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2000
Volume 22, Issue 10
  • ISSN: 1567-2050
  • E-ISSN: 1875-5828

Abstract

Introduction

Arsenic, a metalloid, is well associated as a risk factor for the development and progression of neurodegenerative diseases, including Alzheimer’s Disease (AD), which is characterized by impairment in cognition. However, specific effects of arsenic on Acetylcholinesterase (AChE) activity and inflammatory markers in different brain regions, as well as its impact on behaviour, are not yet fully understood.

Methods

Arsenic was administered (20 mg/kg by gavage for 4 weeks) to male and female mice, and its effects on behaviour were assessed by using the object recognition memory test and light-dark box test. AChE activity and neuronal Nitric Oxide (nNOS) were assessed by histoenzymology, and immunohistochemistry was employed for assessment of Glial Fibrillary Acidic Protein (GFAP).

Results

Both the behavioural tests showed significant impairment of learning and memory functions and development of psychiatric abnormalities in arsenic-fed mice. The histoenzymology and immunohistochemistry analysis of the cortex and hippocampus region of these arsenic-fed mice revealed the increment of AChE activity and inflammatory markers, viz. GFAP and nNOS.

Discussion

The observed increment in AChE activity in the cortex and hippocampus of arsenic-fed mice may contribute to the impairment of learning and memory functions, as well as to the development of psychiatric abnormalities. Furthermore, the enhancement of inflammatory processes in these brain regions may be either a consequence or a contributing factor to the elevated AChE activity, thus establishing a self-fuelling cycle of neuroinflammation and increased AChE activity.

Conclusion

Given the gender bias in neurodegenerative diseases, our findings indicate that arsenic exposure does not lead to significant differences in neuropathological and neurobehavioural outcomes between male and female mice. Moreover, current outcomes underscore the potential of arsenic to act as a neurotoxic agent in AD development.

