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Melatonin Ameliorates Arsenite-Induced Neurotoxicity: Involvement of Autophagy and Mitochondria

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In the present study, the neuroprotective effect of melatonin on arsenite-induced neurotoxicity was investigated in rat primary cultured cortical neurons. Incubation of melatonin prevented arsenite-induced neuronal cell loss in a concentration-dependent manner. Furthermore, melatonin significantly attenuated arsenite-induced elevation in microtubule-associated protein light chain 3 (LC3)-II levels, a biomarker of autophagy. Our fluorescent staining assay showed that melatonin decreased arsenite-induced elevation of co-localized fluorescent puncta of monodansylcadaverine (a specific marker of autophagic vacuoles) and lysotracker red (a specific marker of lysosomes), indicating that melatonin is capable of inhibiting arsenite-induced autophagy and autolysosome formation. Because 3-methyladenine (an autophagic inhibitor) attenuated the arsenite-reduced α-synuclein levels (a protein essential for the neurite outgrowth and synaptic plasticity), melatonin via inhibiting autophagy attenuated the arsenite-reduced α-synuclein levels. At the same time, melatonin ameliorated the arsenite-induced reduction in growth associated protein 43 (a hallmark protein of neurite outgrowth) and discontinuous neurites of rat primary cultured cortical neurons. In addition, melatonin was found to prevent arsenite-induced decreases in cytochrome c oxidase levels (a biomarker of mitochondrial mass) and elevation in co-localized fluorescent puncta of autolysosomes and cytochrome c oxidase. Moreover, melatonin prevented arsenite-induced reduction in peroxisome proliferator-activated receptor gamma co-activator 1 α, a transcriptional co-activator of mitochondrial biosynthesis. Taken together, melatonin may exert its neuroprotective action via inhibiting arsenite-induced autophagy and enhancing mitochondrial biogenesis and thus restoring α-synuclein levels, neuronal integrity, and mitochondrial mass in rat primary cultured cortical neurons.

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References

  1. Danan M, Dally S, Conso F (1984) Arsenic-induced encephalopathy. Neurology 34:15–24

    Article  Google Scholar 

  2. Bolla-Wilson K, Bleecker ML (1987) Neuropsychological impairment following inorganic arsenic exposure. J Occup Med 29:500–503

    CAS  PubMed  Google Scholar 

  3. Tyler CR, Allan AM (2014) The effects of arsenic exposure on neurological and cognitive dysfunction in human and rodent studies: a review. Curr Environ Health Rep 1:132–147

    Article  PubMed Central  PubMed  Google Scholar 

  4. Grandjean P, Herz KT (2014) Trace elements as paradigms of developmental neurotoxicants: lead, methylmercury and arsenic. J Trace Elem Med Biol. doi:10.1016/j.jtemb

    PubMed  Google Scholar 

  5. Jomova K, Valko M (2011) Advances in metal-induced oxidative stress and human disease. Toxicology 283:65–87

    Article  CAS  PubMed  Google Scholar 

  6. Bernstam L, Nriagu J (2000) Molecular aspects of arsenic stress. J Toxicol Environ Health B Crit Rev 3:293–322

    Article  CAS  PubMed  Google Scholar 

  7. Bashir S, Sharma Y, Irshad M, Gupta SD, Dogra TD (2006) Arsenic-induced cell death in liver and brain of experimental rats. Basic Clin Pharmacol Toxicol 98:38–43

    Article  CAS  PubMed  Google Scholar 

  8. Lu TH, Tseng TJ, Su CC, Tang FC, Yen CC, Liu YY, Yang CY, Wu CC et al (2014) Arsenic induces reactive oxygen species-caused neuronal cell apoptosis through JNK/ERK-mediated mitochondria-dependent and GRP 78/CHOP-regulated pathways. Toxicol Lett 224:130–140

    Article  CAS  PubMed  Google Scholar 

  9. Piao F, Ma N, Hiraku Y, Murata M, Oikawa S, Cheng F, Zhong L, Yamauchi T et al (2005) Oxidative DNA damage in relation to neurotoxicity in the brain of mice exposed to arsenic at environmentally relevant levels. J Occup Health 47:445–449

