Skip to main content
SpringerLink
Log in

Neurotoxic Outcomes of Subchronic Manganese Chloride Exposure via Contaminated Water in Adult Male Rats and the Potential Benefits of Ebselen

  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

The neurological effects of manganese (Mn) exposure on adults consuming contaminated water remain unclear. Accordingly, the current experiment was planned to explore the neurotoxic consequences of subchronic Mn exposure via contaminated water and to examine whether ebselen (Ebs) improved these outcomes. Rats exposed to oral MnCl2 (50 mg/kg body weight) for 30 successive days exhibited reduced rearing and ambulation. Furthermore, Mn administration increased brain Mn concentrations and induced superoxide dismutase, catalase, and glutathione depletion. Mn administration also increased lipid peroxidation biomarker levels. Additionally, Mn increased interleukin1-β and prostaglandin E2 levels and altered caspase-3 and Bcl-2 expression. Mn intoxication also induced marked gliosis, numerous vacuolations, and disoriented and pyknotic Purkinje cells as well as marked vascular congestion in brain tissue. Meanwhile, intraperitoneal administration of Ebs (15 mg/kg body weight) to Mn-intoxicated rats improved the behavioral performance and oxidative damage as well as inflammatory, apoptotic, and histopathological changes. The above results indicate that Ebs alleviated Mn neurotoxicity via its antioxidant, anti-inflammatory, and anti-apoptotic activities. Therefore, Ebs could represent a promising agent in the prevention of Mn-induced neurotoxicity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Abbreviations

Mn:

Manganese

Ebs:

Ebselen

CAT:

Catalase

SOD:

Superoxide dismutase

GSH:

Glutathione

DMSO:

Dimethyl sulfoxide

MDA:

Malondialdehyde

DA:

Dopamine

IL1-β:

Interleukin1-β

IP:

Intraperitoneal injection

PGE2:

Prostaglandin E2

References

  1. Ávila DS, Puntel RL, Folmer V, Rocha JBT, dos Santos APM, Aschner M (2014) Manganese neurotoxicity. In: Kostrzewa RM (ed) Handbook of neurotoxicity. Springer New York, New York, pp 843–864. https://doi.org/10.1007/978-1-4614-5836-4_3

    Chapter  Google Scholar 

  2. Erikson KM, Aschner M (2003) Manganese neurotoxicity and glutamate-GABA interaction. Neurochem Int 43(4–5):475–480

    Article  CAS  Google Scholar 

  3. Aschner JL, Aschner M (2005) Nutritional aspects of manganese homeostasis. Mol Asp Med 26(4–5):353–362. https://doi.org/10.1016/j.mam.2005.07.003

    Article  CAS  Google Scholar 

  4. Dobson AW, Erikson KM, Aschner M (2004) Manganese neurotoxicity. Ann N Y Acad Sci 1012:115–128

    Article  CAS  Google Scholar 

  5. Lucchini RG, Guazzetti S, Zoni S, Benedetti C, Fedrighi C, Peli M, Donna F, Bontempi E, Borgese L, Micheletti S, Ferri R, Marchetti S, Smith DR (2014) Neurofunctional dopaminergic impairment in elderly after lifetime exposure to manganese. Neurotoxicology 45:309–317. https://doi.org/10.1016/j.neuro.2014.05.006

    Article  CAS  PubMed  Google Scholar 

  6. Montes S, Riojas-Rodriguez H, Sabido-Pedraza E, Rios C (2008) Biomarkers of manganese exposure in a population living close to a mine and mineral processing plant in Mexico. Environ Res 106(1):89–95. https://doi.org/10.1016/j.envres.2007.08.008

    Article  CAS  PubMed  Google Scholar 

  7. Kim Y, Park JK, Choi Y, Yoo CI, Lee CR, Lee H, Lee JH, Kim SR, Jeong TH, Yoon CS, Park JH (2005) Blood manganese concentration is elevated in iron deficiency anemia patients, whereas globus pallidus signal intensity is minimally affected. Neurotoxicology 26(1):107–111. https://doi.org/10.1016/j.neuro.2004.06.004

    Article  CAS  PubMed  Google Scholar 

  8. Wasserman GA, Liu X, Parvez F, Ahsan H, Levy D, Factor-Litvak P, Kline J, van Geen A, Slavkovich V, LoIacono NJ, Cheng Z, Zheng Y, Graziano JH (2006) Water manganese exposure and children’s intellectual function in Araihazar, Bangladesh. Environ Health Perspect 114(1):124–129

