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A Brief Review of Neurotoxicity Induced by Melamine

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Abstract

In September 2008, in China, tens of thousands of children were hospitalized, several even died, as a result of infant-formula milk adulterated with a synthetic chemical compound, melamine, and in the next few months, this crisis became the focus of attention worldwide. Although there are a number of articles about nephrotoxicity of melamine, the evidence of melamine toxicity on other organs is still scanty. Specially, several recent studies indicated that melamine can perturb the central nervous system (CNS) function and induce cognitive deficits, breaking the previous view that melamine toxicity is limited to the urinary system. This review focuses on some developmental consequences of melamine exposures through various routes in vitro and in vivo, from ethology to molecular and cellular assessments. The evidences demonstrate that the neurotoxic effects of melamine were varied from different route exposure. Finally, the relevant literature on the mechanisms of these aspects has been discussed, and some suggestions towards further researches have been presented.

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References

  • An L, Sun W (2017a) Acute melamine affects spatial memory consolidation via inhibiting hippocampal NMDAR-dependent LTD in rats. Toxicol Sci. doi: 10.1093/toxsci/kfx1039

  • An L, Sun W (2017b) Prenatal melamine exposure impairs spatial cognition and hippocampal synaptic plasticity by presynaptic and postsynaptic inhibition of glutamatergic transmission in adolescent offspring. Toxicol Lett 269:55–64

    Article  CAS  PubMed  Google Scholar 

  • An L, Zhang T (2013) Spatial cognition and sexually dimorphic synaptic plasticity balance impairment in rats with chronic prenatal ethanol exposure. Behav Brain Res 256:564–574

    Article  CAS  PubMed  Google Scholar 

  • An L, Zhang T (2014) Prenatal melamine exposure induces impairments of spatial cognition and hippocampal synaptic plasticity in male adolescent rats. Reprod Toxicol 49:78–85

    Article  CAS  PubMed  Google Scholar 

  • An L, Zhang T (2016) Comparison impairments of spatial cognition and hippocampal synaptic plasticity between prenatal and postnatal melamine exposure in male adult rats. Neurotox Res 29(2):218–229

    Article  CAS  PubMed  Google Scholar 

  • An L, Li Z, Yang Z, Zhang T (2011) Cognitive deficits induced by melamine in rats. Toxicol Lett 206(3):276–280

    Article  CAS  PubMed  Google Scholar 

  • An L, Li Z, Yang Z, Zhang T (2012a) Melamine induced cognitive impairment associated with oxidative damage in rat’s hippocampus. Pharmacol Biochem Behav 102(2):196–202

    Article  CAS  PubMed  Google Scholar 

  • An L, Liu S, Yang Z, Zhang T (2012b) Cognitive impairment in rats induced by nano-CuO and its possible mechanisms. Toxicol Lett 213(2):220–227

    Article  CAS  PubMed  Google Scholar 

  • An L, Yang Z, Zhang T (2013a) Imbalanced synaptic plasticity induced spatial cognition impairment in male offspring rats treated with chronic prenatal ethanol exposure. Alcohol Clin Exp Res 37(5):763–770

    Article  CAS  PubMed  Google Scholar 

  • An L, Yang Z, Zhang T (2013b) Melamine induced spatial cognitive deficits associated with impairments of hippocampal long-term depression and cholinergic system in Wistar rats. Neurobiol Learn Mem 100:18–24

    Article  CAS  PubMed  Google Scholar 

  • An L, Li Z, Zhang T (2014) Reversible effects of vitamins C and E combination on oxidative stress-induced apoptosis in melamine-treated PC12 cells. Free Radic Res 48(2):239–250

    Article  CAS  PubMed  Google Scholar 

  • An L, Fu J, Zhang T (2015) Reversible effects of vitamins C and E combination on cognitive deficits and oxidative stress in the hippocampus of melamine-exposed rats. Pharmacol Biochem Behav 132:152–159

    Article  CAS  PubMed  Google Scholar 

  • Andreyev AY, Kushnareva YE, Starkov AA (2005) Mitochondrial metabolism of reactive oxygen species. Biochemistry (Mosc) 70(2):200–214

