Abstract
Background
Chronic inorganic arsenic (iAs) exposure induces deleterious effects on CNS including oxidative stress, cognitive deficits and altered brain neurochemistry. Little is known about the association between iAs and estrogen receptor expression in brain regions.
Aims and objectives
Owing to the neuroprotective and estrogenic activities of resveratrol (RES), we examined the combined effects of arsenic trioxide (As2O3) and RES on neurobehavioural functions, estrogen signalling and associated neurochemical changes in mouse hippocampus.
Materials and methods
As2O3 alone (2 and 4 mg/kg bw) or along with RES (40 mg/kg bw) was administered orally for 45 days to adult female mice. From days 33 to 45, open field, elevated plus maze and Morris water maze tests were conducted to evaluate locomotion, anxiety and learning and memory. On day 46, animals were euthanized and brain tissue and hippocampi obtained therefrom were processed for atomic absorption spectrophotometry and western blotting respectively.
Results
As2O3 alone exposure resulted in enhanced anxiety levels, reduced locomotion and impaired learning and memory. As2O3-induced behavioural deficits were accompanied by downregulation of estrogen receptor (ERα) expression with a concomitant reduction of BDNF and NMDAR 2B levels in the hippocampus. However, the behavioural alterations and expression of these markers were restored in RES-supplemented mice. Moreover, a dose-dependent iAs accumulation was observed in serum and brain tissues of mice receiving As2O3 alone whereas simultaneous administration of As2O3 with RES facilitated iAs efflux.
Conclusions
These results suggest that reduced ERα expression with associated downregulation of BDNF and NMDAR 2B levels could be a mechanism by which iAs induces cognitive impairment; hence, the modulation of estrogen-NMDAR-BDNF pathway by RES represents a potential avenue to recover behavioural deficits induced by this neurotoxin.
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References
Aydin S, Sahin TT, Bacanli M et al (2016) Resveratrol protects sepsis-induced oxidative DNA damage in liver and kidney of rats. Balkan Med J 33:594–601. https://doi.org/10.5152/balkanmedj.2016.15516
Bae-Jump VL, Zhou C, Boggess JF, Gehrig PA (2008) Arsenic trioxide (As2O3) inhibits expression of estrogen receptor-alpha through regulation of the mitogen-activated protein kinase (MAPK) pathway in endometrial cancer cells. Reprod Sci 15:1011–1017. https://doi.org/10.1177/1933719108324134
Bai Y, Yang H, Zhang G et al (2016) Inhibitory effects of resveratrol on the adhesion, migration and invasion of human bladder cancer cells. Mol Med Rep 15(2):28000872. https://doi.org/10.3892/mmr.2016.6051
Bardullas U, Limón-Pacheco JH, Giordano M et al (2009) Chronic low-level arsenic exposure causes gender-specific alterations in locomotor activity, dopaminergic systems, and thioredoxin expression in mice. Toxicol Appl Pharmacol 239:169–177. https://doi.org/10.1016/j.taap.2008.12.004
Barr FD, Krohmer LJ, Hamilton JW, Sheldon LA (2009) Disruption of histone modification and CARM1 recruitment by arsenic represses transcription at glucocorticoid receptor-regulated promoters. PLoS ONE 4(8):e6766. https://doi.org/10.1371/journal.pone.0006766
Baur JA, Sinclair DA (2006) Therapeutic potential of resveratrol: the in vivo evidence. Nat Rev Drug Discov 5:493–506. https://doi.org/10.1038/nrd2060
