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

Iron oxide nanoparticles (IONPs) have come into focus for their use in medical applications although possible health risks for humans, especially in terms of brain functions, have not yet been fully clarified. The present study investigates the effects of IONPs on neurobehavioural functions in rats. For this purpose, we infused dimercaptosuccinic acid-coated IONPs into the medial prefrontal cortex (mPFC) and caudate putamen (CPu). Saline (VEH) and ferric ammonium citrate (FAC) were administered as controls. One- and 4-week post-surgery mPFC-infused animals were tested for their working memory performance in the delayed alternation T-maze task and in the open field (OF) for motor activity, and CPu-infused rats were tested for their motor activity in the OF. After completion of the experiments, the brains were examined histologically and immunohistochemically. We did not observe any behavioural or structural abnormalities in the rats after administration of IONPs in the mPFC and the CPu. In contrast, administration of FAC into the CPu resulted in decreased motor activity and increased the number of microglia in the mPFC. Perls' Prussian blue staining revealed that FAC- and IONP-treated rats had more iron-containing ramified cells than VEH-treated rats, indicating iron uptake by microglia. Our results demonstrate that local infusions of IONPs into selected brain regions have no adverse impact on locomotor behaviour and working memory.

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

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.

Maternal lipopolysaccharide treatment differentially affects 5-HT(2A) and mGlu2/3 receptor function in the adult male and female rat offspring.

Maternal infection during pregnancy increases the risk for the offspring to develop schizophrenia. However, it is still not fully understood which biochemical mechanisms are responsible for the emergence of neuropsychiatric symptoms following prenatal immune activation. The serotonin (5-hydroxytryptamine, 5-HT) and glutamate system have prominently been associated with the schizophrenia pathophysiology but also with the mechanism of antipsychotic drug actions. Here, we investigated the behavioral and cellular response to 5-HT2A and metabotropic glutamate (mGlu)2/3 receptor stimulation in male and female offspring born to lipopolysaccharide (LPS)-treated mothers. Additionally, we assessed protein expression levels of prefrontal 5-HT2A and mGlu2 receptors. Prenatally LPS-exposed male and female offspring showed locomotor hyperactivity and increased head-twitch behavior in response to the 5-HT2A receptor agonist DOI. In LPS-exposed male offspring, the mGlu2/3 receptor agonist LY379268 failed to reduce DOI-induced prepulse inhibition deficits. In LPS-males, the behavioral changes were further accompanied by enhanced DOI-induced c-Fos protein expression and an up-regulation of prefrontal 5-HT2A receptors. No changes in either 5-HT2A or mGlu2 receptor protein levels were found in female offspring. Our data support the hypothesis of an involvement of maternal infection during pregnancy contributing, at least partially, to the pathology of schizophrenia. Identifying biochemical alterations that parallel the behavioral deficits may help to improve therapeutic strategies in the treatment of this mental illness. Since most studies in rodents almost exclusively include male subjects, our data further contribute to elucidating possible gender differences in the effects of prenatal infection on 5-HT2A and mGlu2/3 receptor function.

Prenatal LPS-exposure--a neurodevelopmental rat model of schizophrenia--differentially affects cognitive functions, myelination and parvalbumin expression in male and female offspring.

Maternal infection during pregnancy increases the risk for the offspring to develop schizophrenia. Gender differences can be seen in various features of the illness and sex steroid hormones (e.g. estrogen) have strongly been implicated in the disease pathology. In the present study, we evaluated sex differences in the effects of prenatal exposure to a bacterial endotoxin (lipopolysaccharide, LPS) in rats. Pregnant dams received LPS-injections (100 µg/kg) at gestational day 15 and 16. The offspring was then tested for prepulse inhibition (PPI), locomotor activity, anxiety-like behavior and object recognition memory at various developmental time points. At postnatal day (PD) 33 and 60, prenatally LPS-exposed rats showed locomotor hyperactivity which was similar in male and female offspring. Moreover, prenatal LPS-treatment caused PPI deficits in pubertal (PD45) and adult (PD90) males while PPI impairments were found only at PD45 in prenatally LPS-treated females. Following prenatal LPS-administration, recognition memory for objects was impaired in both sexes with males being more severely affected. Additionally, we assessed prenatal infection-induced alterations of parvalbumin (Parv) expression and myelin fiber density. Male offspring born to LPS-challenged mothers showed decreased myelination in cortical and limbic brain regions as well as reduced numbers of Parv-expressing cells in the medial prefrontal cortex (mPFC), hippocampus and entorhinal cortex. In contrast, LPS-exposed female rats showed only a modest decrease in myelination and Parv immunoreactivity. Collectively, our data indicate that some of the prenatal immune activation effects are sex dependent and further strengthen the importance of taking into account gender differences in animal models of schizophrenia.

Uptake and metabolism of iron oxide nanoparticles in brain cells.

Magnetic iron oxide nanoparticles (IONPs) are used for various applications in biomedicine, for example as contrast agents in magnetic resonance imaging, for cell tracking and for anti-tumor treatment. However, IONPs are also known for their toxic effects on cells and tissues which are at least in part caused by iron-mediated radical formation and oxidative stress. The potential toxicity of IONPs is especially important concerning the use of IONPs for neurobiological applications as alterations in brain iron homeostasis are strongly connected with human neurodegenerative diseases. Since IONPs are able to enter the brain, potential adverse consequences of an exposure of brain cells to IONPs have to be considered. This article describes the pathways that allow IONPs to enter the brain and summarizes the current knowledge on the uptake, the metabolism and the toxicity of IONPs for the different types of brain cells in vitro and in vivo.