Metals, oxidative stress and neurodegeneration: A focus on iron, manganese and mercury

Abstract

Essential metals are crucial for the maintenance of cell homeostasis. Among the 23 elements that have known physiological functions in humans, 12 are metals, including iron (Fe) and manganese (Mn). Nevertheless, excessive exposure to these metals may lead to pathological conditions, including neurodegeneration. Similarly, exposure to metals that do not have known biological functions, such as mercury (Hg), also present great health concerns. This reviews focuses on the neurodegenerative mechanisms and effects of Fe, Mn and Hg. Oxidative stress (OS), particularly in mitochondria, is a common feature of Fe, Mn and Hg toxicity. However, the primary molecular targets triggering OS are distinct. Free cationic iron is a potent pro-oxidant and can initiate a set of reactions that form extremely reactive products, such as OH•. Mn can oxidize dopamine (DA), generating reactive species and also affect mitochondrial function, leading to accumulation of metabolites and culminating with OS. Cationic Hg forms have strong affinity for nucleophiles, such as –SH and –SeH. Therefore, they target critical thiol- and selenol-molecules with antioxidant properties. Finally, we address the main sources of exposure to these metals, their transport mechanisms into the brain, and therapeutic modalities to mitigate their neurotoxic effects.

Toxicity of organic and inorganic mercury species in differentiated human neurons and human astrocytes

“…Nevertheless, to date it is still not clear why neurons show this enhanced bioavailability for Hg species. Considering brain areas, Hg species seem to persist in cerebellum and cortex in vivo [ 4,38). After long-term incubation for aJI Hg species, but especially for HgC1 2 , a strong increase in the lysosomal integrity was observed.…”

Gene expression profiling of the astrocyte transcriptome in multiple sclerosis normal appearing white matter reveals a neuroprotective role

“…Dysregulation of CNS iron levels has been linked to several neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, where current iron chelating therapeutics have been designed to block the redox-activity of iron and prevent its contribution to disease progression (Farina et al, 2013). Treatments to counteract the neurotoxic effects of iron and oxidative stress, and/or to promote astrocytic expression of MT may also potentially benefit MS patients.…”

Blood-Cerebrospinal Fluid Barrier

“…31 Exposure to MeHg during early fetal development can cause neurodevelopmental injury at doses much lower than those affecting adult brain function. 32,33 Due to the early differentiation and growth of the choroid plexus compared to the subsequent vascularization in the developing brain, it has been suggested that in early development the main portal of molecular transfer from blood into the brain is via the choroid plexus and CSF rather than via the sparsely distributed View Article Online cerebral blood vessels. 34 Therefore, based on the demonstrated active efflux of MeHgCl and thiomersal out of the brain, the blood-CSF barrier might prevent the developing brain as well as the adult brain from further neurotoxic damage induced by the mercury compounds.…”