    Article  CAS  Google Scholar 

  • Basar E, Basar-Eroglu C, Karakas S, Schurmann M (2001) Gamma, alpha, delta, and theta oscillations govern cognitive processes. Int J Psychophysiol 39(2–3):241–248

    Article  CAS  PubMed  Google Scholar 

  • Behrendt RP (2009) Contribution of hippocampal region CA3 to consciousness and schizophrenic hallucinations. Neurosci Biobehav Rev 34(8):1121–1136

    Article  PubMed  Google Scholar 

  • Bondy SC, Campbell A (2005) Developmental neurotoxicology. J Neurosci Res 81(5):605–612

    Article  CAS  PubMed  Google Scholar 

  • Brown CA, Jeong KS, Poppenga RH, Puschner B, Miller DM, Ellis AE et al (2007) Outbreaks of renal failure associated with melamine and cyanuric acid in dogs and cats in 2004 and 2007. J Vet Diagn Investig 19(5):525–531

    Article  Google Scholar 

  • Buzsaki G, Draguhn A (2004) Neuronal oscillations in cortical networks. Science 304(5679):1926–1929

    Article  CAS  PubMed  Google Scholar 

  • Chu CY, Chu KO, Chan JY, Liu XZ, Ho CS, Wong CK et al (2010) Distribution of melamine in rat foetuses and neonates. Toxicol Lett 199(3):398–402

    Article  CAS  PubMed  Google Scholar 

  • Chu CY, Chu KO, Ho CS, Kwok SS, Chan HM, Fung KP et al (2013) Melamine in prenatal and postnatal organs in rats. Reprod Toxicol 35:40–47

    Article  CAS  PubMed  Google Scholar 

  • Collingridge GL, Peineau S, Howland JG, Wang YT (2010) Long-term depression in the CNS. Nat Rev Neurosci 11(7):459–473

    Article  CAS  PubMed  Google Scholar 

  • Cooper DC (2002) The significance of action potential bursting in the brain reward circuit. Neurochem Int 41(5):333–340

    Article  CAS  PubMed  Google Scholar 

  • Doralp S, Leung LS (2008) Cholinergic modulation of hippocampal CA1 basal-dendritic long-term potentiation. Neurobiol Learn Mem 90(2):382–388

    Article  CAS  PubMed  Google Scholar 

  • Fu J, Wang H, Gao J, Yu M, Wang R, Yang Z et al (2016) Rapamycin effectively impedes melamine-induced impairments of cognition and synaptic plasticity in Wistar rats. Mol Neurobiol 54(2):819–832

  • Gossner CM, Schlundt J, Ben Embarek P, Hird S, Lo-Fo-Wong D, Beltran JJ et al (2009) The melamine incident: implications for international food and feed safety. Environ Health Perspect 117(12):1803–1808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Guo C, He Z, Wen L, Zhu L, Lu Y, Deng S et al (2012) Cytoprotective effect of trolox against oxidative damage and apoptosis in the NRK-52e cells induced by melamine. Cell Biol Int 36(2):183–188

    Article  CAS  PubMed  Google Scholar 

  • Halliwell B (2006) Oxidative stress and neurodegeneration: where are we now? J Neurochem 97(6):1634–1658

    Article  CAS  PubMed  Google Scholar 

  • Han YG, Liu SC, Zhang T, Yang Z (2011) Induction of apoptosis by melamine in differentiated PC12 cells. Cell Mol Neurobiol 31(1):65–71

    Article  CAS  PubMed  Google Scholar 

  • Ingelfinger JR (2008) Melamine and the global implications of food contamination. N Engl J Med 359(26):2745–2748

    Article  CAS  PubMed  Google Scholar 

  • Jingbin W, Ndong M, Kai H, Matsuno K, Kayama F (2010) Placental transfer of melamine and its effects on rat dams and fetuses. Food Chem Toxicol 48(7):1791–1795

