Skip to main content

Advertisement

SpringerLink
Log in

Effect of Melatonin on Glutamate: BDNF Signaling in the Cerebral Cortex of Polychlorinated Biphenyls (PCBs)—Exposed Adult Male Rats

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

Various epidemiological survey suggests that the central nervous system is the target for many environmental contaminants. One among them is Aroclor 1254, a mixture of polychlorinated biphenyls (PCBs) which explore a spectrum of biochemical and neurotoxic responses in humans and laboratory animals. Learning and motor coordination deficits are the profound effects of PCBs which may be related to cerebral dysfunction. The aim of the study is to elicit the protective effect of melatonin (Mel), a potent, blood brain permeable antioxidant against the effect of Aroclor 1254 on the signaling of glutamate—principal excitatory neurotransmitter and brain derived neurotrophic factor (BDNF) in the cerebral cortex of adult rats which plays a key role in brain functions. Adult male Wistar rats were grouped into four and treated intraperitonealy (i.p) Group I with corn oil (Control), Group II with PCBs (2 mg/kg/bwt), Group III with PCBs + Mel (2 mg/kg/bwt + 5 mg/kg/bwt) and Group IV with Mel (5 mg/kg/bwt). The protein expression of glutamate signaling molecules and mRNA expressions of GLAST, BDNF signaling molecules were analyzed. The results suggest that simultaneous melatonin treatment significantly attenuated the NMDA receptor mediated glutamate excitotoxicity and protects the inhibition of BDNF signaling caused by PCBs exposure in cerebral cortex of adult male rats.

Graphical Abstract

Schematic pathway illustrating the proposed mechanism by which melatonin protects against A1254 mediated glutamate induced neurodegeneration in the cerebral cortex of adult male rats. PCBs induced neurodegeneration is caused by the overactivation of NMDAR, followed by the activation of voltage dependent calcium channels leading to the increase in intracellular Ca2+ that stimulates calpain. Calpain inturn inhibits the PKA α and neurtrophin BDNF, its receptor and downstream signaling MAPK pathway leading to neurodegeneration. Melatonin had scavenged the ROS produced by PCBS and decreased the NMDAR expression which inturn protected the cells from neurodegeneration.

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
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11

Similar content being viewed by others

References

  1. Safe SH (1994) Dietary and environmental estrogens and antiestrogens and their possible role in human disease. Environ Sci Pollut Res Int 1:29–33

    Article  CAS  PubMed  Google Scholar 

  2. Park HY, Hertz-Picciotto I, Sovcikova E et al (2010) Neurodevelopmental toxicity of prenatal polychlorinated biphenyls (PCBs) by chemical structure and activity: a birth cohort study. Environ Health 23:9–51

    Google Scholar 

  3. Evangelista de Duffard AM, Duffard R (1996) Behavioral toxicology, risk assessment, and chlorinated hydrocarbons. Environ Health Perspect 104:353–360

    Article  PubMed Central  PubMed  Google Scholar 

  4. Tuomisto J, Vartianen T, Tuomisto J (2011) Synopsis on dioxins and PCBs. National Institute for Health and Welfare, Helsinki

    Google Scholar 

  5. Fängström B, Hovander L, Bignert A et al (2005) Concentrations of polybrominateddiphenyl ethers, polychlonnated biphenyls, and polychlorobiphenylols in serum from pregnant Faroese women and their children 7 years later. Environ Sci Technol 39:9457–9463

    Article  PubMed  Google Scholar 

  6. Inoue K, Harada K, Takenaka K et al (2006) Levels and concentration ratios of polychlorinated biphenyls and polybrominateddiphenyl ethers in serum and breast milk in Japanese mothers. Environ Health Perspect 114:1179–1185

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  7. Seegal RF (1996) Epidemiological and laboratory evidence of PCB-induced neurotoxicity. Crit Rev Toxicol 26:709–737

