br Clinical assessment of iron chelation

Clinical assessment of iron chelation
Towards the new concept of conservative iron chelation: iron scavenging and redeployment For any chelator to be of clinical value in disorders of regional siderosis they ought to be endowed with a requisite accessibility to the relevant sites and differential specificity so as to spare unaffected areas of the organism from scavenging an essential element [25]. Different agents with iron chelating features [e.g. DFO, clioquinol, VK28, M30 and natural plant-derived polyphenol flavonoids] have been assessed but not progressed to clinical trial testing for PD [153]. Deferiprone is exceptional among iron chelators in its ability to cross membranes, including the BBB, and to chelate components of the cellular labile iron pool in H-9 dihydrochloride tissue. Deferiprone has the remarkable ability to rescue transfusional hemosiderosis in the heart of β-thalassemia patients without inducing anaemia. This ability of deferiprone is largely attributable to the redeployment of captured iron to extracellular iron free Tf, and subsequent distribution (e.g. for uptake to iron-sulfur cluster and haem biosynthetic machineries) [25]. Thus, this conservative repositioning strategy to subserve iron scavenging and redeployment is under assessment using deferiprone at the relatively low oral dose of 30 mg/kg/day in AD (NCT03234686), PD (NCT02728843 and NCT02655315) and ALS (NCT03293069).
Ferroptosis: a regulated cell death that harnesses the potential of iron
Role of ferroptosis in AD AD results from loss of synapses and neuronal cell death in the brain. The chronic inflammation and degeneration that accompanies AD and the absence of downstream indicators of apoptotic death suggest that an alternate cell death mechanisms may be involved [91], [113], [173]. Elevated brain iron is associated with increased risk of AD and affected regions in the brain show elevated iron. Interestingly, levels of CSF ferritin can strongly indicate the progression of mild cognitive impairment to AD, with higher CSF ferritin predictive of earlier conversion to AD [6]. Further, quantitative susceptibility mapping (QSM) value, a measure of magnetic susceptibility of tissue determined by MRI and used as a proxy for iron level in tissue, of the hippocampus indicated that abnormal levels of elevated iron may not be required for AD progression. However, individuals with Aβ pathology that show higher iron, but within normal range, deteriorate faster than those with lower iron [7]. Furthermore, α-lipoic acid, which can stabilize cognitive function of AD patients by limiting tau hyper-phosphorylation, was recently shown to mitigate tau-induced iron overload and accompanied lipid peroxidation in P301S Tau transgenic mice [238]. These observations implicate a possible involvement of ferroptotic processes as iron appears to accelerate disease progression. Lipid peroxidation, a hallmark feature of ferroptosis, is considered an early event in the pathology of AD [168], [176]. Proteins involved in antioxidant, neuronal communication, neurite outgrowth and energy metabolism are modified thorough extensive binding to 4-hydroxy-2-nonenal (HNE) which is a proximal marker for lipid peroxidation [176]. Deuterated PUFAs (D-PUFA), which may delay ferroptosis, mitigate lipid peroxidation in brain tissue and also reduce Aβ in a mouse model of AD (APP/PS1 transgenic mice) [172], [232]. Recently, the conditional ablation of GPX4 in the forebrain (cerebral cortex and hippocampus) of mice (Gpx4BIKO) was shown to result in AD-like cognitive impairment (special learning and memory) accompanied by hippocampal neurodegeneration, elevated lipid peroxidation (enhanced HNE adducts observed in the cerebral cortex) and neuro-inflammation [91]. These phenotypes were further exacerbated in mice fed with a diet deficient in tocopherol, a lipid soluble antioxidant that serves as a natural anti-ferroptotic compound in the body [91]. Further, AD is accompanied by depletion of GSH in the frontal cortex and hippocampus which correlates with decline in cognitive function [134]. Taken together these data suggest an important role of ferroptosis in AD.