    CAS  PubMed  Google Scholar 

  9. Finkelstein MM, Jerrett M (2007) A study of the relationships between Parkinson’s disease and markers of traffic-derived and environmental manganese air pollution in two Canadian cities. Environ Res 104(3):420–432. https://doi.org/10.1016/j.envres.2007.03.002

    Article  CAS  Google Scholar 

  10. Yoon H, Kim DS, Lee GH, Kim KW, Kim HR, Chae HJ (2011) Apoptosis induced by manganese on neuronal SK-N-MC cell line: endoplasmic reticulum (ER) stress and mitochondria dysfunction. Environ Health Toxicol 26:e2011017. https://doi.org/10.5620/eht.2011.26.e2011017

    Article  PubMed  PubMed Central  Google Scholar 

  11. Yoon H, Lee GH, Kim DS, Kim KW, Kim HR, Chae HJ (2011) The effects of 3, 4 or 5 amino salicylic acids on manganese-induced neuronal death: ER stress and mitochondrial complexes. Toxicol In Vitro 25(7):1259–1268. https://doi.org/10.1016/j.tiv.2011.04.002

    Article  CAS  PubMed  Google Scholar 

  12. Zhang S, Fu J, Zhou Z (2005) Changes in the brain mitochondrial proteome of male Sprague-Dawley rats treated with manganese chloride. Toxicol Appl Pharmacol 202(1):13–17. https://doi.org/10.1016/j.taap.2004.06.001

    Article  CAS  PubMed  Google Scholar 

  13. Shi S, Zhao J, Yang L, Nie X, Han J, Ma X, Wan C, Jiang J (2015) KHSRP participates in manganese-induced neurotoxicity in rat striatum and PC12 cells. J Mol Neurosci 55(2):454–465. https://doi.org/10.1007/s12031-014-0367-7

    Article  CAS  PubMed  Google Scholar 

  14. Alaimo A, Gorojod RM, Beauquis J, Munoz MJ, Saravia F, Kotler ML (2014) Deregulation of mitochondria-shaping proteins Opa-1 and Drp-1 in manganese-induced apoptosis. PLoS One 9(3):e91848. https://doi.org/10.1371/journal.pone.0091848

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wang T, Li X, Yang D, Zhang H, Zhao P, Fu J, Yao B, Zhou Z (2015) ER stress and ER stress-mediated apoptosis are involved in manganese-induced neurotoxicity in the rat striatum in vivo. Neurotoxicology 48:109–119. https://doi.org/10.1016/j.neuro.2015.02.007

    Article  CAS  PubMed  Google Scholar 

  16. Bahar E, Lee G-H, Bhattarai KR, Lee H-Y, Choi M-K, Rashid H-O, Kim J-Y, Chae H-J, Yoon H (2017) Polyphenolic extract of Euphorbia supina attenuates manganese-induced neurotoxicity by enhancing antioxidant activity through regulation of ER stress and ER stress-mediated apoptosis. Int J Mol Sci 18(2):300. https://doi.org/10.3390/ijms18020300

    Article  CAS  PubMed Central  Google Scholar 

  17. Ozyigit F, Kucuk A, Akcer S, Tosun M, Kocak FE, Kocak C, Kocak A, Metineren H, Genc O (2015) Different dose-dependent effects of ebselen in -sciatic nerve ischemia-reperfusion injury in rats. Bosnian J Basic Med Sci 15(4):36–43. https://doi.org/10.17305/bjbms.2015.521

    Article  CAS  Google Scholar 

  18. Kim S-J, Park C, Han AL, Youn M-J, Lee J-H, Kim Y, Kim E-S, Kim H-J, Kim J-K, Lee H-K, Chung S-Y, So H, Park R (2009) Ebselen attenuates cisplatin-induced ROS generation through Nrf2 activation in auditory cells. Hear Res 251(1):70–82. https://doi.org/10.1016/j.heares.2009.03.003

    Article  CAS  PubMed  Google Scholar 

  19. Tak JK, Park J-W (2009) The use of ebselen for radioprotection in cultured cells and mice. Free Radic Biol Med 46(8):1177–1185. https://doi.org/10.1016/j.freeradbiomed.2009.01.023

    Article  CAS  PubMed  Google Scholar 

  20. Takasago T, Peters EE, Graham DI, Masayasu H, Macrae IM (1997) Neuroprotective efficacy of ebselen, an anti-oxidant with anti-inflammatory actions, in a rodent model of permanent middle cerebral artery occlusion. Br J Pharmacol 122(6):1251–1256. https://doi.org/10.1038/sj.bjp.0701426

