Resveratrol inhibits cadmium induced neuronal apoptosis by modulating calcium signalling pathway via regulation of MAPK/mTOR network
Keywords:Apoptosis, Calcium signalling pathway, MAPK, mTOR, Neurotoxicity, Resveratrol
Cadmium, a toxic environmental contaminant, induces oxidative stress leading to various neurodegenerative disorders, where it interferes with homeos-tasis of intracellular free calcium ([Ca2+]i), leading to cellular damage and apoptosis. We investigated whether resveratrol, a plant-derived antioxidant could offer protection against cadmium-induced neuroapoptosis. Primary cortical neurons were exposed to cadmium (10 or 20 µM) with/without prior exposure to resveratrol (5, 10 or 20 µM) for 12 hours and unexposed cells served as control. Resveratrol caused marked reduction in cadmium-induced neuronal apoptosis and down-regulated caspase-3 expressions. Cadmium-induced marked elevations in reactive oxygen species, and ([Ca2+]i) levels were potentially reduced by resveratrol. Resveratrol effectively regulated the alterations observed in the activation levels of mitogen-activated protein kinases (MAPKs) and proteins of mammalian target of rapamycin (mTOR) pathways. Thus, resveratrol effectively protected the cortical neurons exposed to cadmium by modulating the ([Ca2+]i) levels and regulating the MAPK/mTOR pathways.
Abib RT, Peres KC, Barbosa AM, Peres TV, Bernardes A, Zimmermann LM, Quincozes-Santos A, Fiedler HD, Leal RB, Farina M, Gottfried C. Epigallocatechin-3-gallate protects rat brain mitochondria against cadmium-induced damage. Food Chem Toxicol. 2011; 49: 2618-23.
Bai X, Jiang Y. Key factors in mTOR regulation. Cell Mol Life Sci. 2010; 67: 239-53.
Baxter LC, Sparks DL, Johnson SC, Lenoski B, Lopez JE, Connor DJ, Sabbagh MN. Relationship of cognitive measures and gray and white matter in Alzheimers disease. J Alzheimers Dis. 2006; 9: 253-60.
Beyersmann D, Hechtenberg S. Cadmium, gene regulation, and cellular signalling in mammalian cells. Toxicol Appl Pharmacol. 1997; 144: 247-61.
Biagioli M, Pifferi S, Ragghianti M, Bucci S, Rizzuto R, Pinton P. Endoplasmic reticulum stress and alteration in calcium homeostasis are involved in cadmium-induced apoptosis. Cell Calcium. 2008; 43: 184-95.
Bjornsti M, Houghton P. The TOR pathway: a target for cancer therapy. Nat Rev Cancer. 2004; 4: 335-48.
Chen L, Liu L, Huang S. Cadmium activates the mitogen-activated protein kinase (MAPK) pathway via induction of reactive oxygen species and inhibition of protein phosphatases 2A and 5. Free Radic Biol Med. 2008; 45: 1035-44.
Chen L, Xu B, Liu L, Luo Y, Zhou H, Chen W, Shen T, Han X, Kontos CD, Huang S. Cadmium induction of reactive oxygen species activates the mTOR pathway, leading to neuronal cell death. Free Radic Biol Med. 2011; 50: 624-32.
Chen L, Xu B, Liu L, Luo Y, Zhou H, Chen W, Shen T, Han X, Kontos CD, Huang S. Cadmium induction of reactive oxygen species activates the mTOR pathway, leading to neuronal cell death. Free Radic Biol Med. 2011b; 50: 624-32.
Chen S, Xu Y, Xu B Guo M, Zhang Z, Liu L, Ma H, Chen Z, Luo Y, Huang S, Chen L. CaMKII is involved in cadmium activation of MAPK and mTOR pathways leading to neuronal cell death. J Neurochem. 2011c; 119: 1108-18.
Chen S, Gu C, Xu C, Zhang J, Xu Y, Ren Q, Guo M, Huang S, Chen L. Celastrol prevents cadmium-induced neuronal cell death via targeting JNK and PTEN-Akt/mTOR network. J Neurochem. 2014; 128(2): 256-66.
Cheng A, Wang S, Yang D, Xiao R, Mattson MP. Calmodulin mediates brain-derived neurotrophic factor cell survival signaling upstream of Akt kinase in embryonic neocortical neurons. J Biol Chem. 2003; 278: 7591-99.
