Iron-induced oxidative stress and anxiety-like behavior in Wistar rats following systemic iron administration

Iron is a trace element essential to many physiological functions in the human body and notably in the brain where it participates to important metabolic processes. Iron content in the brain is strictly regulated and disruption of the regulatory mechanisms can result in iron deficiency or iron excess. Iron accumulation has beenhypothesized to be involved in the pathogenesis of various neurodegenerative diseases. In rat model, iron excess in the brain is produced using repeated systemic iron administration and affects regions involved in spatial cognitive/memory functions.Cognitivedeficitsare thought to result from iron-induced oxidative stress.It has been suggested that disruption of iron homeostasis modulates anxiety-like behavior in humans and animals but the underlying mechanisms remain unclear. We thus examined the effect of a 15-day 30 mg/kg iron daily administration on anxiety-like behavior using four novelty-based behavioral models of anxiety, i;e. light/dark room test, unfamiliar environment test, elevated plus-maze, and open-field test.We measured iron accumulation and several biomarkers of oxidative stress(antioxidant enzymes:catalaseCAT, superoxide dismutase SOD, anda product of lipid peroxidation: malondialdehyde MDA) in 4 regions of interest (ROI)including the hippocampus, prefrontal cortex, striatum and cerebellum.Compared to controls, iron-treated rats exhibited higher anxiety-like behavior and hadincreasediron content and altered biomarkers of oxidative stress (higher MDA and lower CAT and SOD)in ROI, in particular in the medial prefrontal cortex and hippocampus which are known to be involved in cognitive functions and are part of the anxiety/fear circuit.These results contribute to establish the link between iron accumulation, oxidative stress, and anxiety-like behavior which is acommon comorbidityof neurodegenerative disorders.