Iron chelator desferrioxamine

Exposure of 9L gliosarcoma cells to hydrogen peroxide stimulated PPP, which could be attenuated when the neurons were preincubated with the iron chelator desferrioxamine. 

A study investigating the consequences of diesel exhaust particles in human airway epithelial cells also concluded that any effects of these particles occurred after their endocytosis. However, organic components rather than the metals on the surface of the particles were considered to be responsible for subsequent events. Thus, treatment with the iron chelator desferrioxamine had no inhibitory effect on the secretion of the inflammatory cytokines interleukin-8,... 

The uptake of iron from transferrin into cells has been best studied for reticulocytes, where there is heavy demand for iron for the synthesis of heme. Reticulocytes and, by analogy, other mammalian cells have receptor molecules on their plasma surface which bind transferrin. Characterization of the transferrin receptor from rabbit reticulocytes suggests that it is probably a glycoprotein of molecular weight around 200 000. The number of receptor sites in cells varies in response to the conditions. For example, treatment of K562 cells with the efficient iron chelator desferrioxamine results in an increase in the total number of receptors for transferrin.1142... 

More recently, the notion that the beneficial effects of iron-chelating agents are simply due to chelation of the metal ion has been challenged [64]. This is due to the demonstrated ability of the commonly used hydroxamate iron chelator desferrioxamine to act as a superoxide and hydroxyl-radical scavenger [65]. The relatively stable desferrioxamine nitroxide free radical (T1/2 10 min)... 

A complete hypoxanthine-xanthine oxidase system should give a final A q of about 0.65, corresponding to 150-200 nmol of hydroxyl-ated product. Formation of hydroxylated products can be inhibited almost completely by superoxide dismutase, catalase, or the iron chelator desferrioxamine (Richmond et al., 1981). 

Superoxide generated by xanthine oxidase or in the redox cycling of paraquat can cause the reductive release of F3 from ferritin, a process that is dependent on the activity of microsomal NADPH-cytochrome P-450 reductase [119]. Iron appears to be an essential component in the formation of reactive species such as superoxide and hydroxyl radical via redox cycling of cephaloridine. Addition of EDTA or of the specific iron chelator desferrioxamine to an incubation system containing renal cortex microsomes and cephaloridine depressed cephaloridine-induced peroxidation of microsomal lipids significantly EDTA showed a weaker effect than desferrioxamine at equimolar concentrations. By chelating F3 preferentially [120], desferrioxamine reduced the availability of F2 produced by the iron redox cycle and decreased cephaloridine-stimu-lated peroxidation of membrane lipids [36, 37]. 

In order to retard or prevent this accumulation of iron, a powerful iron chelator, desferrioxamine-B, is administered either by injection or by intravenous infusion. This chelator is capable of forming a very stable complex with iron and then carrying the iron out of the body with the urine or stool. Iron chelation therapy greatly improves the well-being of the patient and extends the lifetime of the patient appreciably (3). 

In ischemia, the endogenous free radical quenching capability of the neurons diminishes further adding to cell stress. Consequently, free radical scavengers such as extract of Ginkgo biloba (Szabo et al., 1991), a-lipoic acid (Block and Schwarz 1997), vitamin E (Celebi et al., 2002), thioredoxin (Shibuki et al., 2000), an ascorbic acid derivative (Kuriyama et al., 2001), mannitol (Gupta and Marmor, 1993), and the iron chelator desferrioxamine (Ophir et al., 1994) have all been shown to be neuroprotective in ischemia-reperfusion injury. 

M. B.H. (1991a) The iron chelator desferrioxamine (desferal) retards 6-hydroxydopamine-induced degeneration of nigrostriatal dopamine neurons. J. Neurochem. 56 1441-1444. 

Reciprocal regulation of the transferrin receptor and ferritin as iron concentrations change is well established [103]. Iron deficiency due to incubation of cells with the iron chelator desferrioxamine, depletes cells of ferritin and induces not only transferrin receptors [104-106] but also doubles the number of surface hemopexin... 

A comparative kinetic analysis of IRPl activation by NO and H2O2 in culture cells yielded the unexpected outcome that NO, unlike H2O2, elicits a slow activation of IRPl which, in kinetic terms rather resembles responses to iron starvation [136], Furthermore, iron starvation and NO result in a slow induction of both IRPl and IRP2, while H2O2 exclusively activates IRPl with rapid kinetics [126, 136]. IRPl induction by H2O2 is biphasic, in contrast to the effects of iron starvation and NO. While the iron chelator desferrioxamine and NO need to be continuously present for IRPl activation, the presence of H2O2 (at a minimal threshold eoncentration of 10 pm) is only required for 10-15 minutes, and then the activation of IRPl can be completed in the absence of the effector [136, 142]. 

