Skip to main content

Advertisement

SpringerLink
Log in

Iron Oxide Nanoparticles Affects Behaviour and Monoamine Levels in Mice

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

Abstract

Iron oxide (Fe2O3) nanoparticles (NPs) attract the attention of clinicians for its unique magnetic and paramagnetic properties, which are exclusively used in neurodiagnostics and therapeutics among the other biomedical applications. Despite numerous research findings has already proved neurotoxicity of Fe2O3-NPs, factors affecting neurobehaviour has not been elucidated. In this study, mice were exposed to Fe2O3-NPs (25 and 50 mg/kg body weight) by oral intubation daily for 30 days. It was observed that Fe2O3-NPs remarkably impair motor coordination and memory. In the treated brain regions, mitochondrial damage, depleted energy level and decreased ATPase (Mg2+, Ca2+ and Na+/K+) activities were observed. Disturbed ion homeostasis and axonal demyelination in the treated brain regions contributes to poor motor coordination. Increased intracellular calcium ([Ca2+]i) and decreased expression of growth associated protein 43 (GAP43) impairs vesicular exocytosis could result in insufficient signal between neurons. In addition, levels of dopamine (DA), norepinephrine (NE) and epinephrine (EP) were found to be altered in the subjected brain regions in correspondence to the expression of monoamine oxidases (MAO). Along with all these factors, over expression of glial fibrillary acidic protein (GFAP) confirms the neuronal damage, suggesting the evidences for behavioural changes.

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.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10

Similar content being viewed by others

References

  1. Wu W, Wu Z, Yu T, Jiang C, Kim WS (2015) Recent progress on magnetic iron oxide nanoparticles: synthesis, surface functional strategies and biomedical applications. Sci Technol Adv Mater 16:e023501

    Article  CAS  Google Scholar 

  2. Weinstein JS, Varallyay CG, Dosa E, Gahramanov S, Hamilton B, Rooney WD, Muldoon LL, Neuwelt EA (2010) Superparamagnetic iron oxide nanoparticles: diagnostic magnetic resonance imaging and potential therapeutic applications in neurooncology and central nervous system inflammatory pathologies, a review. J Cereb Blood Flow Metab 30:15–35

    Article  CAS  PubMed  Google Scholar 

  3. Hahn PSFDD, Lewis JM, Saini S, Elizondo G, Weissleder R, Fretz CJ, Ferrucci JT (1990) First clinical trial of a new superparamagnetic iron oxide for use as an oral gastrointestinal contrast agent in MR imaging. Radiology 175:695–700

    Article  CAS  PubMed  Google Scholar 

  4. Johnson WK, Stoupis C, Torres GM, Rosenberg EB, Ros PR (1996) Superparamagnetic iron oxide (SPIO) as an oral contrast agent in gastrointestinal (GI) magnetic resonance imaging (MRI): comparison with state-of-the-art computed tomography (CT). Magn Reson Imaging 14:43–49

    Article  CAS  PubMed  Google Scholar 

  5. Lodhia J, Mandarano G, Ferris NJ, Eu P, Cowell SF (2010) Development and use of iron oxide nanoparticles (Part 1): synthesis of iron oxide nanoparticles for MRI. Biomed Imaging Interv J 6:e12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yang Y, Glenn AL, Raine A (2008) Brain abnormalities in antisocial individuals: implications for the law. Behav Sci Law 26:65–83

    Article  CAS  PubMed  Google Scholar 

  7. Sun C, Fang C, Stephen Z, Veiseh O, Hansen S, Lee D, Ellenbogen RG, Olson J, Zhang M (2008) Tumor-targeted drug delivery and MRI contrast enhancement by chlorotoxin-conjugated iron oxide nanoparticles. Nanomedicine 3:495–505

    Article  CAS  PubMed  Google Scholar 

  8. Manickam V, Dhakshinamoorthy V, Perumal E (2018) Iron oxide nanoparticles induces cell cycle-Dependent neuronal apoptosis in mice. J Mol Neurosci 64:352–362

