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Molecular Neurobiology

, Volume 52, Issue 2, pp 913–926 | Cite as

Iron Oxide Nanoparticles Induce Dopaminergic Damage: In vitro Pathways and In Vivo Imaging Reveals Mechanism of Neuronal Damage

  • Syed Z. ImamEmail author
  • Susan M. Lantz-McPeak
  • Elvis Cuevas
  • Hector Rosas-Hernandez
  • Serguei Liachenko
  • Yongbin Zhang
  • Sumit Sarkar
  • Jaivijay Ramu
  • Bonnie L. Robinson
  • Yvonne Jones
  • Bobby Gough
  • Merle G. Paule
  • Syed F. Ali
  • Zbigniew K. BiniendaEmail author
Article

Abstract

Various iron-oxide nanoparticles have been in use for a long time as therapeutic and imaging agents and for supplemental delivery in cases of iron-deficiency. While all of these products have a specified size range of ∼40 nm and above, efforts are underway to produce smaller particles, down to ∼1 nm. Here, we show that after a 24-h exposure of SHSY-5Y human neuroblastoma cells to 10 μg/ml of 10 and 30 nm ferric oxide nanoparticles (Fe-NPs), cellular dopamine content was depleted by 68 and 52 %, respectively. Increases in activated tyrosine kinase c-Abl, a molecular switch induced by oxidative stress, and neuronal α-synuclein expression, a protein marker associated with neuronal injury, were also observed (55 and 38 % percent increases, respectively). Inhibition of cell-proliferation, significant reductions in the number of active mitochondria, and a dose-dependent increase in reactive oxygen species (ROS) were observed in neuronal cells. Additionally, using a rat in vitro blood–brain barrier (BBB) model, a dose-dependent increase in ROS accompanied by increased fluorescein efflux demonstrated compromised BBB integrity. To assess translational implications, in vivo Fe-NP-induced neurotoxicity was determined using in vivo MRI and post-mortem neurochemical and neuropathological correlates in adult male rats after exposure to 50 mg/kg of 10 nm Fe-NPs. Significant decrease in T 2 values was observed. Dynamic observations suggested transfer and retention of Fe-NPs from brain vasculature into brain ventricles. A significant decrease in striatal dopamine and its metabolites was also observed, and neuropathological correlates provided additional evidence of significant nerve cell body and dopaminergic terminal damage as well as damage to neuronal vasculature after exposure to 10 nm Fe-NPs. These data demonstrate a neurotoxic potential of very small size iron nanoparticles and suggest that use of these ferric oxide nanoparticles may result in neurotoxicity, thereby limiting their clinical application.

Keywords

Iron-oxide nanoparticles Fe-NPs Neuroblastoma cells Neurotoxicity Dopamine Mitochondria Magnetic resonance imaging 

Notes

Disclaimer

The research reported here was funded by the NCTR/FDA protocol # E −07394.01. This document has been reviewed in accordance with US Food and Drug Administration (FDA) policy and approved for publication. Approval does not signify that the contents necessarily reflect the position or opinions of the FDA nor does mention of trade names or commercial products constitute endorsement or recommendation for use. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the FDA.

Supplementary material

12035_2015_9259_MOESM1_ESM.pdf (447 kb)
ESM 1 (A) Three optimal clusters of caspase 3/7 positive cells was determined via Euclidean squared GAP statistic using K-means from 1 to 10 [49]. Subsequent self-organizing map (SOM) in a 3 × 1 matrix (B) helped distinguish which data points fell into each cluster. Each of the four columns seen within each SOM group corresponds to the PCA data in the following columns: (a) percent of caspase positive cells, (b) mean area of all cells (c) mean area of all nuclei, and (d) mean caspase-positive stain intensity, respectively. In the SOM heat map, green indicates a positive response; with darker green signifying a less positive response Red indicates a negative response, with darker red signifying a less negative response. (PDF 447 kb)
12035_2015_9259_MOESM2_ESM.mov (8.6 mb)
ESM 2 (MOV 8828 kb)

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Copyright information

© Springer Science+Business Media New York (outside the USA) 2015

Authors and Affiliations

  • Syed Z. Imam
    • 1
    Email author
  • Susan M. Lantz-McPeak
    • 1
  • Elvis Cuevas
    • 1
  • Hector Rosas-Hernandez
    • 1
  • Serguei Liachenko
    • 1
  • Yongbin Zhang
    • 2
  • Sumit Sarkar
    • 1
  • Jaivijay Ramu
    • 1
  • Bonnie L. Robinson
    • 1
  • Yvonne Jones
    • 2
  • Bobby Gough
    • 1
  • Merle G. Paule
    • 1
  • Syed F. Ali
    • 1
  • Zbigniew K. Binienda
    • 1
    Email author
  1. 1.Division of NeurotoxicologyUS FDA/National Center for Toxicological ResearchJeffersonUSA
  2. 2.NCTR/ORA Nanotechnology Core FacilityUS FDA/National Center for Toxicological ResearchJeffersonUSA

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