    Article  CAS  PubMed  Google Scholar 

  8. Lin YY, Liu G, Wai CM et al (2008) Bioelectrochemical immunoassay of polychlorinated biphenyl. Anal Chim Acta 612:23–28

    Article  CAS  PubMed  Google Scholar 

  9. National Institute for Occupational Safety and Health: Polychlorobiphenyls: 5503.NIOSH Manual of Analytical Methods, 4th ed. (NIOSH Publication 2003-154 [3rdSupplement])

  10. Javitt DC, Zukin SR (1990) The role of excitatory amino acids in neuropsychiatric illness. J Neuropsychiatry Clin Neurosci 2:44–52

    Article  CAS  PubMed  Google Scholar 

  11. Tsuda M (1996) Cascade of gene expression induced by Ca2+ signals in neurons. Neurochem Int 29:443–451

    Article  CAS  PubMed  Google Scholar 

  12. Berliocchi L, Bano D, Nicotera P (2005) Ca2+ signals and death programmes in neurons. Philos Trans R Soc Lond B Biol Sci 360:2255–2258

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Miyamoto E (2006) Molecular mechanism of neuronal plasticity: induction and maintenance of long-term potentiation in the hippocampus. J Pharmacol Sci 100:433–442

    Article  CAS  PubMed  Google Scholar 

  14. Wu HY, Lynch DR (2006) Calpain and synaptic function. Mol Neurobiol 33:215–236

    Article  PubMed  Google Scholar 

  15. Mattson MP, Meffert MK (2006) Roles for NF-kappaB in nerve cell survival, plasticity, and disease. Cell Death Differ. 13:852–860

    Article  CAS  PubMed  Google Scholar 

  16. Ndountse LT, Chan HM (2009) Role of N-methyl-D-aspartate receptors in polychlorinated biphenyl mediated neurotoxicity. Toxicol Lett 184:50–55

    Article  CAS  PubMed  Google Scholar 

  17. Mattson MP (2008) Glutamate and neurotrophic factors in neuronal plasticity and disease. Ann N Y Acad Sci 1144:97–112

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Cohen-Cory S, Kidane AH, Shirkey NJ et al (2010) Brain-derived neurotrophic factor and the development of structural neuronal connectivity. Dev Neurobiol 70:271–288

    PubMed Central  CAS  PubMed  Google Scholar 

  19. Lee J, Duan W, Mattson MP (2002) Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem 82:1367–1375

    Article  CAS  PubMed  Google Scholar 

  20. Barnabé-Heider F, Miller FD (2003) Endogenously produced neurotrophins regulate survival and differentiation of cortical progenitors via distinct signaling pathways. J Neurosci 23:5149–5160

    PubMed  Google Scholar 

  21. Cheng A, Wang S, Cai J et al (2003) Nitric oxide acts in a positive feedback loop with BDNF to regulate neural progenitor cell proliferation and differentiation in the mammalian brain. Dev Biol 258:319–333

    Article  CAS  PubMed  Google Scholar 

  22. Ernfors P, Bramham CR (2003) The coupling of a trkB tyrosine residue to LTP. Trends Neurosci 26:171–173

    Article  CAS  PubMed  Google Scholar 

  23. Mattson MP (2006) Neuronal life-and-death signaling, apoptosis, and neurodegenerative disorders. Antioxid Redox Signal 8:1997–2006

    Article  CAS  PubMed  Google Scholar 

  24. Nam Y, Shin EJ, Shin SW et al (2014) YY162 prevents ADHD-like behavioral side effects and cytotoxicity induced by Aroclor1254 via interactive signaling between antioxidant potential, BDNF/TrkB, DAT and NET. Food Chem Toxicol 65:280–292

    Article  CAS  PubMed  Google Scholar 

  25. Lee DW, Opanashuk LA (2004) Polychlorinated biphenyl mixture aroclor 1254-induced oxidative stress plays a role in dopaminergic cell injury. Neurotoxicology 25:925–939