    Article  CAS  PubMed  Google Scholar 

  9. Wang J, Zhoua G, Chena C, Yu H, Wang T, Mad Y, Jia G, Gao Y, Li B, Suna J, Li Y, Jiao F, Zhao Y, Chai Z (2007) Acute toxicity and bio distribution of different sized titanium dioxide particles in mice after oral administration. J Toxicol Lett 168:176–185

    Article  CAS  Google Scholar 

  10. Winer JL, Liu CY, Apuzzo ML (2012) The use of nanoparticles as contrast media in neuroimaging: a statement on toxicity. World Neurosurg 78:709–711

    Article  PubMed  Google Scholar 

  11. Wu J, Ding T, Sun J (2013) Neurotoxic potential of iron oxide nanoparticles in the rat brain striatum and hippocampus. Neurotoxicology 34:243–253

    Article  CAS  PubMed  Google Scholar 

  12. Wang B, Feng W, Zhu M, Wang Y, Wang M, Gu Y, Ouyang H, Wang H, Li M, Zhao Y, Chai Z, Wang H (2009) Neurotoxicity of low-dose repeatedly intranasal instillation of nano- and submicron-sized ferric oxide particles in mice. J Nanopart Res 11:41–53

    Article  CAS  Google Scholar 

  13. Yarjanli Z, Kamran G, Abolghasem E, Soheila R, Ali Z (2017) Iron oxide nanoparticles may damage to the neural tissue through iron accumulation, oxidative stress, and protein aggregation. BMC Neurosci 18:51–67

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. De Lima MN, Polydoro M, Laranja DC, Bonatto F, Bromberg E, Moreira JC, Dal-Pizzol F, Schröder N (2005) Recognition memory impairment and brain oxidative stress induced by postnatal iron administration. Eur J Neurosci 21:2521–2528

    Article  PubMed  Google Scholar 

  15. Fredriksson A, Schroder N, Eriksson P, Izquierdo I, Archer T (2000) Maze learning and motor activity deficits in adult mice induced by iron exposure during a critical postnatal period. Brain Res Dev 119:65–74

    Article  CAS  Google Scholar 

  16. Dhakshinamoorthy V, Manickam V, Perumal E (2017) Neurobehavioural toxicity of iron oxide nanoparticles in mice. Neurotox Res 32:187–203

    Article  CAS  PubMed  Google Scholar 

  17. Kumari M, Rajak S, Singh SP, Kumari SL, Kumar PU, Murty USN, Mahboob M, Grover P, Rahman MF (2012) Repeated oral dose toxicity of iron oxide nanoparticles: biochemical and histopathological alterations in different tissues of rats. Nanosci Nanotechnol 12:2149–2159

    Article  CAS  Google Scholar 

  18. Libersat F, Pflueger HJ (2004) Monoamines and the orchestration of behavior. Bioscience 54:17–25

    Article  Google Scholar 

  19. Tzschentke TM (2001) Pharmacology and behavioral pharmacology of the mesocortical dopamine system. Prog Neurobiol 6:241–320

    Article  Google Scholar 

  20. Michelotti GA, Price DT, Schwinn DA (2000) Alpha 1-adrenergic receptor regulation: basic science and clinical implications. Pharmacol Ther 88:281–309

    Article  CAS  PubMed  Google Scholar 

  21. Shetty PK, Galeffi F, Turner DA (2012) Cellular links between neuronal activity and energy homeostasis. Front Pharmacol 3:1–14

    Article  CAS  Google Scholar 

  22. Estelrich J, María JSM, Maria AB (2015) Nanoparticles in magnetic resonance imaging: from simple to dual contrast agents. Int J Nanomed 10:1727–1741

    CAS  Google Scholar 

  23. Sundarraj K, Raghunath A, Panneerselvam L, Perumal E (2017) Iron oxide nanoparticles modulate heat shock proteins and organ specific markers in mice male accessory organs. Toxicol Appl Pharmacol 317:12–24

