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Manganese neurotoxicity and protective effects of resveratrol and quercetin in preclinical research

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Abstract

Background

Exposure to Mn results in a neurological syndrome known as manganism.

Methods

We examined how 4-week Mn exposure (20 mg/kg MnCl2po, 5 days/week) induces neurotoxic effects in rats. Oxidized-to-reduced glutathione ratio (GSSG/GSH), malondialdehyde (MDA), superoxide dismutase (SOD) activity, catalase (CAT) activity, vitamin E content and caspase-3 activity were measured in several rat brain structures. Further, we examined protective effects of the polyphenols: resveratrol (R) or quercetin (QCT) against Mn-induced neurotoxicity.

Results

After exposure to Mn, we found a rise in GSSG/GSH ratio and a reduction in SOD activity in the rat striatum (STR), while in the nucleus accumbens (NAC) decreases in alpha-tocopherol content and in SOD activity were noted. In the frontal cortex (FCX), an enhancement in GSSG/GSH ratio and a reduction in SOD and CAT activities were observed. In the cerebellum (CER), a significant increase in the caspase-3 activity paralleled a rise in the GSSG/GSH ratio and a diminution of SOD activity. In the rat hippocampus (HIP), Mn evoked an enhancement in GSSG/GSH ratio. There were no changes in the MDA levels. Pretreatment with R and QCT protected against the Mn-induced (i) enhancement in GSSG/GSH ratio in the STR, (ii) decreases in the NAC alpha-tocopherol content and (iii) reduction in SOD activity in FCX, NAC and CER.

Conclusion

Repeated Mn administration induces toxic effects in several rat brain structures and treatment with R and QCT may be a potential therapeutic strategy to attenuate the metal neurotoxicity.

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References

  1. Aschner JL, Aschner M. Nutritional aspects of manganese homeostasis. Mol Asp Med 2005;26(4–5):353–62.

    Article  CAS  Google Scholar 

  2. Crossgrove J, Zheng W. Manganese toxicity upon overexposure. NMR Biomed 2004;17(8):544–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Aschner M, Erikson KM, Dorman DC. Manganese dosimetry: species differences and implications for neurotoxicity. Crit Rev Toxicol 2005;35(1):1–32.

    Article  CAS  PubMed  Google Scholar 

  4. Bowler RM, Mergler D, Sassine MP, Larribe F, Hudnell K. Neuropsychiatric effects of manganese on mood. Neurotoxicology 1999;20(2–3):367–78.

    CAS  PubMed  Google Scholar 

  5. Perl DP, Olanow CW. The neuropathology of manganese-induced Parkinsonism. J Neuropathol Exp Neurol 2007;66(8):675–82.

    Article  CAS  PubMed  Google Scholar 

  6. Liu X, Sullivan KA, Madl JE, Legare M, Tjalkens RB. Manganese-induced neurotoxicity: the role of astroglial-derived nitric oxide in striatal interneuron degeneration. Toxicol Sci 2006;91(2):521–31.

    Article  CAS  PubMed  Google Scholar 

  7. Parent A, Carpenter MB, editors. Carpenter’s human neuroanatomy. Baltimore: Williams & Wilkins; 1996.

    Google Scholar 

  8. Guilarte TR. Manganese neurotoxicity: new perspectives from behavioral, neuroimaging, and neuropathological studies in humans and non-human primates. Front Aging Neurosci 2013;5:1–23.

    Article  CAS  Google Scholar 

  9. Klos KJ, Chandler M, Kumar N, Ahlskog JE, Josephs KA. Neuropsychological profiles of manganese neurotoxicity. Eur J Neurol 2006;13(10):1139–41.