    Article  CAS  PubMed  Google Scholar 

  26. Lee DW, Notter SA, Thiruchelvam M et al (2012) Subchronic polychlorinated biphenyl (Aroclor 1254) exposure produces oxidative damage and neuronal death of ventral midbrain dopaminergic systems. Toxicol Sci 125:496–508

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Fonnum F, Mariussen E, Reistad T (2006) Molecular mechanisms involved in the toxic effects of polychlorinated biphenyls (PCBs) and brominated flame retardants (BFRs). J Toxicol Environ Health A 69:21–35

    Article  CAS  PubMed  Google Scholar 

  28. Hilgier W, Łazarewicz JW, Strużynska L et al (2012) Repeated exposure of adult rats to Aroclor 1254 induces neuronal injury and impairs the neurochemical manifestations of the NMDA receptor-mediated intracellular signaling in the hippocampus. Neurotoxicology 33:16–22

    Article  CAS  PubMed  Google Scholar 

  29. Mariussen E, Fonnum F (2001) The effect of polychlorinated biphenyls on the high affinity uptake of the neurotransmitters, dopamine, serotonin, glutamate and GABA, into rat brain synaptosomes. Toxicology 159:11–21

    Article  CAS  PubMed  Google Scholar 

  30. Cleveland DW, Rothstein JD (2001) From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat Rev Neurosci 2:806–819

    Article  CAS  PubMed  Google Scholar 

  31. Selvakumar K, Bavithra S, Ganesh L et al (2013) Polychlorinated biphenyls induced oxidative stress mediated neurodegeneration in hippocampus and behavioral changes of adult rats: anxiolytic-like effects of quercetin. Toxicol Lett 222:45–54

    Article  CAS  PubMed  Google Scholar 

  32. PratheepaKumari R, Selvakumar K, Bavithra S et al (2011) Role of quercetin on PCBs (Aroclor-1254) induced impairment of dopaminergic receptor mRNA expression in cerebral cortex of adult male rats. Neurochem Res 36:1344–1352

    Article  CAS  Google Scholar 

  33. Bavithra S, Selvakumar K, PratheepaKumari R et al (2012) Polychlorinated biphenyl (PCBs)-induced oxidative stress plays a critical role on cerebellar dopaminergic receptor expression: ameliorative role of quercetin. Neurotox Res 2:149–159

    Article  Google Scholar 

  34. Fonnum F, Mariussen E (2009) Mechanisms involved in the neurotoxic effects of environmental toxicants such as polychlorinated biphenyls and brominated flame retardants. J Neurochem 111:1327–1347

    Article  CAS  PubMed  Google Scholar 

  35. Menéndez-González M, Salas-Pacheco JM, Arias-Carrión O (2014) The yearly rate of Relative Thalamic Atrophy (yrRTA): a simple 2D/3D method for estimating deep gray matter atrophy in multiple sclerosis. Front Aging Neurosci 6:219

    PubMed Central  PubMed  Google Scholar 

  36. Peyrot F, Houée-Levin C, Ducrocq C (2006) Melatonin nitrosation promoted by NO*2; comparison with the peroxynitrite reaction. Free Radic Res 40:910–920

    Article  CAS  PubMed  Google Scholar 

  37. Galano A, Tan DX, Reiter RJ (2013) On the free radical scavenging activities of melatonin’s metabolites, AFMK and AMK. J Pineal Res 54:245–257

    Article  CAS  PubMed  Google Scholar 

  38. Lissoni P, Rovelli F, Malugani F et al (2001) Anti-angiogenic activity of melatonin in advanced cancer patients. Neuro Endocrinol Lett 22:45–47

    CAS  PubMed  Google Scholar 

  39. Poeggeler B, Reiter RJ, Tan DX et al (1993) Melatonin, hydroxyl radical-mediated oxidative damage, and aging: a hypothesis. J Pineal Res 14:151–168