Chuang S. M., Wang I. C. and Yang J. L. Roles of JNK, p38 and ERK mitogen-activated protein kinases in the growth inhibition and apoptosis induced by cadmium. Carcinogenesis 2000; 21: 1423-32.
Clapham DE. Calcium signaling. Cell 2007; 131: 1047-58.
Coccini T, Barni S, Vaccarone R, Mustarelli P, Manzo L, Roda E. Pulmonary toxicity of instilled cadmium-doped silica nanoparticles during acute and subacute stages in rats. Histol Histopathol. 2013; 28: 195-209.
Coutant A, Lebeau J, Bidon-Wagner N, Levalois C, Lectard B, Chevillard S. Cadmium-induced apoptosis in lymphoblastoid cell line: Involvement of caspase-dependent and -independent pathways. Biochimie. 2006; 88: 1815-22.
Cullberg KB, Foldager CB, Lind M, Richelsena B, Pedersena SB. Inhibitory effects of resveratrol on hypoxia-induced inflammation in 3T3-L1 adipocytes and macrophages. J Funct Foods. 2014; 7: 171-79.
Deniaud A, Sharaf el dein O, Maillier E, Poncet D, Kroemer G, Lemaire C, Brenner C. Endoplasmic reticulum stress induces calcium-dependent permeability transition, mitochondrial outer membrane permeabilization and apoptosis. Oncogene 2008; 27: 285-99.
Don AS, Tsang CK, Kazdoba TM, DArcangelo G, Young W, Zheng XF. Targeting mTOR as a novel therapeutic strategy for traumatic CNS injuries. Drug Discov Today. 2012; 17: 861-68.
Figueiredo-Pereira ME, Yakushin S, Cohen G. Disruption of the intracellular sulfhydryl homeostasis by cadmium-induced oxidative stress leads to protein thiolation and ubiquitination in neuronal cells. J Biol Chem. 1998; 273: 12703-09.
Fremont L. Biological effects of resveratrol. Life Sciences 2000; 66: 663-73.
Fulda S. Resveratrol and derivatives for the prevention and treatment of cancer. Drug Discovery Today 2010; 15: 757-65.
Green KN, Peers C. Divergent pathways account for two distinct effects of amyloid beta peptides on exocytosis and Ca(2+) currents: involvement of ROS and NF-kappaB. J Neurochem. 2002; 81: 1043-51.
Gulati P, Gaspers LD, Dann SG, Joaquin M, Nobukuni T, Natt F, Kozma SC, Thomas AP, Thomas G. Amino acids activate mTOR complex 1 via Ca2+ /CaM signaling to hVps34. Cell Metab. 2008; 7: 456-65.
Hamanoue M, Sato K, Takamatsu K. Inhibition of p38 mitogen-activated protein kinase-induced apoptosis in cultured mature oligodendrocytes using SB202190 and SB203580. Neurochem Int. 2007; 51: 16-24.
Jiang LF, Yao TM, Zhu ZL, Wang C, Ji LN. Impacts of Cd(II) on the conformation and self-aggregation of Alzheimers tau fragment corresponding to the third repeat of microtubule-binding domain. Biochim Biophys Acta. 2007; 1774: 1414-21
Kim J, Sharma RP. Calcium-mediated activation of c-Jun NH2-terminal kinase (JNK) and apoptosis in response to cadmium in murine macrophages. Toxicol Sci. 2004; 81: 518-27.
Kim S, Moon C, Eun S, Ryu P, Jo S. Identification of ASK1, MKK4, JNK, c-Jun, and caspase-3 as a signaling cascade involved in cadmium-induced neuronal cell apoptosis. Biochem Biophys Res Commun. 2005; 328: 326-34.
Lemarie A, Lagadic-Gossmann D, Morzadec C, Allain N, Fardel O, Vernhet L. Cadmium induces caspase-independent apoptosis in liver Hep3B cells: Role for calcium in signaling oxidative stress-related impairment of mitochondria and relocation of endonuclease G and apoptosis-inducing factor. Free Radic Biol Med. 2004; 36: 1517-31.
Lephart ED, Sommerfeldt JM, Andrus MB. Resveratrol: Influences on gene expression in human skin. J Funct Foods. 2014; 10:377-84.
Lin CY, Hsiao WC, Wright DE, Hsu CL, Lo YC, Hsu GSW, Kao CF. Resveratrol activates the histone H2B ubiquitin ligase, RNF20, in MD A-MB-231 breast cancer cells. J Funct Foods. 2013; 5: 790-800.
