Research Paper Volume 11, Issue 21 pp 9846—9861

Iron overload resulting from the chronic oral administration of ferric citrate induces parkinsonism phenotypes in middle-aged mice

Chao Huang 1, 2, *, , Wenjing Ma 1, 2, 5, *, , Qihui Luo 1, 2, *, , Liangqin Shi 1, 2, , Yu Xia 1, 2, , Chengjie Lao 1, 2, , Wentao Liu 1, 2, , Yuanfeng Zou 2, 3, , Anchun Cheng 2, , Riyi Shi 4, , Zhengli Chen 1, 2, ,

  • 1 Laboratory of Experimental Animal Disease Model, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, P.R. China
  • 2 Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, P.R. China
  • 3 Natural Medicine Research Center, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu 611130, P.R. China
  • 4 Department of Basic Medical Sciences, College of Veterinary Medicine, Purdue University, West Lafayette, IN 47906, USA
  • 5 Sichuan Institute for Food and Drug Control, Chengdu 611130, P.R. China
* Equal contribution

received: August 15, 2019 ; accepted: October 29, 2019 ; published: November 7, 2019 ;

https://doi.org/10.18632/aging.102433
How to Cite

Copyright © 2019 Huang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Iron homeostasis is critical for maintaining normal brain physiological functions, and its mis-regulation can cause neurotoxicity and play a part in the development of many neurodegenerative disorders. The high incidence of iron deficiency makes iron supplementation a trend, and ferric citrate is a commonly used iron supplement. In this study, we found that the chronic oral administration of ferric citrate (2.5 mg/day and 10 mg/day) for 16 weeks selectively induced iron accumulation in the corpus striatum (CPu), substantia nigra (SN) and hippocampus, which typically caused parkinsonism phenotypes in middle-aged mice. Histopathological analysis showed that apoptosis- and oxidative stress-mediated neurodegeneration and dopaminergic neuronal loss occurred in the brain, and behavioral tests showed that defects in the locomotor and cognitive functions of these mice developed. Our research provides a new perspective for ferric citrate as a food additive or in clinical applications and suggests a new potential approach to develop animal models for Parkinson’s disease (PD).

Abbreviations

NDs: neurodegenerative diseases; BBB: blood-brain barrier; Tf/TfR/DMT1: transferrin/transferrin receptor/divalent metal transporter 1; Fpn1: ferroportin-1; SN: substantia nigra; CPu: caudate putamen; DA: dopamine; DOPAC: 3,4-dihydroxyphenylacetic acid; 8-OHdG: 8-hydroxy-2-deoxyguanosine; PC: protein carbonylation; SOD: superoxide dismutase; GSH: glutathione; MDA: malondialdehyde; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; 6-OHDA: 6-hydroxydopamine.