    Article  CAS  PubMed  Google Scholar 

  40. Venkataraman P, Krishnamoorthy G, Vengatesh G et al (2008) Protective role of melatonin on PCB (Aroclor 1,254) induced oxidative stress and changes in acetylcholine esterase and membrane bound ATPases in cerebellum, cerebral cortex and hippocampus of adult rat brain. Int J Dev Neurosci 26:585–591

    Article  CAS  PubMed  Google Scholar 

  41. Venkataraman P, Selvakumar K, Krishnamoorthy G et al (2010) Effect of melatonin on PCB (Aroclor 1254) induced neuronal damage and changes in Cu/Zn superoxide dismutase and glutathione peroxidase-4 mRNA expression in cerebral cortex, cerebellum and hippocampus of adult rats. Neurosci Res 66:189–197

    Article  CAS  PubMed  Google Scholar 

  42. Lowry OH, Rosebrough NJ, Farr AL et al (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  43. Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidiniumthiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159

    Article  CAS  PubMed  Google Scholar 

  44. Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative C(T) method. Nat Protoc 3:1101–1108

    Article  CAS  PubMed  Google Scholar 

  45. Howard AS, Fitzpatrick R, Pessah I et al (2003) Polychlorinated biphenyls induce caspase-dependent cell death in cultured embryonic rat hippocampal but not cortical neurons via activation of the ryanodine receptor. Toxicol Appl Pharmacol 190:72–86

    Article  CAS  PubMed  Google Scholar 

  46. Kennedy MB (2000) Signal-processing machines at the postsynaptic density. Science 290:750–754

    Article  CAS  PubMed  Google Scholar 

  47. Elgersma Y, Silva AJ (1999) Molecular mechanisms of synaptic plasticity and memory. Curr Opin Neurobiol 9:209–213

    Article  CAS  PubMed  Google Scholar 

  48. Ikonomidou C, Bosch F, Miksa M et al (1999) Blockade of NMDA receptors and apoptotic neurodegeneration in the developing brain. Science 283:70–74

    Article  CAS  PubMed  Google Scholar 

  49. Goll DE, Thompson VF, Li H et al (2003) The calpain system. Physiol Rev 83:731–801

    Article  CAS  PubMed  Google Scholar 

  50. Smith SD, Jia Z, Huynh KK et al (2003) Glutamate substitutions at a PKA consensus site are consistent with inactivation of calpain by phosphorylation. FEBS Lett 542:115–118

    Article  CAS  PubMed  Google Scholar 

  51. Liang Z, Liu F, Grundke-Iqbal I et al (2007) Down-regulation of cAMP-dependent protein kinase by over-activated calpain in Alzheimer disease brain. J Neurochem 103:2462–2470

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Vosler PS, Brennan CS, Chen J (2008) Calpain-mediated signaling mechanisms in neuronal injury and neurodegeneration. Mol Neurobiol 38(1):78–100

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Xia Z, Dudek H, Miranti CK et al (1996) Calcium influx via the NMDA receptor induces immediate early gene transcription by a MAP kinase/ERK-dependent mechanism. J Neurosci 16:5425–5436

    CAS  PubMed  Google Scholar 

  54. Croall DE, DeMartino GN (1991) Calcium-activated neutral protease (calpain) system: structure, function, and regulation. Physiol Rev 71:813–847

    CAS  PubMed  Google Scholar 

  55. Takahashi K (1990) Calpain substrate specificity. In: Mellgren RL, Murachi T (eds) Intracellular calcium-dependent proteolysis. CRC Press, Boca Raton, pp 55–74

    Google Scholar 

  56. Jerónimo-Santos A, Vaz SH, Parreira S, Rapaz-Lérias S, Caetano AP, Buée-Scherrer V, Castrén E, Valente CA, Blum D, Sebastião AM, Diógenes MJ (2014) Dysregulation of TrkB receptors and BDNF function by Amyloid-β peptide is mediated by Calpain. Cereb Cortex. [Epub ahead of print] PubMed PMID: 24860020