In various studies in broken systems iron ions have been implicated as a cofac-tor,6.16,20 aithoygh the effective concentrations cannot be considered as physiological. Treatment of intact rat hepatocytes with the iron chelators, desferrioxamine or o-phenanthroline, caused a suppression of a-oxidation,but mitochondrial or peroxisomal 3-oxidation were not affected. The effect on a-oxidation could be reversed, but only partially, by the addition of Fe. It is likely that Fe ions do not readily permeate the hepatocyte membranes, explaining the incomplete restoration. This is in agreement with the almost complete restitution of a-oxidation rates by fortifying the intact cells with iron-saturated chicken ovotransferrin. Addition of Fe to permeabilized cells resulted in a virtually complete reversion of the chelator dependent inhibition. As discussed below, the dependency of a-oxidation on iron ions is due to a hydroxylation step. 

Normally, most iron is stored as ferritin but with increasing iron overload hemosiderin increases. Hemosiderin is found in the parenchymal cells of the liver and this may result in hemosiderosis and even cirrhosis. Treatment is with the iron chelator desferrioxamine and small amounts of ascorbic acid. The effect of ascorbic acid upon iron transport has been reported for dietary iron overload and P-thalassemia. As a result of ascorbic acid administration, serum iron rapidly rises and its careful use in conjunction with the iron chelator desferrioxamine increases urinary iron excretion (O Brien, 1974 Nienuis et ai, 1976 Nienhuis, 1981 Murray, 1982). 

In contrast to many studies that identify beneficial effects of dietary flavonoids against cellular Hpid oxidation, the action of flavonoids on bovine leukemia virus-transformed lamb fibroblasts (line FLK) and HL-60 cells was accompanied by lipid peroxidation [90]. Their toxicity was partly prevented by iron chelator desferrioxamine and antioxidant AA iphenyl-p-phenylene diamine, a result that pointed to the involvement of oxidative stress in their cytotoxicity. Interestingly, the toxicity of quercetin was partly prevented by nontoxic concentrations of other flavonoids examined, thus suggesting potential neutralization of quercetin cytotoxicity by intake of flavonoid mixtures. In another study, supplementation of rat hepatocyte cultures with the flavonoid myricetin led to the formation of phenoxyl radical intermediates, as detected in intact cells by electron paramagnetic resonance (EPR) spectroscopy [220]. These phenoxyl radicals corresponded to one-electron oxidation products of... 

Figure 2 Hydrogen peroxide (H2O2) and the iron chelator desferrioxamine (DSF) affect the expression of EPO and VEGF in the isolated perfused rat kidney. Rat kidneys were hypoxically (PO2 26 1 nunHg) perfused for 3 hr as described (15). EPO and VEGF mRNA levels were measured by competitive RT-PCR.

An elucidation of the mechanisms of brain iron homeostasis, as outlined in figure 1, will help our understanding of AD especially since iron binds to Ap-peptide and enhances beta-amyloid toxicity [35-38]. Excess iron accumulation is a consistent observation in the AD brain. As discussed above, patients with hemochromatosis are at risk developing AD at an earlier age [2]. Brain autopsy samples from AD patients have elevated levels of ferritin iron, particularly in the neurons of the basal ganglia [39] and most amyloid plaques contain iron and ferritin-rich cells [40]. Clinically there is a reported decrease in the rate of decline in AD patients who were treated with the intramuscular iron chelator, desferrioxamine [41]. Iron enhances cleavage of the Ap-peptide domain of APP by the metalloprotease alpha secretase [42, 43]. Part of the protective effect of the major cleavage product of APP, APP(s), may derive from its capacity to scavange metals to diminish metal-catalyzed oxidative stress to neuronal cells [44]. APP is, itself, a metalloprotein [4]. 

Figure 5, Primary screen far drugs targeted to the APP S untranslated region. In a screen of a library of 1,200 FDA-pre-approved compounds phenserine(ACHEi) and the potent intracellular iron chelator, desferrioxamine, were the validated positive control drugs that suppressed APP mRNA translation through APP 5 UTR sequences. In this transfection based screen several lead APP-5 UTR directed drugs were identified to limit luciferase gene expression driven by the APP 5 UTR. As an internal selectivity control for this screen, downstream dicistronic GFP gene expression (at the translational level by a viral internal ribosome entry site (IRES)) was unresponsive to drug action. Several leads (i,e, dimercaptopropanol) were identified to be chelators as described.

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