Dopaminergic cell death in the substantia nigra (SN) is central toParkinson's disease (PD), but the neurodegenerative mechanisms have not been completely elucidated. Iron accumulation in dopaminergic and glial cells in the SN of PD patients may contribute to the generation of oxidative stress, protein aggregation, and neuronal death. The mechanisms involved in iron accumulation also remain unclear. Here, we describe an increase in the expression of an isoform of the divalent metal transporter 1 (DMT1/Nramp2/ Slc11a2) in the SN of PD patients. Using the PD animal model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxication in mice, we showed that DMT1 expression increases in the ventral mesencephalon of intoxicated animals, concomitant with iron accumulation, oxidative stress, and dopaminergic cell loss. In addition, we report that a mutation in DMT1 that impairs iron transport protects rodents against parkinsonism-inducing neurotoxins MPTP and 6-hydroxydopamine. This study supports a critical role for DMT1 in iron-mediated neurodegeneration in PD.iron ͉ oxidative stress ͉ substantia nigra ͉ MPTP ͉ 6-hydroxydopamine P arkinson's disease (PD) is the most frequent neurodegenerative movement disorder worldwide. It is characterized by a preferential degeneration of dopaminergic neurons (DNs) in the substantia nigra pars compacta (SNpc) and the presence of proteinaceous cytoplasmic inclusions, called Lewy bodies, in the remaining DNs (1). Apart from rare, inherited forms of the disease, the etiology of PD remains unknown. Nevertheless, it seems clear that aging, mitochondrial dysfunction, inflammation, and oxidative imbalance are among the factors contributing to its pathophysiology.A rise in iron content localized in glial cells and DNs of the SNpc has been reported in patients with PD (2, 3). This increase of iron is thought to contribute to DN cell death by catalyzing the production of hydroxyl radicals from hydrogen peroxide, a byproduct in dopamine catabolism, and by promoting fibril formation of ␣-synuclein, the most abundant component of Lewy bodies (4). Neuroprotection achieved by pharmacological or genetic chelation of iron in animal models of PD supports the role of iron in neuronal degeneration in PD (5). Yet, the mechanisms underlying the iron increase have not been elucidated. Transferrin-bound iron (TBI) can be incorporated into cells by an endocytotic process, which is initiated by transferrin receptor 1 (TfR1) ligand binding. Following translocation to early endosomes, iron dissociates from transferrin and is transported to the cytoplasm or directly to the mitochondria. In the brain, iron uptake mediated by TfR participates in iron transport through the blood-brain barrier (6), and the density of TBI-binding sites correlates well with the regional distribution of TfR expression on the luminal surface of endothelial cells. However, TBI-binding sites and TfR expression only loosely correlate with the final steady-state distribution of iron (7). Moreover, TBI-binding sites are decreased in nu...

Iron is an essential element for life on earth, participating in a plethora of cellular processes where one-electron transfer reactions are required. Its essentiality, coupled to its scarcity in aqueous oxidative environments, has compelled living organisms to develop mechanisms that ensure an adequate iron supply, at times with disregard to long-term deleterious effects derived from iron accumulation. However, iron is an intrinsic producer of reactive oxygen species, and increased levels of iron promote neurotoxicity because of hydroxyl radical formation, which results in glutathione consumption, protein aggregation, lipid peroxidation and nucleic acid modification. Neurons from brain areas sensitive to degeneration accumulate iron with age and thus are subjected to an ever increasing oxidative stress with the accompanying cellular damage. The ability of these neurons to survive depends on the adaptive mechanisms developed to cope with the increasing oxidative load. Here, we describe the chemical and thermodynamic peculiarities of iron chemistry in living matter, review the components of iron homeostasis in neurons and elaborate on the mechanisms by which iron homeostasis is lost in Parkinson's disease, Alzheimer's disease and other diseases in which iron accumulation has been demonstrated.

The generation of new neurons in the hippocampus is a dynamic process regulated by environmental, endocrine, and pharmacological factors. Since enhancement of hippocampal neurogenesis has been associated with learning and memory, and the locus coeruleusnoradrenergic system has been shown to modulate these cognitive functions, we hypothesized that activation of noradrenergic neurotransmission might enhance neurogenesis in the adult hippocampus. To test this hypothesis in vivo, we induced the release of noradrenaline in the hippocampus by blocking presynaptic inhibitory autoreceptors with the selective alpha2-adrenoceptor antagonist dexefaroxan. Confocal microscopy showed that noradrenergic afferents make contact with proliferating and differentiating cells, suggesting a direct noradrenergic influence on neurogenesis. Chronic systemic treatment of rats with dexefaroxan did not affect cell proliferation per se in the dentate gyrus (as monitored by bromodeoxyuridine-labeling), but promoted the long-term survival of newborn neurons by reducing apoptosis. Dexefaroxan treatment also enhanced the number and complexity of the dendritic arborizations of polysialated neural cell adhesion molecule-positive neurons. The trophic effects of dexefaroxan on newborn cells might involve an increase in brain-derived neurotrophic factor, which was upregulated in afferent noradrenergic fiber projection areas and in neurons in the granule cell layer. By promoting the survival of new endogenously formed neurons, dexefaroxan treatment represents a potential therapeutic strategy for maintaining adult neurogenesis in neurodegenerative conditions, such as Alzheimer's disease, that affect the hippocampus.