Bishayee A, Barnes KF, Bhatia D et al (2010) Resveratrol suppresses oxidative stress and inflammatory response in diethylnitrosamine-initiated rat hepatocarcinogenesis. Cancer Prev Res 3:753–763. https://doi.org/10.1158/1940-6207.CAPR-09-0171
Bodwell JE, Gosse JA, Nomikos AP, Hamilton JW (2006) Arsenic disruption of steroid receptor gene activation: complex dose - response effects are shared by several steroid receptors. Chem Res Toxicol 19:1619–1629. https://doi.org/10.1021/tx060122q
Bodwell JE, Kingsley LA, Hamilton JW (2004) Arsenic at very low concentrations alters glucocorticoid receptor (GR)-mediated gene activation but not GR-mediated gene repression: complex dose-response effects are closely correlated with levels of activated GR and require a functional GR DNA binding d. Chem Res Toxicol 17:1064–1076. https://doi.org/10.1021/tx0499113
Byers SL, Wiles MV, Dunn SL, Taft RA (2012) Mouse estrous cycle identification tool and images. PLoS ONE 7:1–5. https://doi.org/10.1371/journal.pone.0035538
Calderón J, Navarro ME, Jimenez-Capdeville ME et al (2001) Exposure to arsenic and lead and neuropsychological development in Mexican children. Environ Res 85:69–76. https://doi.org/10.1006/enrs.2000.4106
Caligioni CS (2009) Assessing reproductive status/stages in mice. Curr Protoc Neurosci 1–8. https://doi.org/10.1002/0471142301.nsa04is48
Carew MW, Naranmandura H, Shukalek CB et al (2011) Monomethylarsenic diglutathione transport by the human multidrug resistance protein 1 (MRP1/ABCC1). Drug Metab Dispos 39:2298–2304. https://doi.org/10.1124/dmd.111.041673
Carvajal FJ, Mattison HA, Cerpa W (2016) Role of NMDA receptor-mediated glutamatergic signaling in chronic and acute neuropathologies. Neural Plast 2016:2016–2701526. https://doi.org/10.1155/2016/2701526
Chang CY, Guo HR, Tsai WC et al (2015) Subchronic arsenic exposure induces anxiety-like behaviors in normal mice and enhances depression-like behaviors in the chemically induced mouse model of depression. Biomed Res Int 2015(8):1–12. https://doi.org/10.1155/2015/159015
Chatterjee A, Chatterji U (2010) Arsenic abrogates the estrogen-signaling pathway in the rat uterus. Reprod Biol Endocrinol 8:1–11. https://doi.org/10.1186/1477-7827-8-80
Chattopadhyay S, Ghosh S, Chaki S et al (1999) Effect of sodium arsenite on plasma levels of gonadotrophins and ovarian steroidogenesis in mature albino rats: duration-dependent response. J Toxicol Sci 24:425–431
Chattopadhyay S, Pal Ghosh S, Ghosh D, Debnath J (2003) Effect of dietary co-administration of sodium selenite on sodium arsenite-induced ovarian and uterine disorders in mature albino rats. Toxicol Sci 75:412–422. https://doi.org/10.1093/toxsci/kfg194
Chen G-C, Guan L-S, Hu W-L, Wang Z-Y (2002) Functional repression of estrogen receptor a by arsenic trioxide in human breast cancer cells. Anticancer Res 22:633–638
Te CC, Lin WF, Kong ZL et al (2013) Taurine prevented cell cycle arrest and restored neurotrophic gene expression in arsenite-treated SH-SY5Y cells. Amino Acids 45:811–819. https://doi.org/10.1007/s00726-013-1524-y
Chow SK, Chan JY, Fung KP (2004) Suppression of cell proliferation and regulation of estrogen receptor alpha signaling pathway by arsenic trioxide on human breast cancer MCF-7 cells. J Endocrinol 182:325–337
Ciarrocca M, Tomei F, Caciari T et al (2012) Exposure to arsenic in urban and rural areas and effects on thyroid hormones. Inhal Toxicol 24:589–598. https://doi.org/10.3109/08958378.2012.703251