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References

  1. HerreraA. PinedaJ. AntonioM.T. Toxic effects of perinatal arsenic exposure on the brain of developing rats and the beneficial role of natural antioxidants.Environ. Toxicol. Pharmacol.2013361737910.1016/j.etap.2013.03.018 23619517
     [Google Scholar]
  2. ChungJ.Y. Do YuS. HongY.S. Environmental source of arsenic exposure.J. Prev. Med. Public Health201447525310.3961/jpmph.14.036
     [Google Scholar]
  3. PatlollaA.K. TchounwouP.B. Serum acetyl cholinesterase as a biomarker of arsenic induced neurotoxicity in Sprague-Dawley rats.Int. J. Environ. Res. Public Health2005218010.3390/ijerph2005010080
     [Google Scholar]
  4. VaidyaN. HollaB. HeronJ. Neurocognitive analysis of low-level arsenic exposure and executive function mediated by brain anomalies among children, adolescents, and young adults in India.JAMA Netw. Open202365e231281010.1001/jamanetworkopen.2023.12810 37171822
     [Google Scholar]
  5. NaharM.N. InaokaT. FujimuraM. A consecutive study on arsenic exposure and intelligence quotient (IQ) of children in Bangladesh.Environ. Health Prev. Med.201419319419910.1007/s12199‑013‑0374‑2 24368742
     [Google Scholar]
  6. O’BryantS.E. EdwardsM. MenonC.V. GongG. BarberR. Long-term low-level arsenic exposure is associated with poorer neuropsychological functioning: a Project FRONTIER study.Int. J. Environ. Res. Public Health20118386187410.3390/ijerph8030861 21556183
     [Google Scholar]
  7. TylerC.R. AllanA.M. The effects of arsenic exposure on neurological and cognitive dysfunction in human and rodent studies: A review.Curr. Environ. Health Rep.20141213214710.1007/s40572‑014‑0012‑1 24860722
     [Google Scholar]
  8. SenD. SarathiB.P. Arsenicosis: Is it a protective or predisposing factor for mental illness?Iran. J. Psychiatry201274180183 23408762
     [Google Scholar]
  9. MehtaK. PandeyK.K. KaurB. DharP. KalerS. Resveratrol attenuates arsenic-induced cognitive deficits via modulation of Estrogen-NMDAR-BDNF signalling pathway in female mouse hippocampus.Psychopharmacology (Berl.)202123892485250210.1007/s00213‑021‑05871‑2 34050381
     [Google Scholar]
  10. TaheriZ.Z. EsmaeilpourK. AminzadehA. HeidariM.R. JoushiS. Resveratrol attenuates learning, memory, and social interaction impairments in rats exposed to arsenic.BioMed Res. Int.202120211999387310.1155/2021/9993873 34621902
     [Google Scholar]
  11. SrivastavaP. YadavR.S. ChandravanshiL.P. Unraveling the mechanism of neuroprotection of curcumin in arsenic induced cholinergic dysfunctions in rats.Toxicol. Appl. Pharmacol.2014279342844010.1016/j.taap.2014.06.006 24952339
     [Google Scholar]
  12. MónacoN.M. BartosM. DominguezS. Low arsenic concentrations impair memory in rat offpring exposed during pregnancy and lactation: Role of α7 nicotinic receptor, glutamate and oxidative stress.Neurotoxicology201867374510.1016/j.neuro.2018.04.011 29678590
     [Google Scholar]
  13. ChuF. YangW. LiY. Subchronic arsenic exposure induces behavioral impairments and hippocampal damage in rats.Toxics2023111297010.3390/toxics11120970 38133371
     [Google Scholar]
  14. UllasK.S. ChaturvediA. BhaskarY.D. KundapuraN. AminN. DevaramaneV. Increased levels of acetylcholinesterase, paraoxonase 1, and copper in patients with moderate depression- A preliminary study.Rep. Biochem. Mol. Biol.201972174180 30805397
     [Google Scholar]
  15. MoretaM.P.G. Burgos-AlonsoN. TorrecillaM. Marco-ContellesJ. Bruzos-CidónC. Efficacy of acetylcholinesterase inhibitors on cognitive function in alzheimer’s disease. Review of reviews.Biomedicines2021911168910.3390/biomedicines9111689 34829917
     [Google Scholar]
  16. SamadN. JabeenS. ImranI. ZulfiqarI. BilalK. Protective effect of gallic acid against arsenic-induced anxiety−/depression- like behaviors and memory impairment in male rats.Metab. Brain Dis.20193441091110210.1007/s11011‑019‑00432‑1 31119507
     [Google Scholar]
  17. YadavR.S. ChandravanshiL.P. ShuklaR.K. Neuroprotective efficacy of curcumin in arsenic induced cholinergic dysfunctions in rats.Neurotoxicology201132676076810.1016/j.neuro.2011.07.004 21839772
     [Google Scholar]
  18. TutkunL. GunduzozM. TurksoyV.A. Arsenic-induced inflammation in workers.Mol. Biol. Rep.20194622371237810.1007/s11033‑019‑04694‑x 30783936