    Article  CAS  PubMed  Google Scholar 

  10. Erikson KM, Aschner M. Manganese neurotoxicity and glutamate-GABA interaction. Neurochem Int 2003;43(4–5):475–80.

    Article  CAS  PubMed  Google Scholar 

  11. Martinez-Finley EJ, Gavin CE, Aschner M, Gunter TE. Manganese neurotoxicity and the role of reactive oxygen species. Free Radic Biol Med 2013;62:65–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Chtourou Y, Trabelsi K, Fetoui H, Mkannez G, Kallel H, Zeghal N. Manganese induces oxidative stress, redox state unbalance and disrupts membrane bound ATPases on murine neuroblastoma cells in vitro: protective role of silymarin. Neurochem Res 2011;36(8):1546–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. da Silva Santos V, Bisen-Hersh E, Yu Y, Cabral IS, Nardini V, Culbreth M, et al. Anthocyanin-rich açaí (Euterpe oleracea Mart.) extract attenuates manganese-induced oxidative stress in rat primary astrocyte cultures. J Toxicol Environ Health A 2014;77(7):390–404.

    Article  PubMed  CAS  Google Scholar 

  14. Lebda MA, El-Neweshy MS, El-Sayed YS. Neurohepatic toxicity of subacute manganese chloride exposure and potential chemoprotective effects of lycopene. Neurotoxicology 2012;33(1):98–104.

    Article  CAS  PubMed  Google Scholar 

  15. Scholz S, Williamson G. Interactions affecting the bioavailability of dietary polyphenols in vivo. Int J Vitam Nutr Res 2007;77(3):224–35.

    Article  CAS  PubMed  Google Scholar 

  16. Rodrigo R, Miranda A, Vergara L. Modulation of endogenous antioxidant system by wine polyphenols in human disease. Clin Chim Acta 2011;412(5–6):410–24.

    Article  CAS  PubMed  Google Scholar 

  17. Han JH, Tian HZ, Lian YY, Yu Y, Lu CB, Li XM, et al. Quetiapine mitigates the ethanol-induced oxidative stress in brain tissue, but not in the liver, of the rat. Neuropsychiatr Dis Treat 2015;11:1473–82.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Santos D, Milatovic D, Andrade V, Batoreu MC, Aschner M, Marreilha dos Santos AP. The inhibitory effect of manganese on acetylcholinesterase activity enhances oxidative stress and neuroinflammation in the rat brain. Toxicology 2012;292(2–3):90–8.

    Article  CAS  PubMed  Google Scholar 

  19. Santos AP, Lucas RL, Andrade V, Mateus ML, Milatovic D, Aschner M, et al. Protective effects of ebselen (Ebs) and para-aminosalicylic acid (PAS) against manganese (Mn)-induced neurotoxicity. Toxicol Appl Pharmacol 2012;258(3):394–402.

    Article  PubMed  CAS  Google Scholar 

  20. Bhuvaneswari Devi C, Kiran Kumari K, Jyotsna V, Indravathi G. Manganese induced toxic effects on oxidative system and mRNA expression of Mn-Sod and Gpx in albino rat brain: protective effect of alpha tocopherol. Int J Innov Res Sci Eng Technol 2014;3(2):9252–63.

    Google Scholar 

  21. Juan ME, Vinardell MP, Planas JM. The daily oral administration of high doses of trans-resveratrol to rats for 28 days is not harmful. J Nutr 2002;132(2):257–60.

    Article  CAS  PubMed  Google Scholar 

  22. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the Folin phenol reagent. J Biol Chem 1951;193(1):265–75.

    CAS  PubMed  Google Scholar 

  23. Tukozkan N, Erdamar H, Seven I. Measurement of total malondialdehyde in plasma and tissues by high-performance liquid chromatography and thiobarbituric acid assay. Firat Med J 2006;11(2):88–92.

    CAS  Google Scholar 

  24. Gawlik M, Krzyżanowska W, Gawlik MB, Filip M. Optimization of determination of reduced and oxidized glutathione in rat striatum by HPLC method with fluorescence detection and pre-column derivatization. Acta Chromatogr 2014;26(2):335–45.

    Article  CAS  Google Scholar 

  25. Gawlik MT, Gawlik MB, Górka A, Brandys J. Optimization and validation of high-performance liquid chromatographic metod for determination of ó- and α-tocopherol in rat plasma and erythrocytes. Acta Chromatogr 2003; 13:185–95.

    CAS  Google Scholar 

  26. Misra HP, Fridovich I. The role of superoxide anion in the autoxidation of epinephrine and a simple assay for superoxide dismutase. J Biochem Chem 1972;247(10):3170–5.