    Article  CAS  PubMed  Google Scholar 

  24. Paul V, Ekambaram P, Jayakumar AR (1998) Effects of sodium fluoride on locomotor behaviour and a few biochemical parameters in rats. Environ Toxicol Pharmacol 6:187–191

    Article  CAS  PubMed  Google Scholar 

  25. Ekambaram P, Paul V (2003) Effect of vitamin D on chronic behavioral and dental toxicities on sodium fluoride in rats. Fluoride 36(3):189–197

    CAS  Google Scholar 

  26. Dharmalingam P, Kulasekaran G, Ganapasam S (2013) Fisetin enhances behavioral performances and attenuates reactive gliosis and inflammation during aluminum chloride-induced neurotoxicity. NeuroMol Med 15:192–208

    Article  CAS  Google Scholar 

  27. Wenk GL (2004) Assessment of spatial memory using the radial armmaze and Morris water maze. Curr Protoc Neurosci 26:8–15

    Article  Google Scholar 

  28. Hjertén S, Pan H (1983) Purification and characterization of two forms of a low-affinity Ca2+ -ATPase from erythrocyte membranes. Biochim et Biophys Acta 728:281–288

    Article  Google Scholar 

  29. Ohnishi T, Suzuki T, Suzuki Y, Ozawa KA (1982) Comparative study of plasma membrane Mg2+ -ATPase activities in normal, regenerating and malignant cells. Biochim Biophys Acta 684:67–74

    Article  CAS  PubMed  Google Scholar 

  30. Bonting SL, Caravaggio LL, Hawkins NM (1963) Studies on sodium-potassium-activated adenosine triphosphatase. VI. Its role in cation transport in the lens of cat, calf and rabbit. Arch Biochem Biophys 101:47–55

    Article  CAS  PubMed  Google Scholar 

  31. Devasagayam TP, Tarachand U (1987) Decreased lipid peroxidation in rat kidney during gestation. Biochem Biophys Res Commun 145:134–138

    Article  CAS  PubMed  Google Scholar 

  32. Kim JJ, Shih JC, Chen K, Chen LU, Bao S, Marten S, Anagnostaras SG, Fanselow MS, Maeyer ED, Seif I, Thompson RF (1997) Selective enhancement of emotional, but not motor, learning in monoamine oxidase A-deficient mice. Proc Natl Acad Sci USA 94:5929–5933

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chen K, Cases O, Rebrin I, Wu W, Gallaher TK, Seif I, Shih JC (2006) Forebrain-specific expression of monoamine oxidase a reduces neurotransmitter levels, restores the brain structure, and rescues aggressive behavior in monoamine oxidase a-deficient mice. J Biol Chem 282:115–123

    Article  CAS  PubMed  Google Scholar 

  34. Sheng L, Ze Y, Wang L, Yu X, Hong J, Zhao X, Ze X, Liu D, Xu B, Zhu Y, Long Y, Lin A, Zhang C, Zhao Y, Hong F (2015) Mechanisms of TiO2 nanoparticle-induced neuronal apoptosis in rat primary cultured hippocampal neurons. J Biomed Mater Res 103:1141–1149

    Article  CAS  Google Scholar 

  35. Yang J, Liu Q, Wu S, Xi Q, Cai Y (2013) Effects of lanthanum chloride on glutamate level, intracellular calcium concentration and caspases expression in the rat hippocampus. Biometals 26:43–59

    Article  CAS  PubMed  Google Scholar 

  36. Yu JF, Kong LD, Chen Y (2002) Antidepressant activity of aqueous extracts of Curcuma longa in mice. J Ethnopharmacol 83:161–165

    Article  CAS  PubMed  Google Scholar 

  37. Guo C, Sun L, Chen X, Zhang D (2003) Oxidative stress, mitochondrial damage and neurodegenerative diseases. Neural Regen Res 8:2003–2014