  57. Ferrer I, Marin C, Rey MJ, Ribalta T, Goutan E, Blanco R, Tolosa E, Marti E (1999) BDNF and full-length and truncated TrkB expression in Alzheimer disease. Implications in therapeutic strategies. J Neuropathol Exp Neurol 58:729–739

    Article  CAS  PubMed  Google Scholar 

  58. Saido TC, Sorimachi H, Suzuki K (1999) Calpain: new perspectives in molecular diversity and physiological-pathological involvement. FASEB J 8:814–822

    Google Scholar 

  59. Gomes JR, Costa JT, Melo CV, Felizzi F, Monteiro P, Pinto MJ, Inácio AR, Wieloch T, Almeida RD, Grãos M, Duarte CB (2012) Excitotoxicity downregulates TrkB.FL signaling and upregulates the neuroprotective truncated TrkB receptors in cultured hippocampal and striatal neurons. J Neurosci 32:4610–4622

    Article  CAS  PubMed  Google Scholar 

  60. Vidaurre OG, Gascon S, Deogracias R, Sobrado M, Cuadrado E, Montaner J, Rodriguez-Pena A, Diaz-Guerra M (2012) Imbalance of neurotrophin receptor isoforms TrkB-FL/TrkB-T1 induces neuronal death in excitotoxicity. Cell Death Dis 3:256

    Article  Google Scholar 

  61. Bonni A, Brunet A, West AE et al (1999) Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286:1358–1362

    Article  CAS  PubMed  Google Scholar 

  62. Du K, Montminy M (1998) CREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem 273:32377–32379

    Article  CAS  PubMed  Google Scholar 

  63. Numakawa T, Yamagishi S, Adachi N et al (2002) Brain-derived neurotrophic factor-induced potentiation of Ca(2+) oscillations in developing cortical neurons. J Biol Chem 277:6520–6529

    Article  CAS  PubMed  Google Scholar 

  64. Zhang JP, Lencz T, Geisler S et al (2013) Genetic variation in BDNF is associated with antipsychotic treatment resistance in patients with schizophrenia. Schizophr Res 146:285–288

    Article  PubMed Central  PubMed  Google Scholar 

  65. Danbolt NC (2001) Glutamate uptake. Prog Neurobiol 65:1–105

    Article  CAS  PubMed  Google Scholar 

  66. Strużyńska L, Sulkowski G, Dąbrowska-Bouta B (2012) Aroclor 1254 selectively inhibits expression of glial GLT-1 glutamate transporter in the forebrain of chronically exposed adult rat. Toxicology 300:12–18

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The financial assistance from University Grant Commission (UGC), Government of India, New Delhi to Dr. J. Arunakaran is greatly acknowledged.

Author information

Authors and Affiliations

  1. Department of Endocrinology, Dr. ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Chennai, 600 113, India

    S. Bavithra, E. Sugantha Priya & J. Arunakaran

  2. Dr. A. Ramachandran’s Diabetes Hospitals, Guindy, Chennai, 600 032, India

    K. Selvakumar

  3. Department of Biochemistry, Asan Memorial Dental College and Hospital, Asan Nagar, Chengalpattu, 603105, India

    G. Krishnamoorthy

Authors
  1. S. Bavithra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. E. Sugantha Priya
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. Selvakumar
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G. Krishnamoorthy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. J. Arunakaran
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to J. Arunakaran.

Ethics declarations

Conflict of interest

The author(s) declared no potential conflicts of interest with respect to the authorship and/or publication of this article.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bavithra, S., Sugantha Priya, E., Selvakumar, K. et al. Effect of Melatonin on Glutamate: BDNF Signaling in the Cerebral Cortex of Polychlorinated Biphenyls (PCBs)—Exposed Adult Male Rats. Neurochem Res 40, 1858–1869 (2015). https://doi.org/10.1007/s11064-015-1677-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-015-1677-z

Keywords

Search

Navigation