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Azad GK, Tomar RS (2014) Ebselen, a promising antioxidant drug: mechanisms of action and targets of biological pathways. Mol Biol Rep 41(8):4865–4879. https://doi.org/10.1007/s11033-014-3417-x

    Article  CAS  PubMed  Google Scholar 

  22. Yamaguchi T, Sano K, Takakura K, Saito I, Shinohara Y, Asano T, Yasuhara H (1998) Ebselen in acute ischemic stroke: a placebo-controlled, double-blind clinical trial. Ebselen Study Group. Stroke 29(1):12–17

    Article  CAS  Google Scholar 

  23. Ljung K, Vahter M (2007) Time to re-evaluate the guideline value for manganese in drinking water? Environ Health Perspect 115(11):1533–1538. https://doi.org/10.1289/ehp.10316

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bouchard MF, Sauve S, Barbeau B, Legrand M, Brodeur ME, Bouffard T, Limoges E, Bellinger DC, Mergler D (2011) Intellectual impairment in school-age children exposed to manganese from drinking water. Environ Health Perspect 119(1):138–143. https://doi.org/10.1289/ehp.1002321

    Article  CAS  PubMed  Google Scholar 

  25. Hafeman D, Factor-Litvak P, Cheng Z, van Geen A, Ahsan H (2007) Association between manganese exposure through drinking water and infant mortality in Bangladesh. Environ Health Perspect 115(7):1107–1112. https://doi.org/10.1289/ehp.10051

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Woolf A, Wright R, Amarasiriwardena C, Bellinger D (2002) A child with chronic manganese exposure from drinking water. Environ Health Perspect 110(6):613–616

    Article  Google Scholar 

  27. Saritha K, Celia DA, Shahryar HK, Nikolay FM (2014) Brain deposition and neurotoxicity of manganese in adult mice exposed via the drinking water. Arch Toxicol 88 (1). https://doi.org/10.1007/s00204-013-1088-3

    Article  Google Scholar 

  28. Gad SC, Cassidy CD, Aubert N, Spainhour B, Robbe H (2006) Nonclinical vehicle use in studies by multiple routes in multiple species. Int J Toxicol 25(6):499–521. https://doi.org/10.1080/10915810600961531

    Article  CAS  PubMed  Google Scholar 

  29. Santos AP, Lucas RL, Andrade V, Mateus ML, Milatovic D, Aschner M, Batoreu MC (2012) Protective effects of ebselen (Ebs) and para-aminosalicylic acid (PAS) against manganese (Mn)-induced neurotoxicity. Toxicol Appl Pharmacol 258(3):394–402. https://doi.org/10.1016/j.taap.2011.12.003

    Article  CAS  PubMed  Google Scholar 

  30. Dorman DC, Struve MF, Vitarella D, Byerly FL, Goetz J, Miller R (2000) Neurotoxicity of manganese chloride in neonatal and adult CD rats following subchronic (21-day) high-dose oral exposure. J Appl Toxicol 20(3):179–187

    Article  CAS  Google Scholar 

  31. Ladefoged O, Roswall K, Larsen JJ (1994) Acetone potentiation and influence on the reversibility of 2,5-hexanedione-induced neurotoxicity studied with behavioural and morphometric methods in rats. Pharmacol Toxicol 74(4–5):294–299

    Article  CAS  Google Scholar 

  32. Ávila DS, Colle D, Gubert P, Palma AS, Puntel G, Manarin F, Noremberg S, Nascimento PC, Aschner M, Rocha JBT, Soares FAA (2010) A possible neuroprotective action of a vinylic telluride against Mn-induced neurotoxicity. Toxicol Sci 115(1):194–201. https://doi.org/10.1093/toxsci/kfq036

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Julshman K (1983) Analysis of major and minor elements in mollusks from Norway. PhD Institute of Nutrition Direction of Bergen Nygardsangen, Bergen University, Bergen

  34. Aebi H (1984) Catalase in vitro. Methods Enzymol 105:121–126

    Article  CAS  Google Scholar 

  35. Nishikimi M, Appaji N, Yagi K (1972) The occurrence of superoxide anion in the reaction of reduced phenazine methosulfate and molecular oxygen. Biochem Biophys Res Commun 46(2):849–854

    Article  CAS  Google Scholar 

  36. Beutler E, Duron O, Kelly BM (1963) Improved method for the determination of blood glutathione. J Lab Clin Med 61:882–888

    CAS  Google Scholar 

  37. Mihara M, Uchiyama M (1978) Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem 86(1):271–278

    Article  CAS  Google Scholar 

  38. Suvarna SK, Layton C, Bancroft JD (2013) Bancroft’s theory and practice of histological techniques, 7th edn. Churchill Livingstone, Elsevier, London