    Google Scholar 

  38. Havasi A, Li Z, Wang Z, Martin JL, Botla V, Ruchalski K, Schwartz JH, Borkan SC (2008) Hsp27 inhibits Bax activation and apoptosis via a phosphatidylinositol 3-kinase-dependent mechanism. J Biol Chem 283:12305–12313

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Lifshitz J, Kelley BJ, Povlishock JT (2007) Perisomatic thalamic axotomy after diffuse traumatic brain injury is associated with atrophy rather than cell death. J Neuropathol Exp Neurol 66:218–229

    Article  PubMed  Google Scholar 

  40. Magistretti PJ, Allaman IA (2015) Cellular perspective on brain energy metabolism and functional imaging. Neuron 86:883–901

    Article  CAS  PubMed  Google Scholar 

  41. Erecinska M, Silver IA (1989) ATP and brain function. J Cereb Blood Flow Metab 9:2–19

    Article  CAS  PubMed  Google Scholar 

  42. Yu SP (2013) Na+, K+-ATPase: the new face of old player in pathogenesis and apoptotic/hybrid cell death. Biochem Pharmacol 66:1601–1609

    Article  CAS  Google Scholar 

  43. Dribben WH, Eisenman LN, Mennerick S (2010) Magnesium induces neuronal apoptosis by suppressing excitability. Cell Death Dis 1:1–9

    Article  CAS  Google Scholar 

  44. Kadekaro M, Crane AM, Sokoloff L (1985) Differential effects of electrical stimulation of nerve on metabolic activity in spinal cord and dorsal root ganglion in the rat. Proc Natl Acad Sci USA 82:6010–6013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Oloche JJ, Obochi GO (2012) Sodium pump adaptability to tissue-specific regulation: a review. Asian J Biochem 10:180–189

    Article  CAS  Google Scholar 

  46. Hay JC (2007) Calcium: a fundamental regulator of intracellular membrane fusion? EMBO 8:236–240

    Article  CAS  Google Scholar 

  47. Thanawala MS, Regehr WG (2013) Presynaptic calcium influx controls neurotransmitter release in part by regulating the effective size of the readily releasable pool. J Neurosci 33:4625–4633

    Article  PubMed  PubMed Central  Google Scholar 

  48. Xu B, Chen S, Luo Y, Chen Z, Liu L, Zhou H, Chen W, Shen T, Han X, Chen L, Huang S (2011) Calcium signaling is involved in cadmium-induced neuronal apoptosis via induction of reactive oxygen species and activation of MAPK/mTOR network. PLoS ONE 6:e19052

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Tandon A, Bannykh S, Kowalchyk JA, Banerjee A, Martin TFJ, Balch WE (1998) Differential regulation of exocytosis by calcium and CAPS in semi-intact synaptosomes. Neuron 21:147–154

    Article  CAS  PubMed  Google Scholar 

  50. Latchney SE, Masiulis I, Zaccaria KJ, Lagace DC, Powell CM, Mc Casland JS, Eisch AJ (2014) Developmental and adult GAP-43 deficiency in mice dynamically alters hippocampal neurogenesis and mossy fiber volume. Dev Neurosci 36:44–63

    Article  CAS  PubMed  Google Scholar 

  51. Xing Y, Samuvel DJ, Stevens SM, Dubno JR, Schulte BA, Lang H (2012) Age-Related Changes of Myelin Basic Protein in Mouse and Human Auditory Nerve. PLoS ONE 7:1–15

    CAS  Google Scholar 

  52. Wang P, Xie K, Wang C, Bi J (2014) Oxidative stress induced by lipid peroxidation is related with inflammation of demyelination and neurodegeneration in multiple sclerosis. Eur Neurol 72:249–254

    Article  CAS  PubMed  Google Scholar 

  53. Coggan JS, Bittner S, Stiefel KM, Meuth SG, Prescott SA (2015) Physiological dynamics in demyelinating diseases: unraveling complex relationships through computer modeling. Int J Mol Sci 16:21215–21236

