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NMDA Receptor Antagonist MK801 Protects Against 1-Bromopropane-Induced Cognitive Dysfunction

  • Lin Xu
  • Xiaofei Qiu
  • Shuo Wang
  • Qingshan WangEmail author
  • Xiu-Lan ZhaoEmail author
Original Article
  • 109 Downloads

Abstract

Occupational exposure to 1-bromopropane (1-BP) induces learning and memory deficits. However, no therapeutic strategies are currently available. Accumulating evidence has suggested that N-methyl-D-aspartate receptors (NMDARs) and neuroinflammation are involved in the cognitive impairments in neurodegenerative diseases. In this study we aimed to investigate whether the noncompetitive NMDAR antagonist MK801 protects against 1-BP-induced cognitive dysfunction. Male Wistar rats were administered with MK801 (0.1 mg/kg) prior to 1-BP intoxication (800 mg/kg). Their cognitive performance was evaluated by the Morris water maze test. The brains of rats were dissected for biochemical, neuropathological, and immunological analyses. We found that the spatial learning and memory were significantly impaired in the 1-BP group, and this was associated with neurodegeneration in both the hippocampus (especially CA1 and CA3) and cortex. Besides, the protein levels of phosphorylated NMDARs were increased after 1-BP exposure. MK801 ameliorated the 1-BP-induced cognitive impairments and degeneration of neurons in the hippocampus and cortex. Mechanistically, MK801 abrogated the 1-BP-induced disruption of excitatory and inhibitory amino-acid balance and NMDAR abnormalities. Subsequently, MK801 inhibited the microglial activation and release of pro-inflammatory cytokines in 1-BP-treated rats. Our findings, for the first time, revealed that MK801 protected against 1-BP-induced cognitive dysfunction by ameliorating NMDAR function and blocking microglial activation, which might provide a potential target for the treatment of 1-BP poisoning.

Keywords

1-Bromopropane Cognitive dysfunction MK801 N-methyl-D-aspartate receptors Microglia NLRP3 inflammasome 

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81872654, 81703264); Fundamental Research Funds of Shandong University (2016JC020), China, and Natural Science Foundation of Shandong Province (ZR2017MH002), China.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

12264_2018_321_MOESM1_ESM.pdf (60 kb)
Supplementary material 1 (PDF 59 kb)