    Article  CAS  PubMed  Google Scholar 

  • Kahana MJ, Seelig D, Madsen JR (2001) Theta returns. Curr Opin Neurobiol 11(6):739–744

    Article  CAS  PubMed  Google Scholar 

  • Kannan K, Jain SK (2000) Oxidative stress and apoptosis. Pathophysiology 7(3):153–163

    Article  CAS  PubMed  Google Scholar 

  • Ke Y, Duan X, Wen F, Xu X, Tao G, Zhou L et al (2010) Association of melamine exposure with urinary stone and oxidative DNA damage in infants. Arch Toxicol 84(4):301–307

    Article  CAS  PubMed  Google Scholar 

  • Kim JI, Lee HR, Sim SE, Baek J, Yu NK, Choi JH et al (2011a) PI3Kgamma is required for NMDA receptor-dependent long-term depression and behavioral flexibility. Nat Neurosci 14(11):1447–1454

    Article  CAS  PubMed  Google Scholar 

  • Kim SH, Lee IC, Lim JH, Shin IS, Moon C, Park SC et al (2011b) Effects of melamine on pregnant dams and embryo-fetal development in rats. J Appl Toxicol 31(6):506–514

    Article  CAS  PubMed  Google Scholar 

  • Langman CB, Alon U, Ingelfinger J, Englund M, Saland JM, Somers MJ et al (2009) A position statement on kidney disease from powdered infant formula-based melamine exposure in Chinese infants. Pediatr Nephrol 24(7):1263–1266

    Article  PubMed  Google Scholar 

  • Leung LS, Shen B, Rajakumar N, Ma J (2003) Cholinergic activity enhances hippocampal long-term potentiation in CA1 during walking in rats. J Neurosci 23(28):9297–9304

    CAS  PubMed  Google Scholar 

  • Liu G, Li S, Jia J, Yu C, He J, Zhu J (2010) Pharmacokinetic study of melamine in rhesus monkey after a single oral administration of a tolerable daily intake dose. Regul Toxicol Pharmacol 56(2):193–196

    Article  CAS  PubMed  Google Scholar 

  • Ma C, Kang H, Liu Q, Zhu R, Cao Z (2011) Insight into potential toxicity mechanisms of melamine: an in silico study. Toxicology 283(2–3):96–100

    Article  CAS  PubMed  Google Scholar 

  • Mast RW, Jeffcoat AR, Sadler BM, Kraska RC, Friedman MA (1983) Metabolism, disposition and excretion of [14C]melamine in male Fischer 344 rats. Food Chem Toxicol 21(6):807–810

    Article  CAS  PubMed  Google Scholar 

  • Mattson MP (2007) Calcium and neurodegeneration. Aging Cell 6(3):337–350

    Article  CAS  PubMed  Google Scholar 

  • Miller E, Mrowicka M, Zolynski K, Kedziora J (2009) Oxidative stress in multiple sclerosis. Pol Merkur Lekarski 27(162):499–502

    CAS  PubMed  Google Scholar 

  • Parry J (2008) China’s tainted infant formula sickens nearly 13,000 babies. BMJ 337:a1802

    Article  PubMed  Google Scholar 

  • Ragozzino ME, Choi D (2004) Dynamic changes in acetylcholine output in the medial striatum during place reversal learning. Learn Mem 11(1):70–77

    Article  PubMed  PubMed Central  Google Scholar 

  • Rogers JL, Kesner RP (2003) Cholinergic modulation of the hippocampus during encoding and retrieval. Neurobiol Learn Mem 80(3):332–342

    Article  CAS  PubMed  Google Scholar 

  • Sharma K, Paradakar M (2010) The melamine adulteration scandal. Food Security 2(1):97–107

    Article  Google Scholar 

  • Teepker M, Anthes N, Fischer S, Krieg JC, Vedder H (2007) Effects of oxidative challenge and calcium on ATP-levels in neuronal cells. Neurotoxicology 28(1):19–26

    Article  CAS  PubMed  Google Scholar 

  • Toescu EC, Vreugdenhil M (2010) Calcium and normal brain ageing. Cell Calcium 47(2):158–164