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Shi HS, Luo YX, Yin X, Wu HH, Xue G, Geng XH (2015) Reconsolidation of a cocaine associated memory requires DNA methyltransferase activity in the basolateral amygdala. Sci Rep 5:e13327

    Article  CAS  Google Scholar 

  55. Batra J, Sood A (2005) Iron deficiency anaemia: effect on congnitive development in children: a review. Indian J Clin Biochem 20:119–125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Bezem MT, Baumann A, Skjærven L, Meyer R, Kursula P, Martinez A, Flydal MI (2016) Stable preparations of tyrosine hydroxylase provide the solution structure of the full-length enzyme. Sci Rep 6:e30390

    Article  CAS  Google Scholar 

  57. Lovinger DM (2008) Communication networks in the brain neurons, receptors, neurotransmitters and alcohol. Alcohol Res Health 31:196–214

    PubMed  PubMed Central  Google Scholar 

  58. Sasaki M, Shibata E, Tohyama K, Kudo K, Endoh J, Otsuka K, Sakai A (2008) Monoamine neurons in the human brain stem: anatomy, magnetic resonance imaging findings, and clinical implications. Neurorepor 19:1649–1654

    Article  Google Scholar 

  59. Singh C, Bortolatob M, Bali N, Godard SC, Scottd AL, Chend K, Thompsona RF, Shiha JC (2012) Cognitive abnormalities and hippocampal alterations in monoamine oxidase A and B knockout mice. PNAS 110:12816–12821

    Article  Google Scholar 

  60. Maaroufi K, Aissouni LH, Melonc C, Sakly M, Abdelmelek H, Poucet B, Save E (2014) Spatial learning, monoamines and oxidative stress in rats exposed to 900 MHz electromagnetic field in combination with iron overload. Behav Brain Res 258:80–89

    Article  CAS  PubMed  Google Scholar 

  61. Barbelivien A, Nyman L, Haapalinna A, Sirviö J (2001) Inhibition of MAO-A activity enhances behavioural activity of rats assessed using water maze and open arena tasks. Pharmacol Toxicol 88:304–312

    Article  CAS  PubMed  Google Scholar 

  62. Shih JC, Chen K, Ridd MJ (1999) Monoamine oxidase: from genes to behavior. Annu Rev Neurosci 22:197–217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Eisenhofer G, Finberg JP (1994) Different metabolism of norepinephrine and epinephrine by catechol-O-methyltransferase and monoamine oxidase in rats. J Pharmacol Exp Ther 268:1242–1251

    CAS  PubMed  Google Scholar 

  64. Daubner SC, Le T, Wang S (2011) Tyrosine hydroxylase and regulation of dopamine synthesis. Arch Biochem Biophys 508:1–12

    Article  CAS  PubMed  Google Scholar 

  65. Bortolato M, Shih JC (2011) Behavioral outcomes of monoamine oxidase deficiency: preclinical and clinical evidence. Int Rev Neurobiol 100:13–42

    Article  PubMed  PubMed Central  Google Scholar 

  66. Lee HY, Lee GH, Marahatta A, Lin SM, Lee MR, Jang KY, Kim KM, Lee HJ, Lee JW, Bagalkot TR, Chung YC, Lee YC, Kim HR, Chae HJ (2013) The protective role of Bax Inhibitor-1 against chronic mild stress through the inhibition of monoamine oxidase A. Sci Rep 3:e3398

    Article  Google Scholar 

  67. Tabrez S, Jabir NR, Shakil S, Greig NH, Alam Q, Abuzenadah AM, Damanhouri GA, Kamal MA (2012) A synopsis on the role of tyrosine hydroxylase in Parkinson’s disease. CNS Neurol Disord: Drug Targets 11:395–409