    Article  CAS  PubMed  Google Scholar 

  10. Jomova K, Jenisova Z, Feszterova M, Baros S, Liska J, Hudecova D, Rhodes CJ, Valko M (2011) Arsenic: toxicity, oxidative stress and human disease. J Appl Toxicol 31:95–107

    CAS  PubMed  Google Scholar 

  11. Flora SJ (2011) Arsenic-induced oxidative stress and its reversibility. Free Radic Biol Med 51:257–281

    Article  CAS  PubMed  Google Scholar 

  12. Dwivedi N, Mehta A, Yadav A, Binukumar BK, Gill KD, Flora SJ (2011) MiADMSA reverses impaired mitochondrial energy metabolism and neuronal apoptotic cell death after arsenic exposure in rats. Toxicol Appl Pharmacol 256:241–248

    Article  CAS  PubMed  Google Scholar 

  13. Chattopadhyay S, Bhaumik S, Purkayastha M, Basu S, Nag Chaudhuri A, Das Gupta S (2002) Apoptosis and necrosis in developing brain cells due to arsenic toxicity and protection with antioxidants. Toxicol Lett 6:665–676

    Google Scholar 

  14. Chao PL, Fan SF, Chou YH, Lin AMY (2010) N-acetylcysteine attenuates arsenite-induced oxidative injury in DRG explants. Ann N Y Acad Sci 1122:276–288

    Article  Google Scholar 

  15. Teng YC, Tai YI, Lee YH, Lin AM (2013) Role of HO-1 in the arsenite-induced neurotoxicity in primary cultured cortical neurons. Mol Neurobiol 48:281–287

    Article  CAS  PubMed  Google Scholar 

  16. Yadav RS, Sankhwar ML, Shukla RK, Chandra R, Pant AB, Islam F, Khanna VK (2009) Attenuation of arsenic neurotoxicity by curcumin in rats. Toxicol Appl Pharmacol 240:367–376

    Article  CAS  PubMed  Google Scholar 

  17. Galano A, Tan DX, Reiter RJ (2011) Melatonin as a natural ally against oxidative stress: a physicochemical examination. J Pineal Res 51:1–16

    Article  CAS  PubMed  Google Scholar 

  18. Romero A, Ramos E, de Los RC, Egea J, Del Pino J, Reiter RJ (2014) A review of metal-catalyzed molecular damage: protection by melatonin. J Pineal Res 56:343–370

    Article  CAS  PubMed  Google Scholar 

  19. Pal S, Chatterjee AK (2006) Possible beneficial effects of melatonin supplementation on arsenic-induced oxidative stress in Wistar rats. Drug Chem Toxicol 29:423–433

    Article  CAS  PubMed  Google Scholar 

  20. Lin AMY, Fang SF, Chao PL, Yang CH (2007) Melatonin attenuates arsenite-induced apoptosis in rat brain: involvement of mitochondrial and ER pathways and aggregation of α-synuclein. J Pineal Res 43:163–171

    Article  CAS  PubMed  Google Scholar 

  21. Lin AM, Feng SF, Chao PL, Yang CH (2009) Melatonin inhibits arsenite-induced peripheral neurotoxicity. J Pineal Res 46:64–70

    Article  CAS  PubMed  Google Scholar 

  22. Reiter RJ, Tan DX, Rosales-Corral S, Manchester LC (2013) The universal nature, unequal distribution and antioxidant functions of melatonin and its derivatives. Mini Rev Med Chem 13:373–384

    CAS  PubMed  Google Scholar 

  23. Bursch W, Ellinger A, Gerner C, Frohwein U, Schulte-Hermann R (2000) Programmed cell death (PCD): apoptosis autophagic PCD or others? Ann N Y Acad Sci 926:1–12

    Article  CAS  PubMed  Google Scholar 

  24. Klionsky DJ, Emr SD (2000) Autophagy as a regulated pathway of cellular degradation. Science 290:1717–1721

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Levine B (2003) Autophagy in development, tumor suppression, and innate immunity. Harvey Lect 99:47–76

