Systemic exposure to a single dose of ferucarbotran aggravates neuroinflammation in a murine model of experimental autoimmune encephalomyelitis

Medicinal preparations of iron oxide nanoparticles (IONPs) have been used as MRI contrast agents for the diagnosis of hepatic tumors and the assessment of neuroinflammation and blood-brain barrier integrity. However, it remains mostly unclear whether exposure to IONPs affects neuroinflammation under...

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Published in:	International journal of nanomedicine 2019-01, Vol.14, p.1229-1240
Main Authors:	Hsiao, Yai-Ping, Huang, Chung-Hsiung, Lin, Yu-Chin, Jan, Tong-Rong
Format:	Article
Language:	eng
Subjects:	Alzheimers disease Animals Antigens Autoimmunity Brain research Central Nervous System - pathology Cytokines Cytokines - genetics Cytokines - metabolism Dextrans - adverse effects Disease Models, Animal Drug dosages Encephalomyelitis Encephalomyelitis, Autoimmune, Experimental - pathology experimental autoimmune encephalomyelitis Female Ferric oxide ferucarbotran Glycoproteins Homeostasis Humans Immunohistochemistry Inflammation Inflammation - pathology Iron - metabolism Iron compounds iron oxide nanoparticles Laboratory animals Magnetite Nanoparticles - adverse effects Medical research Medicine, Experimental Mice, Inbred C57BL microglia Multiple sclerosis Myelin proteins Nanoparticles neuroinflammation Neurotoxicity NMR Nuclear magnetic resonance Original Research Paralysis RNA, Messenger - genetics RNA, Messenger - metabolism Rodents Severity of Illness Index Spinal cord Spinal Cord - pathology T cell T cells T-Lymphocytes - immunology Veterinary medicine
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Summary:	Medicinal preparations of iron oxide nanoparticles (IONPs) have been used as MRI contrast agents for the diagnosis of hepatic tumors and the assessment of neuroinflammation and blood-brain barrier integrity. However, it remains mostly unclear whether exposure to IONPs affects neuroinflammation under disease conditions. The present study aims to investigate the impact of IONPs on autoimmune-mediated neuroinflammation using a murine model of experimental autoimmune encephalomyelitis (EAE) that mimics human multiple sclerosis. Mice were either left untreated or immunized with myelin oligodendrocyte glyco-protein on day 0 followed by two injections of pertussis toxin for EAE induction. The EAE mice were intravenously administered with a single dose of the carboxydextran-coated IONPs, ferucarbotran (20 mg Fe/kg) and/or saline (as vehicle) on day 18. Symptoms of EAE were daily monitored until the mice were killed on day 30. Tissue sections of the brain and spinal cord were prepared for histopathological examinations. Iron deposition, neuron demyelination and inflammatory cell infiltration were examined using histochemical staining. The infiltration of microglial and T cells, and cytokine expression were examined by immunohistochemical staining and/or reverse transcription polymerase chain reaction (RT-PCR). Iron deposition was detected in both the brain and spinal cord of EAE mice 3 days post-ferucarbotran treatment. The clinical and pathological scores of EAE, percentage of myelin loss and infiltration of inflammatory cells into the spinal cord were significantly deteriorated in EAE mice treated with ferucarbotran. Furthermore, ferucarbotran treatment increased the number of CD3 , Iba-1 , IL-6 , Iba-1 TNF-α and CD3 IFN-γ cells in the spinal cord of EAE mice. A single exposure to ferucarbotran exacerbated neuroinflammation and disease severity of EAE, which might be attributed to the enhanced activation of microglia and T cells. These results demonstrated that the pro-inflammatory effect of ferucarbotran on the central nervous system is closely associated with the deterioration of autoimmunity.
ISSN:	1178-2013 1176-9114 1178-2013