    Google Scholar 

  39. Soliman MM, Abdo Nassan M, Ismail TA (2014) Immunohistochemical and molecular study on the protective effect of curcumin against hepatic toxicity induced by paracetamol in Wistar rats. BMC Complement Altern Med 14:457. https://doi.org/10.1186/1472-6882-14-457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Mohamed AA, Galal AA, Elewa YH (2015) Comparative protective effects of royal jelly and cod liver oil against neurotoxic impact of tartrazine on male rat pups brain. Acta Histochem 117(7):649–658. https://doi.org/10.1016/j.acthis.2015.07.002

    Article  CAS  PubMed  Google Scholar 

  41. Chen M-T, Cheng G-W, Lin C-C, Chen B-H, Huang Y-L (2006) Effects of acute manganese chloride exposure on lipid peroxidation and alteration of trace metals in rat brain. Biol Trace Elem Res 110(2):163–177. https://doi.org/10.1385/bter:110:2:163

    Article  CAS  PubMed  Google Scholar 

  42. Peres TV, Schettinger MRC, Chen P, Carvalho F, Avila DS, Bowman AB, Aschner M (2016) Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies. BMC Pharmacol Toxicol 17:57. https://doi.org/10.1186/s40360-016-0099-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Au C, Benedetto A, Aschner M (2008) Manganese transport in eukaryotes: the role of DMT1. Neurotoxicology 29(4):569–576. https://doi.org/10.1016/j.neuro.2008.04.022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Wetli HA, Buckett PD, Wessling-Resnick M (2006) Small-molecule screening identifies the selanazal drug ebselen as a potent inhibitor of DMT1-mediated iron uptake. Chem Biol 13(9):965–972. https://doi.org/10.1016/j.chembiol.2006.08.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Bouabid S, Tinakoua A, Lakhdar-Ghazal N, Benazzouz A (2016) Manganese neurotoxicity: behavioral disorders associated with dysfunctions in the basal ganglia and neurochemical transmission. J Neurochem 136(4):677–691. https://doi.org/10.1111/jnc.13442

    Article  CAS  PubMed  Google Scholar 

  46. Tran TT, Chowanadisai W, Crinella FM, Chicz-DeMet A, Lonnerdal B (2002) Effect of high dietary manganese intake of neonatal rats on tissue mineral accumulation, striatal dopamine levels, and neurodevelopmental status. Neurotoxicology 23(4–5):635–643

    Article  CAS  Google Scholar 

  47. Donaldson J, McGregor D, LaBella F (1982) Manganese neurotoxicity: a model for free radical mediated neurodegeneration? Can J Physiol Pharmacol 60(11):1398–1405

    Article  CAS  Google Scholar 

  48. Milatovic D, Zaja-Milatovic S, Gupta RC, Yu Y, Aschner M (2009) Oxidative damage and neurodegeneration in manganese-induced neurotoxicity. Toxicol Appl Pharmacol 240(2):219–225. https://doi.org/10.1016/j.taap.2009.07.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Erikson KM, John CE, Jones SR, Aschner M (2005) Manganese accumulation in striatum of mice exposed to toxic doses is dependent upon a functional dopamine transporter. Environ Toxicol Pharmacol 20(3):390–394. https://doi.org/10.1016/j.etap.2005.03.009

    Article  CAS  PubMed  Google Scholar 

  50. Vezér T, Kurunczi A, Náray M, Papp A, Nagymajtényi L (2007) Behavioral effects of subchronic inorganic manganese exposure in rats. Am J Ind Med 50(11):841–852. https://doi.org/10.1002/ajim.20485

    Article  CAS  PubMed  Google Scholar 

  51. Chtourou Y, Trabelsi K, Fetoui H, Mkannez G, Kallel H, Zeghal N (2011) Manganese induces oxidative stress, redox state unbalance and disrupts membrane bound ATPases on murine neuroblastoma cells in vitro: protective role of silymarin. Neurochem Res 36(8):1546–1557. https://doi.org/10.1007/s11064-011-0483-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Betteridge DJ (2000) What is oxidative stress? Metab Clin Exp 49(2 Suppl 1):3–8

    Article  CAS  Google Scholar 

  53. Deavall DG, Martin EA, Horner JM, Roberts R (2012) Drug-induced oxidative stress and toxicity. J Toxicol 2012:13. https://doi.org/10.1155/2012/645460