     [Google Scholar]
  19. SunX. HeY. GuoY. Arsenic affects inflammatory cytokine expression in Gallus gallus brain tissues.BMC Vet. Res.201713115710.1186/s12917‑017‑1066‑8 28583123
     [Google Scholar]
  20. JingH. YanN. FanR. Arsenic activates the NLRP3 inflammasome and disturbs the Th1/Th2/Th17/Treg balance in the hippocampus in mice.Biol. Trace Elem. Res.202320173395340310.1007/s12011‑022‑03421‑1 36100822
     [Google Scholar]
  21. BustaffaE. StoccoroA. BianchiF. MiglioreL. Genotoxic and epigenetic mechanisms in arsenic carcinogenicity.Arch. Toxicol.20148851043106710.1007/s00204‑014‑1233‑7 24691704
     [Google Scholar]
  22. ThakurM. RachamallaM. NiyogiS. DatusaliaA.K. FloraS.J.S. Molecular mechanism of arsenic-induced neurotoxicity including neuronal dysfunctions.Int. J. Mol. Sci.202122181007710.3390/ijms221810077 34576240
     [Google Scholar]
  23. DringenR. SpillerS. NeumannS. KoehlerY. Uptake, metabolic effects and toxicity of arsenate and arsenite in astrocytes.Neurochem. Res.201641346547510.1007/s11064‑015‑1570‑9 25862194
     [Google Scholar]
  24. DucourneauV.R.R. DoliqueT. Hachem-DelaunayS. Cancer pain is not necessarily correlated with spinal overexpression of reactive glia markers.Pain2014155227529110.1016/j.pain.2013.10.008 24120461
     [Google Scholar]
  25. ZhangB. WangG. HeJ. Icariin attenuates neuroinflammation and exerts dopamine neuroprotection via an Nrf2-dependent manner.J. Neuroinflammation20191619210.1186/s12974‑019‑1472‑x 31010422
     [Google Scholar]
  26. RathnasamyG. SivakumarV. RangarajanP. FouldsW.S. LingE.A. KaurC. NF-κB-mediated nitric oxide production and activation of caspase-3 cause retinal ganglion cell death in the hypoxic neonatal retina.Invest. Ophthalmol. Vis. Sci.20145595878588910.1167/iovs.13‑13718 25139733
     [Google Scholar]
  27. DuttaA. PhukanB.C. RoyR. Garcinia morella extract confers dopaminergic neuroprotection by mitigating mitochondrial dysfunctions and inflammation in mouse model of Parkinson’s disease.Metab. Brain Dis.20223761887190010.1007/s11011‑022‑01001‑9 35622265
     [Google Scholar]
  28. RosadoJ.L. RonquilloD. KordasK. Arsenic exposure and cognitive performance in Mexican school children.Environ. Health Perspect.200711591371137510.1289/ehp.9961 17805430
     [Google Scholar]
  29. PandeyR. GargA. GuptaK. Arsenic induces differential neurotoxicity in male, female, and E2-deficient females: Comparative effects on hippocampal neurons and cognition in adult rats.Mol. Neurobiol.20225952729274410.1007/s12035‑022‑02770‑1 35175559
     [Google Scholar]
  30. Vogel-CierniaA. MatheosD.P. BarrettR.M. The neuron-specific chromatin regulatory subunit BAF53b is necessary for synaptic plasticity and memory.Nat. Neurosci.201316555256110.1038/nn.3359 23525042
     [Google Scholar]
  31. MazumderM.K. GiriA. KumarS. BorahA. A highly reproducible mice model of chronic kidney disease: Evidences of behavioural abnormalities and blood-brain barrier disruption.Life Sci.2016161273610.1016/j.lfs.2016.07.020 27493078
     [Google Scholar]
  32. MazumderM.K. PaulR. BhattacharyaP. BorahA. Neurological sequel of chronic kidney disease: From diminished Acetylcholinesterase activity to mitochondrial dysfunctions, oxidative stress and inflammation in mice brain.Sci. Rep.201991309710.1038/s41598‑018‑37935‑3 30816118
     [Google Scholar]
  33. PaulR. BorahA. Global loss of acetylcholinesterase activity with mitochondrial complexes inhibition and inflammation in brain of hypercholesterolemic mice.Sci. Rep.2017711792210.1038/s41598‑017‑17911‑z 29263397
     [Google Scholar]
  34. SchindelinJ. Arganda-CarrerasI. FriseE. Fiji: An open-source platform for biological-image analysis.Nat. Methods20129767668210.1038/nmeth.2019 22743772
     [Google Scholar]
  35. DuttaA. RoyR. PandeyM. Arsenic-induced mice model of Parkinson’s disease: Revealing the neurotoxicity of arsenic through mitochondrial complexes inhibition and dopaminergic neurodegeneration in the substantia nigra region of brain.Brain Res.2025185114949310.1016/j.brainres.2025.149493 39909295
     [Google Scholar]
