM, Gottfried C, Leal RB, Goncalves CA (2009) S100B secretion is stimulated by IL-1beta in glial cultures and hippocampal slices of rats: likely involvement of MAPK pathway. J Neuroimmunol 206:52–57
Delmas D, Jannin B, Latruffe N (2005) Resveratrol: preventing properties against vascular alterations and ageing. Mol Nutr Food Res 49:377–395
Donato R (2001) S100: a multigenic family of calcium-modulated proteins of the EF-hand type with intracellular and extracellular functional roles. Int J Biochem Cell Biol 33:637–668
dos Santos AQ, Nardin P, Funchal C, de Almeida LM, Jacques-Silva MC, Wofchuk ST, Goncalves CA, Gottfried C (2006) Resveratrol increases glutamate uptake and glutamine synthetase activity in C6 glioma cells. Arch Biochem Biophys 453:161–167
Dringen R (2000) Metabolism and functions of glutathione in brain. Prog Neurobiol 62:649–671
Dringen R, Hamprecht B (1997) Involvement of glutathione peroxidase and catalase in the disposal of exogenous hydrogen peroxide by cultured astroglial cells. Brain Res 759:67–75
Dringen R, Pawlowski PG, Hirrlinger J (2005) Peroxide detoxification by brain cells. J Neurosci Res 79:157–165
Feng Z, Zhang JT (2004) Protective effect of melatonin on beta-amyloid-induced apoptosis in rat astroglioma C6 cells and its mechanism. Free Radic Biol Med 37:1790–1801
Fremont L (2000) Biological effects of resveratrol. Life Sci 66:663–673
Funchal C, Dos Santos AQ, Jacques-Silva MC, Zamoner A, Gottfried C, Wajner M, Pessoa-Pureur R (2005) Branched-chain alpha-keto acids accumulating in maple syrup urine disease induce reorganization of phosphorylated GFAP in C6-glioma cells. Metab Brain Dis 20:205–217
Gloire G, Legrand-Poels S, Piette J (2006) NF-kappaB activation by reactive oxygen species: fifteen years later. Biochem Pharmacol 72:1493–1505
Goncalves CA, Concli Leite M, Nardin P (2008) Biological and methodological features of the measurement of S100B, a putative marker of brain injury. Clin Biochem 41:755–763
Gottfried C, Tramontina F, Goncalves D, Goncalves CA, Moriguchi E, Dias RD, Wofchuk ST, Souza DO (2002) Glutamate uptake in cultured astrocytes depends on age: a study about the effect of guanosine and the sensitivity to oxidative stress induced by H(2)O(2). Mech Ageing Dev 123:1333–1340
Guasch RM, Tomas M, Minambres R, Valles S, Renau-Piqueras J, Guerri C (2003) RhoA and lysophosphatidic acid are involved in the actin cytoskeleton reorganization of astrocytes exposed to ethanol. J Neurosci Res 72:487–502
Had-Aissouni L, Re DB, Nieoullon A, Kerkerian-Le Goff L (2002) Importance of astrocytic inactivation of synaptically released glutamate for cell survival in the central nervous system—are astrocytes vulnerable to low intracellular glutamate concentrations? J Physiol Paris 96:317–322
Hall A (1998) Rho GTPases and the actin cytoskeleton. Science 279:509–514
Halliwell B (2006) Reactive species and antioxidants. Redox biology is a fundamental theme of aerobic life. Plant Physiol 141:312–322
Han Y, Brasier AR (1997) Mechanism for biphasic rel A. NF-kappaB1 nuclear translocation in tumor necrosis factor alpha-stimulated hepatocytes. J Biol Chem 272:9825–9832
He F, Sun YE (2007) Glial cells more than support cells? Int J Biochem Cell Biol 39:661–665
Hertz L (2006) Glutamate, a neurotransmitter—and so much more. A synopsis of Wierzba III. Neurochem Int 48:416–425
Jang M, Cai L, Udeani GO, Slowing KV, Thomas CF, Beecher CW, Fong HH, Farnsworth NR, Kinghorn AD, Mehta RG, Moon RC, Pezzuto JM (1997) Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 275:218–220
Kleindienst A, Ross Bullock M (2006) A critical analysis of the role of the neurotrophic protein S100B in acute brain injury. J Neurotrauma 23:1185–1200
Kranenburg O, Moolenaar WH (2001) Ras-MAP kinase signaling by lysophosphatidic acid and other G protein-coupled receptor agonists. Oncogene 20:1540–1546
Kundu JK, Surh YJ (2004) Molecular basis of chemoprevention by resveratrol: NF-kappaB and AP-1 as potential targets. Mutat Res 555:65–80
Leite MC, Galland F, Brolese G, Guerra MC, Bortolotto JW, Freitas R, Almeida LM, Gottfried C, Goncalves CA (2008) A simple, sensitive and widely applicable ELISA for S100B: methodological features of the measurement of this glial protein. J Neurosci Methods 169:93–99