    Article  CAS  Google Scholar 

  54. Aoyama K, Nakaki T (2013) Impaired glutathione synthesis in neurodegeneration. Int J Mol Sci 14(10):21021–21044. https://doi.org/10.3390/ijms141021021

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Rifaioglu MM, Motor S, Davarci I, Tuzcu K, Sefil F, Davarci M, Nacar A (2014) Protective effect of ebselen on experimental testicular torsion and detorsion injury. Andrologia 46(10):1134–1140. https://doi.org/10.1111/and.12204

    Article  CAS  PubMed  Google Scholar 

  56. Satoh T, Ishige K, Sagara Y (2004) Protective effects on neuronal cells of mouse afforded by ebselen against oxidative stress at multiple steps. Neurosci Lett 371(1):1–5. https://doi.org/10.1016/j.neulet.2004.04.055

    Article  CAS  PubMed  Google Scholar 

  57. Mouithys-Mickalad Mareque A, Faez JM, Chistiaens L, Kohnen S, Deby C, Hoebeke M, Lamy M, Deby-Dupont G (2004) In vitro evaluation of glutathione peroxidase (GPx)-like activity and antioxidant properties of some Ebselen analogues. Redox Report, Commun Free Rad Res 9(2):81–87. https://doi.org/10.1179/135100004225004788

    Article  CAS  Google Scholar 

  58. Ramesh G, MacLean AG, Philipp MT (2013) Cytokines and chemokines at the crossroads of neuroinflammation, neurodegeneration, and neuropathic pain. Mediat Inflamm 2013:20. https://doi.org/10.1155/2013/480739

    Article  CAS  Google Scholar 

  59. Ye L, Huang Y, Zhao L, Li Y, Sun L, Zhou Y, Qian G, Zheng JC (2013) IL-1β and TNF-α induce neurotoxicity through glutamate production: a potential role for neuronal glutaminase. J Neurochem 125(6):897–908. https://doi.org/10.1111/jnc.12263

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Belvisi M, Haddad E, Battram C, Birrell M, Foster M, Webber S (2000) Anti-inflammatory properties of ebselen in a model of sephadex-induced lung inflammation. Eur Respir J 15(3):579–581

    Article  CAS  Google Scholar 

  61. Tsujimoto Y (1998) Role of Bcl-2 family proteins in apoptosis: apoptosomes or mitochondria? Genes Cells, Devoted Mol Cell Mech 3(11):697–707

    Article  CAS  Google Scholar 

  62. Lakhani SA, Masud A, Kuida K, Porter GA Jr, Booth CJ, Mehal WZ, Inayat I, Flavell RA (2006) Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science (N Y) 311(5762):847–851. https://doi.org/10.1126/science.1115035

    Article  CAS  Google Scholar 

  63. Chinnaiyan AM, Orth K, O'Rourke K, Duan H, Poirier GG, Dixit VM (1996) Molecular ordering of the cell death pathway: Bcl-2 and Bcl-x function upstream of the CED-3-like apoptotic proteases. J Biol Chem 271(9):4573–4576. https://doi.org/10.1074/jbc.271.9.4573

    Article  CAS  PubMed  Google Scholar 

  64. Tarale P, Chakrabarti T, Sivanesan S, Naoghare P, Bafana A, Krishnamurthi K (2016) Potential role of epigenetic mechanism in manganese induced neurotoxicity. Biomed Res Int 2016:2548792. https://doi.org/10.1155/2016/2548792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Yang X, Chang HY, Baltimore D (1998) Autoproteolytic activation of pro-caspases by oligomerization. Mol Cell 1(2):319–325

    Article  CAS  Google Scholar 

Download references

Acknowledgments

Grateful thanks to Dr. Mohamed Metwally, Assistant Professor of Pathology, and Dr. Nesma Elnasery, Lecturer of Histology, Faculty of Veterinary Medicine, Zagazig University, for their valuable help in the histopathological and immunohistochemical investigations.

Author information

Authors and Affiliations

  1. Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44511, Egypt

    Walaa M. El-hady

  2. Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, Zagazig, 44511, Egypt

    Azza A. A. Galal

Authors
  1. Walaa M. El-hady
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Azza A. A. Galal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Azza A. A. Galal.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

El-hady, W.M., Galal, A.A.A. Neurotoxic Outcomes of Subchronic Manganese Chloride Exposure via Contaminated Water in Adult Male Rats and the Potential Benefits of Ebselen. Biol Trace Elem Res 186, 208–217 (2018). https://doi.org/10.1007/s12011-018-1291-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-018-1291-4

Keywords

Search

Navigation