  36. MadathilK.S. KaruppagounderS.S. HaobamR. VargheseM. RajammaU. MohanakumarK.P. Nitric oxide synthase inhibitors protect against rotenone-induced, oxidative stress mediated parkinsonism in rats.Neurochem. Int.201362567468310.1016/j.neuint.2013.01.007 23353925
     [Google Scholar]
  37. FloraS.J.S. GuptaR. Beneficial effects of Centella asiatica aqueous extract against arsenic-induced oxidative stress and essential metal status in rats.Phytother. Res.2007211098098810.1002/ptr.2208
     [Google Scholar]
  38. GuptaR. FloraS.J.S. Protective value of Aloe vera against some toxic effects of arsenic in rats.Phytother. Res.2005191232810.1002/ptr.1560
     [Google Scholar]
  39. YadavR.S. SankhwarM.L. ShuklaR.K. Attenuation of arsenic neurotoxicity by curcumin in rats.Toxicol. Appl. Pharmacol.2009240336737610.1016/j.taap.2009.07.017 19631675
     [Google Scholar]
  40. NiñoS.A. Martel-GallegosG. Castro-ZavalaA. Chronic arsenic exposure Increases Aβ(1-42) production and receptor for advanced glycation end products expression in rat brain.Chem. Res. Toxicol.2018311132110.1021/acs.chemrestox.7b00215 29155576
     [Google Scholar]
  41. DelgadoJ.M. DufourL. GrimaldoJ.I. CarrizalesL. RodríguezV.M. Jiménez-CapdevilleM.E. Effects of arsenite on central monoamines and plasmatic levels of adrenocorticotropic hormone (ACTH) in mice.Toxicol. Lett.20001171-2616710.1016/S0378‑4274(00)00240‑X 11033234
     [Google Scholar]
  42. Kyi-Tha-ThuC. HtwayS.M. SuzukiT. NoharaK. Win-ShweT.T. Gestational arsenic exposure induces anxiety-like behaviors in F1 female mice by dysregulation of neurological and immunological markers.Environ. Health Prev. Med.20232804310.1265/ehpm.23‑00046 37407491
     [Google Scholar]
  43. ChandravanshiL.P. ShuklaR.K. SultanaS. PantA.B. KhannaV.K. Early life arsenic exposure and brain dopaminergic alterations in rats.Int. J. Dev. Neurosci.20143819110410.1016/j.ijdevneu.2014.08.009 25179238
     [Google Scholar]
  44. NairA. MorsyM.A. JacobS. Dose translation between laboratory animals and human in preclinical and clinical phases of drug development.Drug Dev. Res.201879837338210.1002/ddr.21461 30343496
     [Google Scholar]
  45. YunusF. KhanS. ChowdhuryP. MiltonA. HussainS. RahmanM. A Review of groundwater arsenic contamination in Bangladesh: The millennium development goal era and beyond.Int. J. Environ. Res. Public Health201613221510.3390/ijerph13020215 26891310
     [Google Scholar]
  46. MehtaK. KaurB. PandeyK.K. KalerS. DharP. Curcumin supplementation shows modulatory influence on functional and morphological features of hippocampus in mice subjected to arsenic trioxide exposure.Anat. Cell Biol.202053335536510.5115/acb.18.169 32929054
     [Google Scholar]
  47. Ben-AriS. ToiberD. SasA.S. SoreqH. Ben-ShaulY. Modulated splicing‐associated gene expression in P19 cells expressing distinct acetylcholinesterase splice variants.J. Neurochem.200697s1243410.1111/j.1471‑4159.2006.03725.x 16635247
     [Google Scholar]
  48. YousefM.I. El-DemerdashF.M. RadwanF.M.E. Sodium arsenite induced biochemical perturbations in rats: Ameliorating effect of curcumin.Food Chem. Toxicol.200846113506351110.1016/j.fct.2008.08.031 18809455
     [Google Scholar]
  49. RoyS. ChattorajA. BhattacharyaS. Arsenic-induced changes in optic tectal histoarchitecture and acetylcholinesterase-acetylcholine profile in Channa punctatus: Amelioration by selenium.Comp. Biochem. Physiol. C Toxicol. Pharmacol.20061441162410.1016/j.cbpc.2006.04.018 16916622
     [Google Scholar]
  50. SharmaA. KshetrimayumC. SadhuH.G. KumarS. Arsenic-induced oxidative stress, cholinesterase activity in the brain of Swiss albino mice, and its amelioration by antioxidants Vitamin E and Coenzyme Q10.Environ. Sci. Pollut. Res. Int.20182524239462395310.1007/s11356‑018‑2398‑z 29948670
     [Google Scholar]
  51. Suarez-LopezJ.R. HoodN. Suárez-TorresJ. GahaganS. GunnarM.R. López-ParedesD. Associations of acetylcholinesterase activity with depression and anxiety symptoms among adolescents growing up near pesticide spray sites.Int. J. Hyg. Environ. Health2019222798199010.1016/j.ijheh.2019.06.001 31202795
     [Google Scholar]
  52. WangX. LiP. DingQ. WuC. ZhangW. TangB. Observation of Acetylcholinesterase in stress-induced depression phenotypes by two-photon fluorescence imaging in the mouse brain.J. Am. Chem. Soc.201914152061206810.1021/jacs.8b11414 30638380