Cobley JN, Fiorello ML, Bailey DM (2018) 13 Reasons why the brain is susceptible to oxidative stress. Redox Biol 15:490–503. https://doi.org/10.1016/j.redox.2018.01.008
Dennis AP, O’Malley BW (2005) Rush hour at the promoter: how the ubiquitin-proteasome pathway polices the traffic flow of nuclear receptor-dependent transcription. J Steroid Biochem Mol Biol 93:139–151. https://doi.org/10.1016/j.jsbmb.2004.12.015
Diamanti-Kandarakis E, Bourguignon JP, Giudice LC et al (2009) Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocr Rev 30:293–342
Dias GP, Cocks G, Do Nascimento Bevilaqua MC et al (2016) Resveratrol: a Potential Hippocampal Plasticity Enhancer. Oxid Med Cell Longev 2016(2016):9651236. https://doi.org/10.1155/2016/9651236
Du J, Zhou N, Liu H et al (2012) Arsenic induces functional re-expression of Estrogen receptor α by demethylation of DNA in Estrogen receptor-negative human breast cancer. PLoS ONE 7:1–10. https://doi.org/10.1371/journal.pone.0035957
Emadi A, Gore SD (2010) Arsenic trioxide - An old drug rediscovered. Blood Rev 24:191–199. https://doi.org/10.1016/j.blre.2010.04.001
Gangopadhyay S, Sharma V, Chauhan A, Srivastava V (2019) Potential facet for prenatal arsenic exposure paradigm: linking endocrine disruption and epigenetics. Nucl 62:127–142
Gehm BD, Mcandrews JM, Chien P-Y, Jameson JL (1997) Resveratrol, a polyphenolic compound found in grapes and wine, is an agonist for the estrogen receptor. Physiology 94:14138–14143. https://doi.org/10.1073/pnas.94.25.14138
Guan H, Li S, Guo Y et al (2016) Subchronic exposure to arsenic represses the TH/TRβ1-CaMK IV signaling pathway in mouse cerebellum. Int J Mol Sci 17:1–16. https://doi.org/10.3390/ijms17020157
Gutiérrez-Torres DS, González-Horta C, Del Razo LM et al (2015) Prenatal exposure to sodium arsenite alters placental glucose 1, 3, and 4 transporters in Balb/c mice. Biomed Res Int 2015(2015):175025. https://doi.org/10.1155/2015/175025
Haberny KA, Paule MG, Scallet AC et al (2002) Ontogeny of the N-methyl-D-aspartate (NMDA) receptor system and susceptibility to neurotoxicity. Toxicol Sci 68:9–17. https://doi.org/10.1093/toxsci/68.1.9
Hall JM, Greco CW (2019) Perturbation of nuclear hormone receptors by endocrine disrupting chemicals: mechanisms and pathological consequences of exposure. Cells 9
Hill DS, Wlodarczyk BJ, Mitchell LE, Finnell RH (2009) Arsenate-induced maternal glucose intolerance and neural tube defects in a mouse model. Toxicol Appl Pharmacol 239:29–36. https://doi.org/10.1016/j.taap.2009.05.009
Hoda U, Agarwal NB, Vohora D et al (2016) Resveratrol suppressed seizures by attenuating IL-1beta, IL1-Ra, IL-6, and TNF-alpha in the hippocampus and cortex of kindled mice. Nutr Neurosci 8305:1–8. https://doi.org/10.1080/1028415X.2016.1189057
Htway SM, Sein MT, Nohara K, Win-Shwe TT (2019) Effects of developmental arsenic exposure on the social behavior and related gene expression in C3H adult male mice. Int J Environ Res Public Health 16(2):174. https://doi.org/10.3390/ijerph16020174
Hu W, Feng Z, Xu J et al (2019) Brain-derived neurotrophic factor modified human umbilical cord mesenchymal stem cells-derived cholinergic-like neurons improve spatial learning and memory ability in Alzheimer’s disease rats. Brain Res 1710:61–73. https://doi.org/10.1016/j.brainres.2018.12.034
Hughes MF, Beck BD, Chen Y et al (2011) Arsenic exposure and toxicology: a historical perspective. Toxicol Sci 123:305–332. https://doi.org/10.1093/toxsci/kfr184