Lortet S, Samuel D, Had-Aissouni L, Masmejean F, Kerkerian-Le Goff L, Pisano P (1999) Effects of PKA and PKC modulators on high affinity glutamate uptake in primary neuronal cell cultures from rat cerebral cortex. Neuropharmacology 38:395–402
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Mangoura D, Sakellaridis N, Jones J, Vernadakis A (1989) Early and late passage C-6 glial cell growth: similarities with primary glial cells in culture. Neurochem Res 14:941–947
Markiewicz I, Lukomska B (2006) The role of astrocytes in the physiology and pathology of the central nervous system. Acta Neurobiol Exp (Wars) 66:343–358
McBean GJ, Roberts PJ (1985) Neurotoxicity of l-glutamate and dl-threo-3-hydroxyaspartate in the rat striatum. J Neurochem 44:247–254
McKenna MC (2007) The glutamate–glutamine cycle is not stoichiometric: fates of glutamate in brain. J Neurosci Res 85:3347–3358
Murias M, Jager W, Handler N, Erker T, Horvath Z, Szekeres T, Nohl H, Gille L (2005) Antioxidant, prooxidant and cytotoxic activity of hydroxylated resveratrol analogues: structure–activity relationship. Biochem Pharmacol 69:903–912
Nakano H, Nakajima A, Sakon-Komazawa S, Piao JH, Xue X, Okumura K (2006) Reactive oxygen species mediate crosstalk between NF-kappaB and JNK. Cell Death Differ 13:730–737
Papa S, Bubici C, Zazzeroni F, Pham CG, Kuntzen C, Knabb JR, Dean K, Franzoso G (2006) The NF-kappaB-mediated control of the JNK cascade in the antagonism of programmed cell death in health and disease. Cell Death Differ 13:712–729
Parker KK, Norenberg MD, Vernadakis A (1980) “Transdifferentiation” of C6 glial cells in culture. Science 208:179–181
Pervaiz S (2004) Chemotherapeutic potential of the chemopreventive phytoalexin resveratrol. Drug Resist Updat 7:333–344
Quincozes-Santos A, Andreazza AC, Nardin P, Funchal C, Goncalves CA, Gottfried C (2007) Resveratrol attenuates oxidative-induced DNA damage in C6 Glioma cells. Neurotoxicology 28:886–891
Rothstein JD, Martin LJ, Kuncl RW (1992) Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis. N Engl J Med 326:1464–1468
Schulz JB, Lindenau J, Seyfried J, Dichgans J (2000) Glutathione, oxidative stress and neurodegeneration. Eur J Biochem 267:4904–4911
Silverstein FS, Buchanan K, Johnston MV (1986) Perinatal hypoxia-ischemia disrupts striatal high-affinity [3H]glutamate uptake into synaptosomes. J Neurochem 47:1614–1619
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
Slater SJ, Seiz JL, Cook AC, Stagliano BA, Buzas CJ (2003) Inhibition of protein kinase C by resveratrol. Biochim Biophys Acta 1637:59–69
Soleas GJ, Diamandis EP, Goldberg DM (1997) Resveratrol: a molecule whose time has come? And gone? Clin Biochem 30:91–113
Tramontina F, Leite MC, Goncalves D, Tramontina AC, Souza DF, Frizzo JK, Nardin P, Gottfried C, Wofchuk ST, Goncalves CA (2006) High glutamate decreases S100B secretion by a mechanism dependent on the glutamate transporter. Neurochem Res 31:815–820
Van Eldik LJ, Wainwright MS (2003) The Janus face of glial-derived S100B: beneficial and detrimental functions in the brain. Restor Neurol Neurosci 21:97–108
Vieira de Almeida LM, Pineiro CC, Leite MC, Brolese G, Leal RB, Gottfried C, Goncalves CA (2008) Protective effects of resveratrol on hydrogen peroxide induced toxicity in primary cortical astrocyte cultures. Neurochem Res 33:8–15
Virgili M, Contestabile A (2000) Partial neuroprotection of in vivo excitotoxic brain damage by chronic administration of the red wine antioxidant agent, trans-resveratrol in rats. Neurosci Lett 281:123–126
Zhu D, Tan KS, Zhang X, Sun AY, Sun GY, Lee JC (2005) Hydrogen peroxide alters membrane and cytoskeleton properties and increases intercellular connections in astrocytes. J Cell Sci 118:3695–3703
Acknowledgments
This work was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), and FINEP/Rede IBN 01.06.0842-00.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Quincozes-Santos, A., Nardin, P., de Souza, D.F. et al. The Janus Face of Resveratrol in Astroglial Cells. Neurotox Res 16, 30–41 (2009). https://doi.org/10.1007/s12640-009-9042-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12640-009-9042-0