References

  1. 1.
    Kim Y, Park J, Moon Y. Hematopoietic and reproductive toxicity of 2-bromopropane, a recently introduced substitute for chlorofluorocarbons. Toxicol Lett 1999, 108: 309–313.CrossRefGoogle Scholar
  2. 2.
    Moon HI, Shin S, Byeon SH. Exposure monitoring and health risk assessment of 1-bromopropane as a cleaning solvent in the workplace. Hum Ecol Risk Assess 2015, 21: 744–752.CrossRefGoogle Scholar
  3. 3.
    Wang TH, Wu ML, Wu YH, Tsai WJ, Lin KP, Wang CL, et al. Neurotoxicity associated with exposure to 1-bromopropane in golf-club cleansing workers. Clin Toxicol 2015, 53: 823–826.CrossRefGoogle Scholar
  4. 4.
    Samukawa M, Ichihara G, Oka N, Kusunoki S. A case of severe neurotoxicity associated with exposure to 1-bromopropane, an alternative to ozone-depleting or global-warming solvents. Arch Intern Med 2012, 172: 1257–1260.CrossRefGoogle Scholar
  5. 5.
    Ichihara G, Kitoh J, Yu X, Asaeda N, Iwai H, Kumazawa T, et al. 1-Bromopropane, an alternative to ozone layer depleting solvents, is dose-dependently neurotoxic to rats in long-term inhalation exposure. Toxicol Sci 2000, 55: 116–123.CrossRefGoogle Scholar
  6. 6.
    Sohn YK, Suh JS, Kim JW, Seo HH, Kim JY, Kim HY, et al. A histopathologic study of the nervous system after inhalation exposure of 1-bromopropane in rat. Toxicol Lett 2002, 131: 195–201.CrossRefGoogle Scholar
  7. 7.
    Guo Y, Yuan H, Jiang LL, Yang JL, Zeng T, Xie KQ, et al. Involvement of decreased neuroglobin protein level in cognitive dysfunction induced by 1-bromopropane in rats. Brain Res 2015, 1600: 1–16.CrossRefGoogle Scholar
  8. 8.
    Zhong ZX, Zeng T, Xie KQ, Zhang CL, Chen JJ, Bi Y, et al. Elevation of 4-hydroxynonenal and malondialdehyde modified protein levels in cerebral cortex with cognitive dysfunction in rats exposed to 1-bromopropane. Toxicology 2013, 306: 16–23.CrossRefGoogle Scholar
  9. 9.
    Chalupka S. Reducing workplace exposure to 1-bromopropane. Workplace Health Saf 2014, 62: 128.CrossRefGoogle Scholar
  10. 10.
    Ichihara G, Li W, Shibata E, Ding X, Wang H, Liang Y, et al. Neurologic abnormalities in workers of a 1-bromopropane factory. Environ Health Perspect 2004, 112: 1319–1325.CrossRefGoogle Scholar
  11. 11.
    Ichihara G, Miller JK, Ziolkowska A, Itohara S, Takeuchi Y. Neurological disorders in three workers exposed to 1-bromopropane. J Occup Environ Med 2002, 44: 1–7.CrossRefGoogle Scholar
  12. 12.
    Majersik JJ, Caravati EM, Steffens JD. Severe neurotoxicity associated with exposure to the solvent 1-bromopropane (n-propyl bromide). Clin Toxicol (Phila) 2007, 45: 270–276.CrossRefGoogle Scholar
  13. 13.
    Yu X, Ichihara G, Kitoh J, Xie Z, Shibata E, Kamijima M, et al. Neurotoxicity of 2-bromopropane and 1-bromopropane, alternative solvents for chlorofluorocarbons. Environ Res 2001, 85: 48–52.CrossRefGoogle Scholar
  14. 14.
    Soto D, Altafaj X, Sindreu C, Bayes A. Glutamate receptor mutations in psychiatric and neurodevelopmental disorders. Commun Integr Biol 2014, 7: e27887.CrossRefGoogle Scholar
  15. 15.
    Bi H, Sze CI. N-methyl-D-aspartate receptor subunit NR2A and NR2B messenger RNA levels are altered in the hippocampus and entorhinal cortex in Alzheimer’s disease. J Neurol Sci 2002, 200: 11–18.CrossRefGoogle Scholar
  16. 16.
    Huang X, Ni W, Zhang C. Calcium-impermeable NMDA receptor: a novel target for addiction. Neurosci Bull 2017, 33: 357–358.CrossRefGoogle Scholar
  17. 17.
    Verkhratsky A, Kirchhoff F. NMDA receptors in glia. Neuroscientist 2007, 13: 28–37.CrossRefGoogle Scholar
  18. 18.
    Sze C, Bi H, Kleinschmidt-DeMasters BK, Filley CM, Martin LJ. N-Methyl-D-aspartate receptor subunit proteins and their phosphorylation status are altered selectively in Alzheimer’s disease. J Neurol Sci 2001, 182: 151–159.CrossRefGoogle Scholar
  19. 19.
    Chang YC, Kim HW, Rapoport SI, Rao JS. Chronic NMDA administration increases neuroinflammatory markers in rat frontal cortex: cross-talk between excitotoxicity and neuroinflammation. Neurochem Res 2008, 33: 2318–2323.CrossRefGoogle Scholar
  20. 20.
    Rammes G, Mattusch C, Wulff M, Seeser F, Kreuzer M, Zhu K, et al. Involvement of GluN2B subunit containing N-methyl-D-aspartate (NMDA) receptors in mediating the acute and chronic synaptotoxic effects of oligomeric amyloid-beta (Aβ) in murine models of Alzheimer’s disease (AD). Neuropharmacology 2017, 123: 100–115.CrossRefGoogle Scholar