Iland HJ, Seymour JF (2013) Role of arsenic trioxide in acute promyelocytic leukemia. Curr Treat Options Oncol 14:170–184. https://doi.org/10.1007/s11864-012-0223-3
Jing J, Zheng G, Liu M et al (2012) Changes in the synaptic structure of hippocampal neurons and impairment of spatial memory in a rat model caused by chronic arsenite exposure. Neurotoxicology 33:1230–1238. https://doi.org/10.1016/j.neuro.2012.07.003
Kaltreider RC, Davis AM, Lariviere JP, Hamilton JW (2001) Arsenic alters the function of the glucocorticoid receptor as a transcription factor. Environ Health Perspect 109:245–251. https://doi.org/10.1289/ehp.01109245
Kannan GM, Tripathi N, Dube SN et al (2001) Toxic effects of arsenic (III) on some hematopoietic and central nervous system variables in rats and guinea pigs. J Toxicol - Clin Toxicol 39:675–682. https://doi.org/10.1081/CLT-100108508
Karim Y, Siddique AE, Hossen F et al (2019) Dose-dependent relationships between chronic arsenic exposure and cognitive impairment and serum brain-derived neurotrophic factor. Environ Int 131:105029. https://doi.org/10.1016/j.envint.2019.105029
Kenyon EM, Del Razo LM, Hughes MF (2005) Tissue distribution and urinary excretion of inorganic arsenic and its methylated metabolites in mice following acute oral administration of arsenate. Toxicol Sci 85:468–475. https://doi.org/10.1093/toxsci/kfi107
Kenyon EM, Hughes MF, Adair BM et al (2008) Tissue distribution and urinary excretion of inorganic arsenic and its methylated metabolites in C57BL6 mice following subchronic exposure to arsenate in drinking water. Toxicol Appl Pharmacol 232:448–455. https://doi.org/10.1016/j.taap.2008.07.018
Klinge CM, Blankenship KA, Risinger KE et al (2005) Resveratrol and estradiol rapidly activate MAPK signaling through estrogen receptors α and β in endothelial cells. J Biol Chem 280:7460–7468. https://doi.org/10.1074/jbc.M411565200
Klinge CM, Risinger KE, Watts MB et al (2003) Estrogenic activity in white and red wine extracts. J Agric Food Chem 51:1850–1857. https://doi.org/10.1021/jf0259821
Kodali M, Parihar VK, Hattiangady B et al (2015) Resveratrol prevents age-related memory and mood dysfunction with increased hippocampal neurogenesis and microvasculature, and reduced glial activation. Sci Rep 5:8075. https://doi.org/10.1038/srep08075
Leslie EM (2012) Arsenic-glutathione conjugate transport by the human multidrug resistance proteins (MRPs/ABCCs). J Inorg Biochem 108:141–149. https://doi.org/10.1016/j.jinorgbio.2011.11.009
Li J, Guo Y, Duan X, Li B (2020) Tissue- and region-specific accumulation of arsenic species, especially in the brain of mice, after long-term arsenite exposure in drinking water. Biol Trace Elem Res 198:168–176. https://doi.org/10.1007/s12011-020-02033-x
Liu B, Pan S, Dong X et al (2006) Opposing effects of arsenic trioxide on hepatocellular carcinomas in mice. Cancer Sci 97:675–681. https://doi.org/10.1111/j.1349-7006.2006.00230.x
Liu C, Zhang X, Deng J et al (2011) Effects of prochloraz or propylthiouracil on the cross-talk between the HPG, HPA, and HPT axes in zebrafish. Environ Sci Technol 45:769–775. https://doi.org/10.1021/es102659p
Luo J, Qiu Z, Shu W et al (2009) Effects of arsenic exposure from drinking water on spatial memory, ultra-structures and NMDAR gene expression of hippocampus in rats. Toxicol Lett 184:121–125. https://doi.org/10.1016/j.toxlet.2008.10.029