    CAS  Google Scholar 

  27. Beer B, Sizer W. A spectrophotometry method for measuring the breakdown of hydrogen peroxidase by catalase. J Biol Chem 1952;195(1):133–9.

    Google Scholar 

  28. Yamada M, Ohno S, Okayasu I, Okeda R, Hatakeyama S, Watanabe H, et al. Chronic manganese poisoning: a neuropathological study with determination of manganese distribution in the brain. Acta Neuropathol 1986;70(3–4):273–8.

    Article  CAS  PubMed  Google Scholar 

  29. Santos D, Batoréu MC, Tavares de Almeida I, Davis Randall L, Mateus ML, Andrade V, et al. Evaluation of neurobehavioral and neuroinflammatory end-points in the post-exposure period in rats sub-acutely exposed to manganese. Toxicology 2013;314(1):95–9.

    Article  CAS  PubMed  Google Scholar 

  30. Kwakye GF, Paoliello MM, Mukhopadhyay S, Bowman AB, Aschner M. Manganese-induced Parkinsonism and Parkinson’s disease: shared and distinguishable features. Int J Environ Res Public Health 2015;12(7):7519–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Milatovic D, Zaja-Milatovic S, Gupta RC, Yu Y, Aschner M. Oxidative damage and neurodegeneration in manganese-induced neurotoxicity. Toxicol Appl Pharmacol 2009;240(2):219–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gavin CE, Gunter KK, Gunter TE. Manganese and calcium transport in mitochondria: implications for manganese toxicity. Neurotoxicology 1999;20(2–3):445–53.

    CAS  PubMed  Google Scholar 

  33. Alaimo A, Gorojod RM, Beauquis J, Muñoz MJ, Saravia F, Kotler ML. Deregulation of mitochondria-shaping proteins Opa-1 and Drp-1 in manganese-induced apoptosis. PLoS One 2014;9(3):e91848.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Lloyd RV. Mechanism of the manganese-catalyzed autoxidation of dopamine. Chem Res Toxicol 1995;8(1):111–6.

    Article  CAS  PubMed  Google Scholar 

  35. Costa L, Aschner M. Manganese in Health and Disease. Cambridge: The Royal Society of Chemistry; 2015 [chapter 8].

    Google Scholar 

  36. Hybertson BM, Gao B, Bose SK, McCord JM. Oxidative stress in health and disease: the therapeutic potential of Nrf2 activation. Mol Asp Med 2011;32(4–6):234–46.

    Article  CAS  Google Scholar 

  37. Choi CJ, Anantharam V, Saetveit NJ, Houk RS, Kanthasamy A, Kanthasamy AG. Normal cellular prion protein protects against manganese-induced oxidative stress and apoptotic cell death. Toxicol Sci 2007;98(2):495–509.

    Article  CAS  PubMed  Google Scholar 

  38. Alaimo A, Gorojod RM, Miglietta EA, Villarreal A, Ramos AJ, Kotler ML. Manganese induces mitochondrial dynamics impairment and apoptotic cell death: a study in human Gli36 cells. Neurosci Lett 2013;554:76–81.

    Article  CAS  PubMed  Google Scholar 

  39. Chen MT, Yiin SJ, Sheu JY, Huang YL. Brain lipid peroxidation and changes of trace metals in rats following chronic manganese chloride exposure. J Toxicol Environ Health A 2002;65(3–4):305–16.

    Article  CAS  PubMed  Google Scholar 

  40. Desole MS, Esposito G, Migheli R, Fresu L, Sircana S, Zangani D, et al. Cellular defence mechanisms in the striatum of young and aged rats subchronically exposed to manganese. Neuropharmacology 1995;34(3):289–95.

    Article  CAS  PubMed  Google Scholar 

  41. Desole MS, Esposito G, Migheli R, Sircana S, Delogu MR, Fresu L, et al. Glutathione deficiency potentiates manganese toxicity in rat striatum and brainstem and in PC12 cells. Pharmacol Res 1997;36(4):285–92.

    Article  CAS  PubMed  Google Scholar 

  42. Fernsebner K, Zorn J, Kanawati B, Walker A, Michalke B. Manganese leads to an increase in markers of oxidative stress as well as to a shift in the ratio of Fe(II)/(III) in rat brain tissue. Metallomics 2014;6(4):921–31.