    Article  CAS  PubMed  Google Scholar 

  • Tyan YC, Yang MH, Jong SB, Wang CK, Shiea J (2009) Melamine contamination. Anal Bioanal Chem 395(3):729–735

    Article  CAS  PubMed  Google Scholar 

  • Wang H, Gao N, Li W, Yang Z, Zhang T (2015) Melamine induces autophagy in mesangial cells via enhancing ROS level. Toxicol Mech Methods 25(7):581–587

    CAS  PubMed  Google Scholar 

  • Wang H, Gao N, Li Z, Yang Z, Zhang T (2016) Autophagy alleviates melamine-induced cell death in PC12 cells via decreasing ROS level. Mol Neurobiol 53(3):1718–1729

    Article  CAS  PubMed  Google Scholar 

  • Wang Y, Liu F, Wei Y, Liu D (2011) The effect of exogenous melamine on rat hippocampal neurons. Toxicol Ind Health 27:571–576

    Article  PubMed  Google Scholar 

  • Wu YT, Huang CM, Lin CC, Ho WA, Lin LC, Chiu TF et al (2009) Determination of melamine in rat plasma, liver, kidney, spleen, bladder and brain by liquid chromatography-tandem mass spectrometry. J Chromatogr A 1216(44):7595–7601

    Article  CAS  PubMed  Google Scholar 

  • Xie G, Zheng X, Qi X, Cao Y, Chi Y, Su M et al (2010) Metabonomic evaluation of melamine-induced acute renal toxicity in rats. J Proteome Res 9(1):125–133

    Article  CAS  PubMed  Google Scholar 

  • Xu X, An L, Mi X, Zhang T (2013) Impairment of cognitive function and synaptic plasticity associated with alteration of information flow in theta and gamma oscillations in melamine-treated rats. PLoS One 8(10):e77796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang J, An L, Yao Y, Yang Z, Zhang T (2011) Melamine impairs spatial cognition and hippocampal synaptic plasticity by presynaptic inhibition of glutamatergic transmission in infant rats. Toxicology 289(2–3):167–174

    Article  CAS  PubMed  Google Scholar 

  • Yang JJ, Tian YT, Yang Z, Zhang T (2010a) Effect of melamine on potassium currents in rat hippocampal CA1 neurons. Toxicol in Vitro 24(2):397–403

    Article  CAS  PubMed  Google Scholar 

  • Yang JJ, Yang Z, Zhang T (2010b) Action potential changes associated with impairment of functional properties of sodium channels in hippocampal neurons induced by melamine. Toxicol Lett 198(2):171–176

    Article  CAS  PubMed  Google Scholar 

  • Yang Y, Xiong GJ, Yu DF, Cao J, Wang LP, Xu L et al (2012) Acute low-dose melamine affects hippocampal synaptic plasticity and behavior in rats. Toxicol Lett 214(1):63–68

    Article  CAS  PubMed  Google Scholar 

  • Zhang H, Wang H, Xiao X, Zhang T (2016) Melamine alters glutamatergic synaptic transmission of CA3-CA1 synapses Presynaptically through autophagy activation in the rat hippocampus. Neurotox Res 29(1):135–142

    Article  CAS  PubMed  Google Scholar 

  • Zucker RS, Regehr WG (2002) Short-term synaptic plasticity. Annu Rev Physiol 64:355–405

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Authors thank Xiaoliang Li and Yang Yang for revised, further improved, and polished in language of the manuscript.

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Authors and Affiliations

  1. Medical College of Acupuncture-Moxibustion and Rehabilitation, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

    Lei An & Wei Sun

  2. South China Research Center for Acupuncture-Moxibustion, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China

    Lei An & Wei Sun

  3. Department of Physiology, University of Saskatchewan, Saskatoon, S7N 5E5, Canada

    Lei An

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Correspondence to Lei An or Wei Sun.

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An, L., Sun, W. A Brief Review of Neurotoxicity Induced by Melamine. Neurotox Res 32, 301–309 (2017). https://doi.org/10.1007/s12640-017-9731-z

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