Liu Y, Templeton DM. Initiation of caspase-independent death in mouse mesangial cells by Cd2+: Involvement of p38 kinase and CaMK-II. J Cell Physiol. 2008; 217: 307-18.
Lohmann RD, Beyersmann D. Cadmium and zinc mediated changes of the Ca2+ -dependent endonuclease in apoptosis. Biochem Biophys Res Commun. 1993; 190: 1097-1103.
Lopez E, Figueroa S, Oset-Gasque MJ, Gonzalez MP. Apoptosis and necrosis: two distinct events induced by cadmium in cortical neurons in culture. Br J Pharmacol. 2003; 138: 901-11.
Lopez E, Arce C, Oset-Gasque MJ, Canadas S, Gonzalez MP. Cadmium induces reactive oxygenspecies generation and lipid peroxidation in cortical neurons in culture. Free Radic Biol Med. 2006; 40: 940-51.
Lu HF, Sue CC, Yu CS, Chen SC, Chen GW, Chung JG. Diallyl disulfide (DADS) induced apoptosis undergo caspase-3 activity in human bladder cancer T24 cells. Food Chem Toxicol. 2004; 42: 1543-52.
Lukawski K, Nieradko B, Sieklucka-Dziuba M. Effects of cadmium on memory processes in mice exposed to transient cerebral oligemia. Neurotoxicol Teratol. 2005; 27: 575-84.
Maehama T, Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998; 273: 13375-78.
Mao WP, Ye JL, Guan ZB, Zhao JM, Zhang C, Zhang NN, Jiang P, Tian T. Cadmium induces apoptosis in human embryonic kidney (HEK) 293 cells by caspase-dependent and -independent pathways acting on mitochondria. Toxicol in Vitro 2007; 21: 343-54.
Mendez-Armenta M, Rios C. Cadmium neurotoxicity. Environ Toxicol Pharmacol. 2007; 23: 350-58.
Misra UK, Gawdi G, Akabani G, Pizzo SV. Cadmium-induced DNA synthesis and cell proliferation in macrophages: The role of intracellular calcium and signal transduction mechanisms. Cell Signal 2002; 14: 327-40.
Misra UK, Gawdi G, Pizzo SV. Induction of mitogenic signalling in the 1LN prostate cell line on exposure to submicromolar concentrations of cadmium+. Cell Signal 2003; 15: 1059-70.
Napolitano JR, Liu MJ, Bao S, Crawford M, Nana-Sinkam P, Cormet-Boyaka E, Knoell DL. Cadmium-mediated toxicity of lung epithelia is enhanced through NF-kappaB mediated transcriptional activation of the human zinc transporter ZIP8. Am J Physiol Lung Cell Mol Physiol. 2012; 302: L909-18.
Neher E, Sakaba T. Multiple roles of calcium ions in the regulation of neurotransmitter release. Neuron 2008; 59: 861-72.
Nemmiche S, Chabane-Sari D, Kadri M, Guiraud P. Cadmium-induced apoptosis in the BJAB human B cell line: Involvement of PKC/ERK1/2/JNK signaling pathways in HO-1 expression. Toxicology 2012; 300: 103-111.
Nishimura Y, Yamaguchi JY, Kanada A, Horimoto K, Kanemaru K, Satoh M, Oyama Y. Increase in intracellular Cd2+ concentration of rat cerebellar granule neurons incubated with cadmium chloride: Cadmium cytotoxicity under external Ca2+ -free condition. Toxicol in Vitro 2006; 20: 211-16.
Okuda B, Iwamoto Y, Tachibana H, Sugita M. Parkinsonism after acute cadmium poisoning. Clin Neurol Neurosurg. 1997; 99: 263-65.
Oliveira H, Lopes T, Almeida T, Pereira Mde L, Santos C. Cadmium induced genetic instability in mice testis. Hum Exp Toxicol. 2012; 31: 1228-36.
Panayi AE, Spyrou NM, Iversen BS, White MA, Part P. Determination of cadmium and zinc in Alzheimers brain tissue using inductively coupled plasma mass spectrometry. J Neurol Sci. 2002; 195: 1-10
Pihl RO, Parkes M. Hair element content in learning disabled children. Science 1977; 198: 204-06.