Luo JH, Qiu ZQ, Zhang L, Shu WQ (2012) Arsenite exposure altered the expression of NMDA receptor and postsynaptic signaling proteins in rat hippocampus. Toxicol Lett 211:39–44. https://doi.org/10.1016/j.toxlet.2012.02.021
Moreno Ávila CL, Limón-Pacheco JH, Giordano M, Rodríguez VM (2016) Chronic exposure to arsenic in drinking water causes alterations in locomotor activity and decreases striatal mRNA for the D2 Dopamine Receptor in CD1 Male Mice. J Toxicol 2016(2016):4763434. https://doi.org/10.1155/2016/4763434
Nagaraja TN, Desiraju T (1994) Effects on operant learning and brain acetylcholine esterase activity in rats following chronic inorganic arsenic intake. Hum Exp Toxicol 13:353–356. https://doi.org/10.1177/096032719401300511
Nair A, Jacob S (2016) A simple practice guide for dose conversion between animals and human. J Basic Clin Pharm 7:27. https://doi.org/10.4103/0976-0105.177703
Nakamura S, Nagano S, Nagao H et al (2013) Arsenic trioxide prevents osteosarcoma growth by inhibition of gli transcription via dna damage accumulation. PLoS One 8:1–12. https://doi.org/10.1371/journal.pone.0069466
Ong PS, Chan SY, Ho PC (2011) Differential augmentative effects of buthionine sulfoximine and ascorbic acid in As2O3-induced ovarian cancer cell death: oxidative stress-independent and -dependent cytotoxic potentiation. Int J Oncol 38:1731–1739. https://doi.org/10.3892/ijo.2011.986
Pandey R, Rai V, Mishra J et al (2017) Arsenic induces hippocampal neuronal apoptosis and cognitive impairments via an up-regulated BMP2/Smad-dependent reduced BDNF/TrkB signaling in rats. Toxicol Sci 159:137–158. https://doi.org/10.1093/TOXSCI/KFX124
Pang C, Cao L, Wu F et al (2015) The effect of trans-resveratrol on post-stroke depression via regulation of hypothalamus-pituitary-adrenal axis. Neuropharmacology 97:447–456. https://doi.org/10.1016/j.neuropharm.2015.04.017
Paoletti P, Bellone C, Zhou Q (2013) NMDA receptor subunit diversity: Impact on receptor properties, synaptic plasticity and disease. Nat Rev Neurosci 14:383–400. https://doi.org/10.1038/nrn3504
Powell BL, Moser B, Stock W et al (2011) Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia : North American Leukemia Intergroup Study C9710 Arsenic trioxide improves event-free and overall survival for adults with acute promyelocytic leukemia. Cancer 116:3751–3757. https://doi.org/10.1182/blood-2010-02-269621
Ramos-Chavez L, a., Rendon-Lapez CRR, Zepeda A, et al (2015) Neurological effects of inorganic arsenic exposure: altered cysteine/glutamate transport, NMDA expression and spatial memory impairment. Front Cell Neurosci 9:1–12. https://doi.org/10.3389/fncel.2015.00021
Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22:659–661. https://doi.org/10.1096/fj.07-9574LSF
Rodriguez KF, Mellouk N, Ungewitter EK et al (2020) In utero exposure to arsenite contributes to metabolic and reproductive dysfunction in male offspring of CD-1 mice. Reprod Toxicol 95:95–103. https://doi.org/10.1016/j.reprotox.2020.05.006
Rosado JL, Ronquillo D, Kordas K et al (2007) Arsenic exposure and cognitive performance in Mexican Schoolchildren. Environ Health Perspect 115:1371–1375. https://doi.org/10.1289/ehp.9961
Roy A, Kordas K, Lopez P et al (2011) Association between arsenic exposure and behavior among first-graders from Torre??n, Mexico. Environ Res 111:670–676. https://doi.org/10.1016/j.envres.2011.03.003
Scheindlin S (2005) The duplicitous nature of inorganic arsenic. Mol Interv 5:60–64. https://doi.org/10.1124/mi.5.2.1
