Effects of Local Administration of Iron Oxide Nanoparticles in the Prefrontal Cortex, Striatum, and Hippocampus of Rats

Abstract

Iron oxide nanoparticles (IONPs) are used for diverse medical approaches, although the potential health risks, for example adverse effects on brain functions, are not fully clarified. Several in vitro studies demonstrated that the different types of brain cells are able to accumulate IONPs and reported a toxic potential for IONPs, at least for microglia. However, little information is available for the in vivo effects of direct application of IONPs into the brain over time. Therefore, we examined the cellular responses and the distribution of iron in the rat brain at different time points after local infusion of IONPs into selected brain areas. Dispersed IONPs or an equivalent amount of low molecular weight iron complex ferric ammonium citrate or vehicle were infused into the medial prefrontal cortex (mPFC), the caudate putamen (CPu), or the dorsal hippocampus (dHip). Rats were sacrificed 1 day, 1 week, or 4 weeks post-infusion and brain sections were histologically examined for treatment effects on astrocytes, microglia, and neurons. Glial scar formation was observed in the mPFC and CPu 1 week post-infusion independent of the substance and probably resulted from the infusion procedure. Compared to vehicle, IONPs did not cause any obvious additional adverse effects and no additional tissue damage, while the infusion of ferric ammonium citrate enhanced neurodegeneration in the mPFC. Results of iron staining indicate that IONPs were mainly accumulated in microglia. Our results demonstrate that local infusions of IONPs in selected brain areas do not cause any additional adverse effects or neurodegeneration compared to vehicle.

Local Administrations of Iron Oxide Nanoparticles in the Prefrontal Cortex and Caudate Putamen of Rats Do Not Compromise Working Memory and Motor Activity

“…Neurons were not damaged and most of the IONPs were probably taken up by microglial cells. These findings support our in vivo findings for the mPFC and CPu that IONPs have low toxic potential (Irrsack et al 2021 ). Nevertheless, further behavioural studies should be performed in this regard to be able to exclude potential dysfunction of the investigated areas over time.…”

“…Treatment effects on astroglial distribution and reactivity after infusion of VEH, FAC or IONPs were assessed by GFAP-immunohistochemistry. GFAP-expression demonstrates a glial scar formation at the infusion site as expected after such procedures (Irrsack et al 2021 ). The one-way ANOVA did not show a significant effect for treatment in the mPFC ( p = 0.525; F 2, 12 = 0.681; Fig.…”

“…Furthermore, functional modifications of the coating are possible, such as binding drugs to the DMSA coat for delivery to the site of action by an external magnetic field, radiolabelling of DMSA for radionuclide therapy of solid tumours or to attach fluorescent dyes to track the fate of IONPs (Petters et al 2016 ; Willmann and Dringen 2018 ; Martins et al 2021 ; Stanković et al 2023 ). Recently, we showed that intracranial applications of DMSA-coated IONPs into the medial prefrontal cortex (mPFC), caudate putamen (CPu) and dorsal hippocampus had no major adverse effects on neurons (Irrsack et al 2021 ), confirming the low toxic potential of those IONPs that has been reported for cultured neurons (Petters and Dringen 2015 ).…”

“…Microglia may play a neuroprotective role by taking up iron (Bishop et al 2011 ; Urrutia et al 2013 ; Olmedo-Díaz et al 2017 ), migrate to the region of impact and phagocytosis of apoptotic cells and cell debris to maintain neuronal functioning (Galloway et al 2019 ). We have previously reported an increased neurodegeneration 1 week after FAC-infusion into the mPFC as indicated by an increased number of Fluorojade-C positive cells, and that the infusion itself caused neuronal loss in the mPFC after 4 weeks (Irrsack et al 2021 ). Thus, we conclude that the strong microglial immune reaction after FAC-infusion protected cortical neurons from cell death and facilitated a proper working memory performance in the T-maze.…”

“…We previously showed that intracerebral administration of IONPs to the mPFC, CPu and dorsal hippocampus had no neurotoxic effects (Irrsack et al 2021 ). Nevertheless, IONPs may impair brain function without overt structural lesions, for example by affecting physiological processes, which may have an impact on behaviour (Manickam et al 2019 ).…”