     [Google Scholar]
  53. ReitzC. BrayneC. MayeuxR. Epidemiology of Alzheimer disease.Nat. Rev. Neurol.20117313715210.1038/nrneurol.2011.2 21304480
     [Google Scholar]
  54. DongS. DuanY. HuY. ZhaoZ. Advances in the pathogenesis of Alzheimer’s disease: A re-evaluation of amyloid cascade hypothesis.Transl. Neurodegener.2012111810.1186/2047‑9158‑1‑18 23210692
     [Google Scholar]
  55. SinghJ.C.H. KakalijR.M. KshirsagarR.P. KumarB.H. KomakulaS.S.B. DiwanP.V. Cognitive effects of vanillic acid against streptozotocin-induced neurodegeneration in mice.Pharm. Biol.201553563063610.3109/13880209.2014.935866 25472801
     [Google Scholar]
  56. ChellammalH.S.J. MenonB.V.V. HasanM.H. Neuropharmacological studies of ethanolic extract of Vaccinium corymbosum on Alzheimer’s type dementia and catatonia in Swiss albino mice.J HerbMed Pharmacol202110224124810.34172/jhp.2021.27
     [Google Scholar]
  57. WisessaowapakC. VisitnonthachaiD. WatcharasitP. SatayavivadJ. Prolonged arsenic exposure increases tau phosphorylation in differentiated SH-SY5Y cells: The contribution of GSK3 and ERK1/2.Environ. Toxicol. Pharmacol.20218410362610.1016/j.etap.2021.103626 33621689
     [Google Scholar]
  58. AriafarS. MakhdoomiS. MohammadiM. Arsenic and tau phosphorylation: A mechanistic review.Biol. Trace Elem. Res.2023201125708572010.1007/s12011‑023‑03634‑y 37211576
     [Google Scholar]
  59. SharmaR. AbubakarM.D. BishtP. Arsenic exposure and amyloid precursor protein Processing: A focus on alzheimer’s disease.Curr. Mol. Pharmacol.2023Epub ahead of print10.2174/0118761429272806231020045840 37921143
     [Google Scholar]
  60. AhmedG. RahamanS. PerezE. KhanK.M. Associations of environmental exposure to arsenic, manganese, lead, and associations of environmental exposure to arsenic, manganese, lead, and cadmium with alzheimer ’ s disease: A review of recent evidence from mechanistic studies.J. Xenobiot.20251524710.3390/jox15020047
     [Google Scholar]
  61. DuanX. XuG. LiJ. Arsenic induces continuous inflammation and regulates Th1/Th2/Th17/Treg balance in liver and kidney in vivo.Mediators Inflamm.2022202211410.1155/2022/8414047 35210942
     [Google Scholar]
  62. PeknyM. PeknaM. Astrocyte reactivity and reactive astrogliosis: costs and benefits.Physiol. Rev.20149441077109810.1152/physrev.00041.2013 25287860
     [Google Scholar]
  63. HopeB.T. MichaelG.J. KniggeK.M. VincentS.R. Neuronal NADPH diaphorase is a nitric oxide synthase.Proc. Natl. Acad. Sci. USA19918872811281410.1073/pnas.88.7.2811 1707173
     [Google Scholar]
  64. FirdausF. ZafeerM.F. AnisE. AhmadM. AfzalM. Ellagic acid attenuates arsenic induced neuro-inflammation and mitochondrial dysfunction associated apoptosis.Toxicol. Rep.2018541141710.1016/j.toxrep.2018.02.017 29854611
     [Google Scholar]
  65. DasU.N. Acetylcholinesterase and butyrylcholinesterase as possible markers of low-grade systemic inflammation.Med. Sci. Monit.20071312RA214RA221 18049445
     [Google Scholar]
  66. KarimM.R. SalamM. AliN. QuamruzzamanQ. Association between arsenic exposure and plasma cholinesterase activity: A population based study in Bangladesh.Environ. Health201091810.1186/1476‑069X‑9‑36
     [Google Scholar]
  67. TeodorakB.P. FerreiraG.K. FerreiraG. Acute administration of fenproporex increased acetylcholinesterase activity in brain of young rats.An Acad Bras Cienc201587138910.1590/0001‑3765201520140638
     [Google Scholar]
  68. BiswasS.K. Does the interdependence between oxidative stress and inflammation explain the antioxidant paradox?Oxid. Med. Cell. Longev.201620161569893110.1155/2016/5698931 26881031
     [Google Scholar]
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Arsenic Exposure Induces Cognitive Impairment in Mice with Increased Acetylcholinesterase Activity and Inflammation in the Cortex and Hippocampus: Implications for Alzheimer’s Disease
Curr Alzheimer Res 22, 745 (2025); https://doi.org/10.2174/0115672050390649250904100840
/content/journals/car/10.2174/0115672050390649250904100840
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  • Article Type:     Research Article
Keyword(s): acetylcholinesterase; Alzheimer’s disease; Arsenic neurotoxicity; cognition; GFAP; Nnos

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