  21. 21.
    Mony L, Kew JN, Gunthorpe MJ, Paoletti P. Allosteric modulators of NR2B-containing NMDA receptors: molecular mechanisms and therapeutic potential. Br J Pharmacol 2009, 157: 1301–1317.CrossRefGoogle Scholar
  22. 22.
    Fang M, Li J, Tiu SC, Zhang L, Wang M, Yew DT. N-methyl-D-aspartate receptor and apoptosis in Alzheimer’s disease and multiinfarct dementia. J Neurosci Res 2005, 81: 269–274.CrossRefGoogle Scholar
  23. 23.
    Fueta Y, Ishidao T, Arashidani K, Endo Y, Hori H. Hyperexcitability of the hippocampal CA1 and the dentate gyrus in rats subchronically exposed to a substitute for chlorofluorocarbons, 1-bromopropane vapor. J Occup Health 2002, 44: 156–165.CrossRefGoogle Scholar
  24. 24.
    Song L, Pei L, Yao S, Wu Y, Shang Y. NLRP3 inflammasome in neurological diseases, from functions to therapies. Front Cell Neurosci 2017, 11: 63.PubMedPubMedCentralGoogle Scholar
  25. 25.
    Fang X, Sun D, Wang Z, Yu Z, Liu W, Pu Y, et al. MiR-30a positively regulates the inflammatory response of microglia in experimental autoimmune encephalomyelitis. Neurosci Bull 2017, 33: 603–615.CrossRefGoogle Scholar
  26. 26.
    Gonzalez H, Elgueta D, Montoya A, Pacheco R. Neuroimmune regulation of microglial activity involved in neuroinflammation and neurodegenerative diseases. J Neuroimmunol 2014, 274: 1–13.CrossRefGoogle Scholar
  27. 27.
    Thomas DM, Kuhn DM. MK-801 and dextromethorphan block microglial activation and protect against methamphetamine-induced neurotoxicity. Brain Res 2005, 1050: 190–198.CrossRefGoogle Scholar
  28. 28.
    Rosi S, Vazdarjanova A, Ramirez-Amaya V, Worley PF, Barnes CA, Wenk GL. Memantine protects against LPS-induced neuroinflammation, restores behaviorally-induced gene expression and spatial learning in the rat. Neuroscience 2006, 142: 1303–1315.CrossRefGoogle Scholar
  29. 29.
    Subramanian K, Mohideen SS, Suzumura A, Asai N, Murakumo Y, Takahashi M, et al. Exposure to 1-bromopropane induces microglial changes and oxidative stress in the rat cerebellum. Toxicology 2012, 302: 18–24.CrossRefGoogle Scholar
  30. 30.
    Han EH, Yang JH, Kim HK, Choi JH, Khanal T, Do MT, et al. 1-Bromopropane up-regulates cyclooxygenase-2 expression via NF-kappaB and C/EBP activation in murine macrophages. Food Chem Toxicol 2012, 50: 1616–1622.CrossRefGoogle Scholar
  31. 31.
    Xu YP, Wang S, Jiang LL, Wang H, Yang YL, Li M, et al. Identify melatonin as a novel therapeutic reagent in the treatment of 1-bromopropane(1-BP) intoxication. Medicine 2016, 95: 8.CrossRefGoogle Scholar
  32. 32.
    Wang S, Irving G, Jiang L, Wang H, Li M, Wang X, et al. Oxidative stress mediated hippocampal neuron apoptosis participated in carbon disulfide-induced rats cognitive dysfunction. Neurochem Res 2017, 42: 583–594.CrossRefGoogle Scholar
  33. 33.
    Wu X, Wang R, Jiang Q, Wang S, Yao Y, Shao L. Determination of amino acid neurotransmitters in rat hippocampi by HPLC-UV using NBD-F as a derivative. Biomed Chromatogr 2014, 28: 459–462.CrossRefGoogle Scholar
  34. 34.
    Pini RT, do Vales LD, Braga Costa TM, Almeida SS. Effects of cafeteria diet and high fat diet intake on anxiety, learning and memory in adult male rats. Nutr Neurosci 2017, 20: 396–408. CrossRefGoogle Scholar
  35. 35.
    Hyman BT, Van Hoesen GW, Kromer LJ, Damasio AR. Perforant pathway changes and the memory impairment of Alzheimer’s disease. Ann Neurol 1986, 20: 472–481.CrossRefGoogle Scholar
  36. 36.
    Sze CI, Bi H, Kleinschmidt-DeMasters BK, Filley CM, Martin LJ. Selective regional loss of exocytotic presynaptic vesicle proteins in Alzheimer’s disease brains. J Neurol Sci 2000, 175: 81–90.CrossRefGoogle Scholar
  37. 37.
    Mohideen SS, Ichihara S, Banu S, Liu F, Kitoh J, Ichihara G. Changes in neurotransmitter receptor expression levels in rat brain after 4-week exposure to 1-bromopropane. Neurotoxicology 2009, 30: 1078–1083.CrossRefGoogle Scholar
  38. 38.
    Lamsa K, Heeroma JH, Kullmann DM. Hebbian LTP in feed-forward inhibitory interneurons and the temporal fidelity of input discrimination. Nat Neurosci 2005, 8: 916–924.CrossRefGoogle Scholar
  39. 39.
    Aoki C, Venkatesan C, Go CG, Mong JA, Dawson TM. Cellular and subcellular localization of NMDA-R1 subunit immunoreactivity in the visual cortex of adult and neonatal rats. J Neurosci 1994, 14: 5202–5222.CrossRefGoogle Scholar
  40. 40.