    Article  CAS  PubMed  Google Scholar 

  43. Roels H, Meiers G, Delos M, Ortega I, Lauwerys R, Buchet JP, et al. Influence of the route of administration and the chemical form (MnCl2, MnO2) on the absorption and cerebral distribution of manganese in rats. Arch Toxicol 1997;71(4):223–30.

    Article  CAS  PubMed  Google Scholar 

  44. Marí M, Morales A, Colell A, García-Ruiz C, Fernández-Checa JC. Mitochondrial glutathione, a key survival antioxidant. Antioxid Redox Signal 2009; 11(11):2685–700.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Morello M, Zatta P, Zambenedetti P, Martorana A, D’Angelo V, Melchiorri G, et al. Manganese intoxication decreases the expression of manganoproteins in the rat basal ganglia: an immunohistochemical study. Brain Res Bull 2007;74(6):406–15.

    Article  CAS  PubMed  Google Scholar 

  46. Latronico T, Branà MT, Merra E, Fasano A, Di Bari G, Casalino E, et al. Impact of manganese neurotoxicity on MMP-9 production and superoxide dismutase activity in rat primary astrocytes. Effect of resveratrol and therapeutical implications for the treatment of CNS diseases. Toxicol Sci 2013;135(1):218–28.

    Article  CAS  PubMed  Google Scholar 

  47. Ledig M, Tholey G, Megias-Megias L, Kopp P, Wedler F. Combined effects of ethanol and manganese on cultured neurons and glia. Neurochem Res 1991;16(5):591–6.

    Article  CAS  PubMed  Google Scholar 

  48. Khan MM, Ho BT, Davis CM, Major LF, Saini N, Hawley RJ. Trace element levels in human alcoholic brain. Alcohol 1984;1(5):397–401.

    Article  CAS  PubMed  Google Scholar 

  49. Plauth A, Geikowski A, Cichon S, Wowro SJ, Liedgens L, Rousseau M, et al. Hormetic shifting of redox environment by pro-oxidative resveratrol protects cells against stress. Free Radic Biol Med 2016;99:608–22.

    Article  CAS  PubMed  Google Scholar 

  50. Plauth A, Geikowski A, Cichon S, Wowro SJ, Liedgens L, Rousseau M, et al. Data of oxygen- and pH-dependent oxidation of resveratrol. Data Brief 2016;9:433–7.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Lv C, Hong T, Yang Z, Zhang Y, Wang L, Dong M, et al. Effect of quercetin in the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced mouse model of Parkinson’s disease. Evid Based Complement Altern Med 2012;2012:1–6.

    Google Scholar 

  52. Caruana M, Cauchi R, Vassallo N. Putative role of red wine polyphenols against brain pathology in Alzheimer’s and Parkinson’s disease. Front Nutr 2016;3(31):1–16.

    Google Scholar 

  53. Molino S, Dossena M, Buonocore D, Ferrari F, Venturini L, Ricevuti G, et al. Polyphenols in dementia: from molecular basis to clinical trials. Life Sci 2016;161:69–77.

    Article  CAS  PubMed  Google Scholar 

  54. Das J, Ramani R, Suraju MO. Polyphenol compounds and PKC signaling. Biochim Biophys Acta 2016;1860(10):2107–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Toxicology, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland

    Maciej Gawlik, Małgorzata B. Gawlik, Irena Smaga & Małgorzata Filip

  2. Institute of Pharmacology, Polish Academy of Sciences, Laboratory of Drug Addiction Pharmacology, Kraków, Poland

    Małgorzata Filip

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  1. Maciej Gawlik
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  2. Małgorzata B. Gawlik
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  3. Irena Smaga
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  4. Małgorzata Filip
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Correspondence to Maciej Gawlik.

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Gawlik, M., Gawlik, M.B., Smaga, I. et al. Manganese neurotoxicity and protective effects of resveratrol and quercetin in preclinical research. Pharmacol. Rep 69, 322–330 (2017). https://doi.org/10.1016/j.pharep.2016.11.011

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