Iron, neuro-bioavailability and depression

Abstract

Medical management of iron deficiency (ID) requires to consider its consequences in biochemical and physiological plural functions, beyond heme/hemoglobin disrupted synthesis. Fatigue, muscle weakness, reduced exercise capacity, changes in thymia and modified emotional behaviors are the commonest symptoms integrated in the history of ID, dependent or not of the hemoglobin concentration. The relationship between depression and absolute ID (AID) is a condition which is often unrecognized. Neuro-bioavailability and brain capture of blood iron are necessary for an appropriate synthesis of neurotransmitters (serotonin, dopamine, noradrenaline). These neurotransmitters, involved in emotional behaviors, depend on neuron aromatic hydoxylases functioning with iron as essential cofactor. Noradrenaline also has impact on neuroplasticity via brain-derived neurotrophic factor (BDNF), which is key for prefrontal and hippocampus neurons playing a role in depression. Establishing the formal relationship between depression and AID remains difficult. Intracerebral reduced iron is still hard to quantify by neuroimaging and single-photon emission computed tomography (SPECT) now tends to explore the neurotransmission pathways. AID has to be looked for and identified in the context of depression, major episode or resistant to conventional treatment such as serotonin reuptake inhibitor, and even in the absence of anemia, microcytosis or hypochromia (non-anemic ID). Confronted to brain imaging, blood iron status evaluation is indicated, especially in depressed, treatment-resistant, iron-deficient young women. In patients suffering from depression, increase in the prevalence of AID should be considered, in order to deliver a suitable treatment, considering both anti-depressive program and iron supplementation if AID.

Keywords: deficiency; depression; iron; neuro‐availability.

FIGURE 1

Schematic representation of the body distribution of the type 1 transferrin receptor (TfR1). In the central nervous system (CNS), endothelial cells of the blood–brain barrier (BBB) expressed a great density of the TfR1, just after erythroid precursors did and above other parts of the body. Oligodendrocytes and choroid plexuses‐dependent local transferrin added, in brain, iron transport provided by plasma transferrin synthetized by hepatocytes. Choroid plexuses secrete transferrin in cerebrospinal fluid (CSF). Brain transferrin can capture Fe³⁺ in interstitial fluid, thanks to ceruloplasmin ferrous iron oxidation

FIGURE 2

Intracerebral metabolism of iron and its neuro‐bioavailability. Brain endothelial cells propose two pathways for brain iron distribution from blood: a facilitated transporter pathway and a transcytosis pathway. The facilitated transporting pathway is linked to the ability of endothelial cells to reduce Fe³⁺ to Fe²⁺ within the vacuole, via acidification and STEAP3 protein. Ferrous iron Fe²⁺ uses transmembrane transporters to reach the brain interstitial fluid: DMT1, to get out the vacuole and export Fe²⁺ to the cytosol; ferroportin leading to appropriate Fe²⁺ increased in the brain interstitium, so as to make iron available to the astrocyte or to be re‐oxydated to Fe³⁺ due to the ceruloplasmin activity. The transcytosis pathway implicates endocytosis and exocytosis of the complex transferrin receptor (TfR1)‐Fe³⁺‐bound transferrin, from the luminal pole to the cerebral extracellular matrix (ECM) and interstitial fluid

FIGURE 3

Iron implication in neurotransmitter production and function. Serotonin plays an important role in changes in emotional state. It is particularly involved in the management of moods, is associated with the state of happiness and leading the individual to maintain an emotional situation that is favorable to him. Dopamine is the main neurotransmitter of the motivational component of reward and reinforcement. Synthesis of serotonin and dopamine is dependent on brain hydroxylases which use iron and tetrahydrobiopterin (BH4) as cofactors. Their synthesis is hampered and deficient in case of iron deficiency