Seibenhener ML, Wooten MC (2015) Use of the open field maze to measure locomotor and anxiety-like behavior in mice. J Vis Exp 1–6. https://doi.org/10.3791/52434
Shin J, Seol I, Son C (2010) Interpretation of animal dose and human equivalent dose for drug development. J Korean Orient Med 31:1–7
Srivastava P, Dhuriya YK, Gupta R et al (2018) Protective effect of curcumin by modulating BDNF/DARPP32/CREB in arsenic-induced alterations in dopaminergic signaling in rat corpus striatum. Mol Neurobiol 55:445–461. https://doi.org/10.1007/s12035-016-0288-2
Stenoien DL, Simeoni S, Sharp ZD, Mancini MA (2000) Subnuclear dynamics and transcription factor function. J Cell Biochem Suppl Suppl 35:99–106. https://doi.org/10.1002/1097-4644(2000)79:35+%3c99::aid-jcb1132%3e3.0.co;2-w
Stoica a, Pentecost E, Martin MB, (2000) Effects of arsenite on estrogen receptor-alpha expression and activity in MCF-7 breast cancer cells. Endocrinology 141:3595–3602. https://doi.org/10.1210/endo.141.10.7704
Sun BF, Wang QQ, Yu ZJ et al (2015) Exercise prevents memory impairment induced by arsenic exposure in mice: implication of hippocampal BDNF and CREB. PLoS One 10:1–15. https://doi.org/10.1371/journal.pone.0137810
Sun HJ, Xiang P, Luo J et al (2016) Mechanisms of arsenic disruption on gonadal, adrenal and thyroid endocrine systems in humans: a review. Environ Int 95:61–68. https://doi.org/10.1016/j.envint.2016.07.020
Tadanobu I, Zhang YF, Shigeo M et al (1990) The effect of arsenic trioxide on brain monoamine metabolism and locomotor activity of mice. Toxicol Lett 54:345–353. https://doi.org/10.1016/0378-4274(90)90202-W
Tian Z, Wang J, Xu M et al (2016) Resveratrol improves cognitive impairment by regulating apoptosis and synaptic plasticity in streptozotocin-induced diabetic rats. Cell Physiol Biochem 40:1670–1677. https://doi.org/10.1159/000453216
Tolins M, Ruchirawat M, Landrigan P (2014) The developmental neurotoxicity of arsenic: cognitive and behavioral consequences of early life exposure. Ann Glob Heal 80:303–314. https://doi.org/10.1016/j.aogh.2014.09.005
Torres-Pérez M, Tellez-Ballesteros RI, Ortiz-López L et al (2015) Resveratrol enhances neuroplastic changes, including hippocampal neurogenesis, and memory in Balb/C mice at six months of age. PLoS ONE 10:1–21. https://doi.org/10.1371/journal.pone.0145687
Tripathi N, Kannan GM, Pant BP et al (1997) Arsenic-induced changes in certain neurotransmitter levels and their recoveries following chelation in rat whole brain. Toxicol Lett 92:201–208. https://doi.org/10.1016/S0378-4274(97)00058-1
Tyler CR, Allan AM (2014) The effects of arsenic exposure on neurological and cognitive dysfunction in human and rodent studies: a review. Curr Environ Heal Reports 1:132–147. https://doi.org/10.1007/s40572-014-0012-1
Valkonen S, Savolainen H, Järvisalo J (1983) Arsenic distribution and neurochemical effects in peroral sodium arsenite exposure of rats. Bull Environ Contam Toxicol 30:303–308. https://doi.org/10.1007/BF01610137
Vorhees CV, Williams MT (2006) Morris water maze: procedures for assessing spatial and related forms of learning and memory. Nat Protoc 1:848–858. https://doi.org/10.1038/nprot.2006.116
Walf AA, Frye CA (2007) The use of the elevated plus maze as an assay of anxiety-related behavior in rodents. Nat Protoc 2:322–328. https://doi.org/10.1038/nprot.2007.44
Wang L, Wang R, Fan L et al (2017) Arsenic trioxide is an immune adjuvant in liver cancer treatment. Mol Immunol 81:118–126. https://doi.org/10.1016/j.molimm.2016.12.001