Polak P, Hall MN. mTOR and the control of whole body metabolism. Curr Opin Cell Biol. 2009; 21: 209-18.
Prabu SM, Shagirtha K, Renugadevi J. Naringenin in combina-tion with vitamins C and E potentially protects oxidative stress-mediated hepatic injury in cadmium-intoxicated rats. J Nutr Sci Vitaminol (Tokyo). 2011; 57: 177-85.
Ravikumar B, Vacher C, Berger Z, Davies JE, Luo S, Oroz LG, Scaravilli F, Easton DF, Duden R, O'Kane CJ, Rubinsztein DC. Inhibition of mTOR induces autophagy and reduces toxicity of polyglutamine expansions in fly and mouse models of Huntington disease. Nat Genet. 2004; 36: 585-95.
Ruiz A, Matute C, Alberdi E. Endoplasmic reticulum Ca2+ Release through ryanodine and IP3 receptors contributes to neuronal excitotoxicity. Cell Calcium 2009; 46: 273-81.
Sinicropi MS, Amantea D, Caruso A, Saturnino C. Chemical and biological properties of toxic metals and use of chelating agents for the pharmacological treatment of metal poisoning. Arch Toxicol. 2010; 84: 501-20.
Son YO, Lee JC, Hitron JA, Pan J, Zhang Z, Shi X. Cadmium induces intracellular Ca2+ - and H2O2-dependent apoptosis through JNK- and p53-mediated pathways in skin epidermal cell line. Toxicol Sci. 2010; 113: 127-37.
Sovak M. Grape extract, resveratrol, and its analogs: A review. J Med Food 2001; 4: 93-105.
Stohs SJ, Bagchi D. Oxidative mechanisms in the toxicity of metal ions. Free Radic Biol Med. 1995; 18: 321-36.
Surmeier DJ, Guzman JN, Sanchez-Padilla J. Calcium, cellular aging, and selective neuronal vulnerability in Parkinsons disease. Cell Calcium 2010; 47: 175-82.
Swiech L, Perycz M, Malik A, Jaworski J. Role of mTOR in physiology and pathology of the nervous system. Biochim Biophys Acta. 2008; 1784: 116-32.
Thevenod F. Cadmium and cellular signaling cascades: To be or not to be? Toxicol Appl Pharmacol. 2009; 238: 221-39.
Vacotto M, Coso O, Fiszer de Plazas S. Programmed cell death and differential JNK, p38 and ERK response in a prenatal acute hypoxic hypoxia model. Neurochem Int. 2008; 52: 857-63.
Wang S, Tang M, Pei B, Xiao X, Wang J, Hang H, Wu L. Cadmium-induced germline apoptosis in Caenorhabditis elegans: The roles of HUS1, p53, and MAPK signalling pathways. Toxicol Sci. 2008; 102: 345-51.
Wang L, Cao J, Chen D, Liu X, Lu H, Liu Z. Role of oxidative stress, apoptosis, and intracellular homeostasis in primary cultures of rat proximal tubular cells exposed to cadmium. Biol Trace Elem Res. 2009; 127: 53-68.
Wright RO, Amarasiriwardena C, Woolf AD, Jim R, Bellinger DC. Neuropsychological correlates of hair arsenic, manganese, and cadmium levels in school-age children residing near a hazardous waste site. Neurotoxicology 2006; 27: 210-16.
Xie Z, Zhang Y, Li A, Li P, Ji W, Huang D. Cd-induced apoptosis was mediated by the release of Ca2+ from intracellular Ca storage. Toxicol Lett. 2010; 192: 115-18
Xu B, Chen S, Luo Y, Chen Z, Liu L, Zhou H, Chen W, Shen T, Han X, Chen L, Huang S. Calcium signaling is involved in cadmium-induced neuronal apoptosis via induction of reactive oxygen species and activation of MAPK/mTOR net-work. PLoS One 2011; 6: e19052.
Yan Y, Bian JC, Zhong LX, Zhang Y, Sun Y, Liu ZP. Oxidative stress and apoptotic changes of rat cerebral cortical neurons exposed to cadmium in vitro. Biomed Environ Sci. 2012; 25: 172-81.
Yang CS, Tzou BC, Liu YP, Tsai MJ, Shyue SK, Tzeng SF. Inhibition of cadmium-induced oxidative injury in rat primary astrocytes by the addition of antioxidants and the reduction of intracellular calcium. J Cell Biochem. 2008; 103: 825-34.
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