    Article  CAS  Google Scholar 

  68. Nakashima A (2012) Proteasomal degradation of tyrosine hydroxylase and neurodegeneration. J Neurochem 120:199–201

    Article  CAS  PubMed  Google Scholar 

  69. Rosengren L, Wikkelso C, Hagberg L (1994) A sensitive ELISA for glial fibrillary acidic protein-application in CSF of adults. J Neurosci Methods 51:197–213

    Article  CAS  PubMed  Google Scholar 

  70. Herrmann MI, Vos P, Wunderlich MT, de Bruijn CH, Lamers KJ (2000) Release of glial tissue-specific proteins after acute stroke: a comparative analysis of serum concentrations of protein S-100B and glial fibrillary acidic protein. Stroke 31:2670–2677

    Article  CAS  PubMed  Google Scholar 

  71. Rosengren LE, Lycke J (1995) Andersen. Glial fibrillary acidic protein in CSF of multiple sclerosis patients: relation to neurological deficit. J Neurol Sci 133:61–65

    Article  CAS  PubMed  Google Scholar 

  72. Nylén K, Karlsson JE, Blomstrand C, Tarkowski A, Trysberg E, Rosengren LE (2002) Cerebrospinal fluid neurofilament and glial fibrillary acidic protein in patients with cerebral vasculitis. J Neurosci Res 67:844–851

    Article  CAS  PubMed  Google Scholar 

  73. Petzold A, Keir G, Kay A, Kerr M, Thompson EJ (2006) Axonal damage and outcome in subarachnoid haemorrhage. J NeurolNeurosurg Psychiatry 77:753–759

    Article  CAS  Google Scholar 

  74. Vos PE, Jacobs B, Andriessen TM, Lamers KJ, Borm GF, Beems T (2010) GFAP and S100B are biomarkers of traumatic brain injury: an observational cohort study. Neurology 75:1786–1793

    Article  CAS  PubMed  Google Scholar 

  75. Brahmachari S, Fung YK, Pahan K (2006) Induction of glial fibrillary acidic protein expression in astrocytes by nitric oxide. The Journal of Neuroscience 26:4930–4939

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Vargas MR, Johnson JA (2010) Astrogliosis in amyotrophic lateral sclerosis: role and therapeutic potential of astrocytes. Neurotherapeautics 7:471–481

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors would like to acknowledge Sophisticated Analytical Instrument Facility, All India Institute of Medical science (AIIMS), New Delhi, for the technical assistance in transmission electron microscopy. The authors are also grateful to Mr. Monojit Bhattacharjee, Bharathiar University, Coimbatore, for his assistance in HPLC analysis. Vijayprakash Manickam acknowledges the UGC-BSR fellowship (UGC-BSR-No.F.7-25/2007) funded by UGC-BSR, New Delhi, India. We also thank the UGC-SAP DRS II (F-3-30/2013), DST FIST (SR/FST/LSI-618/2014) and DST-SERB (EMR/2014/000600), New Delhi, India for their partial financial assistance.

Author information

Author notes

  1. Vijayprakash Manickam and Vasanth Dhakshinamoorthy have equally contributed to this research work.

Authors and Affiliations

  1. Molecular Toxicology Laboratory, Department of Biotechnology, Bharathiar University, Coimbatore, Tamil Nadu, 641 046, India

    Vijayprakash Manickam, Vasanth Dhakshinamoorthy & Ekambaram Perumal

Authors
  1. Vijayprakash Manickam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vasanth Dhakshinamoorthy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ekambaram Perumal
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ekambaram Perumal.

Ethics declarations

Conflict of interest

The authors declare no conflict of interest.

Ethical Approval

All procedures performed in this study involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOC 3412 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Manickam, V., Dhakshinamoorthy, V. & Perumal, E. Iron Oxide Nanoparticles Affects Behaviour and Monoamine Levels in Mice. Neurochem Res 44, 1533–1548 (2019). https://doi.org/10.1007/s11064-019-02774-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-019-02774-9

Keywords

Search

Navigation