    Ramirez A, Arbuckle MR. The N-methyl-D-aspartate receptor: memory, madness, and more. Biol Psychiatry 2017, 82: e1–e3.CrossRefGoogle Scholar
  41. 41.
    Hallett PJ, Dunah AW, Ravenscroft P, Zhou S, Bezard E, Crossman AR, et al. Alterations of striatal NMDA receptor subunits associated with the development of dyskinesia in the MPTP-lesioned primate model of Parkinson’s disease. Neuropharmacology 2005, 48: 503–516.CrossRefGoogle Scholar
  42. 42.
    Flavin HJ, Seyfried TN. Enhanced aspartate release related to epilepsy in (EL) mice. J Neurochem 1994, 63: 592–595.CrossRefGoogle Scholar
  43. 43.
    Bradford HF. Glutamate, GABA and epilepsy. Prog Neurobiol 1995, 47: 477–511.CrossRefGoogle Scholar
  44. 44.
    Jia N, Sun Q, Su Q, Dang S, Chen G. Taurine promotes cognitive function in prenatally stressed juvenile rats via activating the Akt-CREB-PGC1alpha pathway. Redox Biol 2016, 10: 179–190.CrossRefGoogle Scholar
  45. 45.
    Chan CY, Sun HS, Shah SM, Agovic MS, Ho I, Friedman E, et al. Direct interaction of taurine with the NMDA glutamate receptor subtype via multiple mechanisms. Adv Exp Med Biol 2013, 775: 45–52.CrossRefGoogle Scholar
  46. 46.
    Fueta Y, Fukunaga K, Ishidao T, Hori H. Hyperexcitability and changes in activities of Ca2+/calmodulin-dependent kinase II and mitogen-activated protein kinase in the hippocampus of rats exposed to 1-bromopropane. Life Sci 2002, 72: 521–529.CrossRefGoogle Scholar
  47. 47.
    Suda M, Honma T, Miyagawa M, Wang RS. Alteration of brain levels of neurotransmitters and amino acids in male F344 rats induced by three-week repeated inhalation exposure to 1-bromopropane. Ind Health 2008, 46: 348–359.CrossRefGoogle Scholar
  48. 48.
    Mayer ML, Vyklicky L Jr, Clements J. Regulation of NMDA receptor desensitization in mouse hippocampal neurons by glycine. Nature 1989, 338: 425–427.CrossRefGoogle Scholar
  49. 49.
    Johnson JW, Ascher P. Glycine potentiates the NMDA response in cultured mouse brain neurons. Nature 1987, 325: 529–531.CrossRefGoogle Scholar
  50. 50.
    Papouin T, Ladepeche L, Ruel J, Sacchi S, Labasque M, Hanini M, et al. Synaptic and extrasynaptic NMDA receptors are gated by different endogenous coagonists. Cell 2012, 150: 633–646.CrossRefGoogle Scholar
  51. 51.
    Graeber MB, Streit WJ. Microglia: biology and pathology. Acta Neuropathol 2010, 119: 89–105.CrossRefGoogle Scholar
  52. 52.
    Alimonti A, Ristori G, Giubilei F, Stazi MA, Pino A, Visconti A, et al. Serum chemical elements and oxidative status in Alzheimer’s disease, Parkinson disease and multiple sclerosis. Neurotoxicology 2007, 28: 450–456.CrossRefGoogle Scholar
  53. 53.
    Le W, Wu J, Tang Y. Protective microglia and their regulation in Parkinson’s disease. Front Mol Neurosci 2016, 9: 89.CrossRefGoogle Scholar
  54. 54.
    Zhang XF, Thompson M, Xu YH. Multifactorial theory applied to the neurotoxicity of paraquat and paraquat-induced mechanisms of developing Parkinson’s disease. Lab Investig 2016, 96: 496–507.CrossRefGoogle Scholar
  55. 55.
    Bayer TA, Multhaup G. Involvement of amyloid beta precursor protein (AbetaPP) modulated copper homeostasis in Alzheimer’s disease. J Alzheimers Dis 2005, 8: 201–206; discussion 209–215.CrossRefGoogle Scholar
  56. 56.
    Hayashi Y, Ishibashi H, Hashimoto K, Nakanishi H. Potentiation of the NMDA receptor-mediated responses through the activation of the glycine site by microglia secreting soluble factors. Glia 2006, 53: 660–668.CrossRefGoogle Scholar
  57. 57.
    Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T, et al. Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci 2003, 23: 8692–8700.CrossRefGoogle Scholar
  58. 58.
    Han RZ, Hu JJ, Weng YC, Li DF, Huang Y. NMDA receptor antagonist MK-801 reduces neuronal damage and preserves learning and memory in a rat model of traumatic brain injury. Neurosci Bull 2009, 25: 367–375.CrossRefGoogle Scholar
  59. 59.
    Jha S, Srivastava SY, Brickey WJ, Iocca H, Toews A, Morrison JP, et al. The inflammasome sensor, NLRP3, regulates CNS inflammation and demyelination via caspase-1 and interleukin-18. J Neurosci 2010, 30: 15811–15820.CrossRefGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS 2018

Authors and Affiliations

  1. 1.School of Public HealthShandong UniversityJinanChina
  2. 2.School of Public HealthDalian Medical UniversityDalianChina
  3. 3.School of PharmacyLiaocheng UniversityLiaochengChina

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