    PubMed  Google Scholar 

  26. Uchiyama Y, Shibata M, Koike M, Yoshimura K, Sasaki M (2008) Autophagy-physiology and pathophysiology. Histochem Cell Biol 129:407–420

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Cuervo AM (2004) Autophagy: in sickness and in health. Trends Cell Biol 14:70–77

    Article  PubMed  Google Scholar 

  28. Tzeng YW, Lee LY, Chao PL, Lee HC, Wu RT, Lin AM (2010) Role of autophagy in protection afforded by hypoxic preconditioning against MPP+-induced neurotoxicity in SH-SY5Y cells. Free Radic Biol Med 49:839–846

    Article  CAS  PubMed  Google Scholar 

  29. Viscomi MT, D’Amelio M, Cavallucci V, Latini L, Bisicchia E, Nazio F, Fanelli F, Maccarrone M et al (2012) Stimulation of autophagy by rapamycin protects neurons from remote degeneration after acute focal brain damage. Autophagy 8:222–235

    Article  CAS  PubMed  Google Scholar 

  30. Zhu JH, Horbinski C, Guo F, Watkins S, Uchiyama Y, Chu CT (2000) Regulation of autophagy by extracellular signal-regulated protein kinases during 1-methyl-4-phenylpyridinium-induced cell death. Am J Pathol 170:75–86

    Article  Google Scholar 

  31. Chang CF, Huang HJ, Lee HC, Hung KC, Wu RT, Lin AM (2012) Melatonin attenuates kainic acid-induced neurotoxicity in mouse hippocampus via inhibition of autophagy and α-synuclein aggregation. J Pineal Res 52:312–321

    Article  CAS  PubMed  Google Scholar 

  32. Cheng TJ, Wang YJ, Kao WW, Chen RJ, Ho YS (2007) Protection against arsenic trioxide-induced autophagic cell death in U118 human glioma cells by use of lipoic acid. Food Chem Toxicol 45:1027–1038

    Article  CAS  PubMed  Google Scholar 

  33. Teng YC, Jeng CJ, Huang HJ, Lin AMY (2015) Role of autophagy in arsenite-induced neurotoxicity: the involvement of α-synuclein. Toxicol Lett 233(3):239–45

  34. Kubli DA, Gustafsson ÅB (2012) Mitochondria and mitophagy: the yin and yang of cell death control. Circ Res 111:1208–1221

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Xilouri M, Vogiatzi T, Vekrellis K, Stefanis L (2008) Alpha-synuclein degradation by autophagic pathways: a potential key to Parkinson’s disease pathogenesis. Autophagy 4:917–919

    Article  CAS  PubMed  Google Scholar 

  36. Cheng F, Vivacqua G, Yu S (2011) The role of α-synuclein in neurotransmission and synaptic plasticity. J Chem Neuroanat 42:242–248

    Article  CAS  PubMed  Google Scholar 

  37. Nopparat C, Porter JE, Ebadi M, Govitrapong P (2010) The mechanism for the neuroprotective effect of melatonin against methamphetamine-induced autophagy. J Pineal Res 49:382–389

    Article  CAS  PubMed  Google Scholar 

  38. Jeong JK, Moon MH, Lee YJ, Seol JW, Park SY (2012) Melatonin-induced autophagy protects against human prion protein-mediated neurotoxicity. J Pineal Res 53:138–146

    Article  CAS  PubMed  Google Scholar 

  39. Zheng Y, Hou J, Liu J, Yao M, Li L, Zhang B, Zhu H, Wang Z (2014) Inhibition of autophagy contributes to melatonin-mediated neuroprotection against transient focal cerebral ischemia in rats. J Pharmacol Sci 124:354–364

    Article  CAS  PubMed  Google Scholar 

  40. Zhou H, Chen J, Lu X, Shen C, Zeng J, Chen L, Pei Z (2012) Melatonin protects against rotenone-induced cell injury via inhibition of Omi and Bax-mediated autophagy in Hela cells. J Pineal Res 52:120–127