Wasserman GA, Liu X, Parvez F et al (2004) Water arsenic exposure and children’s intellectual function in Araihazar, Bangladesh. Environ Health Perspect 112:1329–1333. https://doi.org/10.1289/ehp.6964
Xu D, Li Y, Zhang B et al (2016) Resveratrol alleviate hypoxic pulmonary hypertension via anti-inflammation and anti-oxidant pathways in rats. Int J Med Sci 13:942–954. https://doi.org/10.7150/ijms.16810
Yadav RS, Sankhwar ML, Shukla RK et al (2009) Attenuation of arsenic neurotoxicity by curcumin in rats. Toxicol Appl Pharmacol 240:367–376. https://doi.org/10.1016/j.taap.2009.07.017
Yadav RS, Shukla RK, Sankhwar ML et al (2010) Neuroprotective effect of curcumin in arsenic-induced neurotoxicity in rats. Neurotoxicology 31:533–539. https://doi.org/10.1016/j.neuro.2010.05.001
Yu M, Xue J, Li Y et al (2013) Resveratrol protects against arsenic trioxide-induced nephrotoxicity by facilitating arsenic metabolism and decreasing oxidative stress. Arch Toxicol 87:1025–1035. https://doi.org/10.1007/s00204-013-1026-4
Zhang W, Xue J, Ge M et al (2013) Resveratrol attenuates hepatotoxicity of rats exposed to arsenic trioxide. Food Chem Toxicol 51:87–92. https://doi.org/10.1016/j.fct.2012.09.023
Zhang Z, Gao L, Cheng Y et al (2014a) Resveratrol, a natural antioxidant, has a protective effect on liver injury induced by inorganic arsenic exposure. Biomed Res Int 2014:7. https://doi.org/10.1155/2014/617202
Zhang Z, Gao L, Cheng Y, et al (2014b) Resveratrol, a natural antioxidant, has a protective effect on liver injury induced by inorganic arsenic exposure. Biomed Res Int 2014:. https://doi.org/10.1155/2014/617202
Acknowledgements
We acknowledge the support extended by Dr. S.B. Ray (Professor, Department of Anatomy, AIIMS, New Delhi) in final review of manuscript.
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This study was financially supported by the Department of Anatomy, All India Institute of Medical Sciences, New Delhi (India).
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Mehta K and Dhar P designed and conceptualized the study. Mehta K wrote the original draft and edited the manuscript. Mehta K performed the experimental procedures, data collection, analysis. Pandey KK and Kaur B helped in performing the behavioural assessment. Kaler S performed final review and editing of the manuscript. All the authors evaluated the final submission and agreed with its content.
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Highlights
• iAs exposure induces hippocampus-mediated behavioural deficits.
• Differential effects of iAs exposure on ER expression; iAs exposure reduced the ERα expression but did not alter ERβ expression.
• iAs exposure reduced the levels of potential biomarkers of cognitive function (Glutamate receptor NMDAR 2B subunit and BDNF).
• RES improved cognitive performance and restored the ERα, NMDAR 2B and BDNF expression levels.
• The proposed mechanisms of neuroprotective effects augmented by RES might include its inherent antioxidative properties and estrogenic actions.
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Mehta, K., Pandey, K.K., Kaur, B. et al. Resveratrol attenuates arsenic-induced cognitive deficits via modulation of Estrogen-NMDAR-BDNF signalling pathway in female mouse hippocampus. Psychopharmacology 238, 2485–2502 (2021). https://doi.org/10.1007/s00213-021-05871-2
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DOI: https://doi.org/10.1007/s00213-021-05871-2