    Article  CAS  PubMed  Google Scholar 

  41. Clough RL, Dermentzaki G, Haritou M, Petsakou A, Stefanis L (2011) Regulation of α-synuclein expression in cultured cortical neurons. J Neurochem 117:275–285

    Article  CAS  PubMed  Google Scholar 

  42. Liu G, Wang P, Li X, Li Y, Xu S, Uéda K, Chan P, Yu S (2013) α-Synuclein promotes early neurite outgrowth in cultured primary neurons. J Neural Transm 120:1331–1343

    Article  CAS  PubMed  Google Scholar 

  43. Longo B, Vezzani A, Mello LE (2005) Growth-associated protein 43 expression in hippocampal molecular layer of chronic epileptic rats treated with cycloheximide. Epilepsia Suppl 5:125–128

    Article  Google Scholar 

  44. Maekawa F, Tsuboi T, Oya M, Aung KH, Tsukahara S, Pellerin L, Nohara K (2013) Effects of sodium arsenite on neurite outgrowth and glutamate AMPA receptor expression in mouse cortical neurons. Neurotoxicology 37:197–206

    Article  CAS  PubMed  Google Scholar 

  45. Aung KH, Kurihara R, Nakashima S, Maekawa F, Nohara K, Kobayashi T, Tsukahara S (2013) Inhibition of neurite outgrowth and alteration of cytoskeletal gene expression by sodium arsenite. Neurotoxicology 34:226–235

    Article  CAS  PubMed  Google Scholar 

  46. Janda E, Isidoro C, Carresi C, Mollace V (2012) Defective autophagy in Parkinson’s disease: role of oxidative stress. Mol Neurobiol 46:639–661

    Article  CAS  PubMed  Google Scholar 

  47. Lee J, Giordano S, Zhang J (2012) Autophagy, mitochondria and oxidative stress: cross-talk and redox signaling. Biochem J 41:523–540

    Article  Google Scholar 

  48. Scarpulla RC, Vega RB, Kelly DP (2012) Transcriptional integration of mitochondrial biogenesis. Trends Endocrinol Metab 23:459–466

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  49. Wareski P, Vaarmann A, Choubey V, Safiulina D, Liiv J, Kuum M, Kaasik A (2009) PGC-1α and PGC-1β regulate mitochondrial density in neurons. J Biol Chem 284:21379–21385

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Vaughan RA, Mermier CM, Bisoffi M, Trujillo KA, Conn CA (2014) Dietary stimulators of the PGC-1 superfamily and mitochondrial biosynthesis in skeletal muscle. A mini-review. J Physiol Biochem 70:271–284

    Article  CAS  PubMed  Google Scholar 

  51. Guo P, Pi H, Xu S, Zhang L, Li Y, Li M, Cao Z, Tian L et al (2014) Melatonin improves mitochondrial function by promoting MT1/SIRT1/PGC-1 alpha-dependent mitochondrial biogenesis in cadmium-induced hepatotoxicity in vitro. Toxicol Sci 142:182–195

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Teodoro BG, Baraldi FG, Sampaio IH, Bomfim LH, Queiroz AL, Passos MA, Carneiro EM, Alberici LC et al (2014) Melatonin prevents mitochondrial dysfunction and insulin resistance in rat skeletal muscle. J Pineal Res 57:155–167

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

The authors express their gratitude to Dr. L.S. Kao, Dean of School of Life Sciences, National Yang-Ming University, for her encouragement and support. This study was supported by NSC101-2320-B-010-044-MY3, VGHTPE-V102C-011, and a grant from the Ministry of Education, Aim for the Top University Plan, Taipei, Taiwan, ROC.

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Authors and Affiliations

  1. Institute of Physiology, National Yang-Ming University, Taipei, Taiwan

    Y. C. Teng & Y. I. Tai

  2. Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan

    H. J. Huang & A. M. Y. Lin

  3. Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan

    A. M. Y. Lin

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Teng, Y.C., Tai, Y.I., Huang, H.J. et al. Melatonin Ameliorates Arsenite-Induced Neurotoxicity: Involvement of Autophagy and Mitochondria. Mol Neurobiol 52, 1015–1022 (2015). https://doi.org/10.1007/s12035-015-9250-y

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