Brain iron in the ferrocene-loaded rat: Its chelation and influence on dopamine metabolism

Ward, Roberta J.; Dexter, David T.; Florence, Anne; Aouad, Fouad; Hider, Robert C.; Jenner, Peter; Crichton, Robert R.

doi:10.1016/0006-2952(94)00521-m

Cited by 63 publications

(49 citation statements)

References 15 publications

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“…However, several investigators have demonstrated that DFO can enter the brain (Ikeda et al, 1989;Keberle, 1964). Intraperitoneally injection of DFO to ferrocene-loaded rats significantly reduced the brain iron content after only 2 weeks of administration, it has clearly shown that DFO are able to cross the BBB (Ward et al, 1995). DFO produced a significant reduction in iron uptake by the brain in the 15-day old rats (Crowe and Morgan, 1994).…”

Section: Discussionmentioning

confidence: 97%

“…Carbonyl iron diet can also cause changes in several other organs. Administration of ferrocene can also result in an increase of iron contents in heart, liver, spleen and pancreas (Ward et al, 1995). An additive increase in hepatocellularinjury, promotion liver fibrogenesis and cirrhosis was reported when ethanol is administrated to iron-loaded rats (Tector et al, 1995;Tsukamoto et al, 471 1995).…”

Section: Introductionmentioning

confidence: 91%

“…Treatment with ferrocene to rats for 4 weeks showed up to 50% increase in iron content in various brain regions including, SN, cerebellum and cerebral cortex (Ward et al, 1995). A new animal model of cerebral infraction was developed by magnetic embolization with carbonyl iron particles (Akai et al, 1995).…”

Section: Introductionmentioning

confidence: 98%

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Desferrioxamine and vitamin E protect against iron and MPTP-induced neurodegeneration in mice

Lan

Jiang

1997

J. Neural Transmission

151

112

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Summary.To elucidate the neuroprotective effects of the iron chelator desferrioxamine (DFO) and the antioxidant vitamin E on excessive ironinduced free radical damage, a chronic iron-loaded mice model was established. The relationship between striatal iron content, oxidized to reduced glutathione ratio, hydroxyl radical ('OH) levels and dopamine concentrations were observed in DFO or vitamin E pretreated iron-loaded/1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP)-treated C57BL/6 mice. The results demonstrated that both DFO and vitamin E inhibit the iron accumulation and thus reverses the increase in oxidized glutathione (GSSG), oxidized to reduced glutathione ratios, "OH and lipid peroxidation levels. The striatal dopamine concentration was elevated to normal value. Our data suggested that: (1) iron may induce neuronal damage and thus excessive iron in the brain may contribute to the neuronal loss in PD; (2) iron chelators and antioxidants may serve as potential therapeutic agents in retarding the progression of neurodegeneration.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 91%

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Desferrioxamine and vitamin E protect against iron and MPTP-induced neurodegeneration in mice

Lan

Jiang

1997

J. Neural Transmission

151

112

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“…If not properly buffered, hydroxyl radicals can stimulate protein oxidation and lipid peroxidation, which is thought to contribute to macromolecular injury and neuronal death. Iron is the most abundant metal in the brain and some degree of accessible reactive iron is necessary for brain viability as it serves as a cofactor in DNA, RNA, and protein synthesis and for heme and non-heme enzymes involved in both mitochondrial respiration and neurotransmitter synthesis (4). Although iron deficiencies early in life are known to result in impairments in brain development (5), high concentrations of iron may result in cellular toxicity (6) in part due to its ability to catalyze the production of toxic oxygen radicals.…”

Section: Parkinson Disease (Pd)mentioning

confidence: 99%

Inhibition of Prolyl Hydroxylase Protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Neurotoxicity

Lee

Rajagopalan

Siddiq

et al. 2009

Journal of Biological Chemistry

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Hypoxia-inducible factor (HIF) plays an important role in cell survival by regulating iron, antioxidant defense, and mitochondrial function. Pharmacological inhibitors of the iron-dependent enzyme class prolyl hydroxylases (PHD), which target ␣ subunits of HIF proteins for degradation, have recently been demonstrated to alleviate neurodegeneration associated with stroke and hypoxic-ischemic injuries. Here we report that inhibition of PHD by 3,4-dihydroxybenzoate (DHB) protects against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigral dopaminergic cell loss and up-regulates HIF-1␣ within these neurons. Elevations in mRNA and protein levels of HIF-dependent genes heme oxygenase-1 (Ho-1) and manganese superoxide dismutase (Mnsod) following DHB pretreatment alone are also maintained in the presence of MPTP. MPTP-induced reductions in ferroportin and elevations in nigral and striatal iron levels were reverted to levels comparable with that of untreated controls with DHB pretreatment. Reductions in pyruvate dehydrogenase mRNA and activity resulting from MPTP were also found to be attenuated by DHB. In vitro, the HIF pathway was activated in N27 cells grown at 3% oxygen treated with either PHD inhibitors or an iron chelator. Concordant with our in vivo data, the MPP ؉ -elicited increase in total iron as well as decreases in cell viability were attenuated in the presence of DHB. Taken together, these data suggest that protection against MPTP neurotoxicity may be mediated by alterations in iron homeostasis and defense against oxidative stress and mitochondrial dysfunction brought about by cellular HIF-1␣ induction. This study provides novel data extending the possible therapeutic utility of HIF induction to a Parkinson disease model of neurodegeneration, which may prove beneficial not only in this disorder itself but also in other diseases associated with metal-induced oxidative stress.Parkinson disease (PD) 2 is a neurodegenerative disorder primarily associated with loss of dopaminergic (DAergic) neurons of the pars compacta region of the substantia nigra (SNpc). Dopaminergic neurons are particularly prone to oxidative damage due to high levels of inherent reactive oxygen species that are produced during dopamine synthesis or its breakdown by monoamine oxidases or autoxidation to quinones (1-3). Importantly, iron bound to neuromelanin within DAergic neurons can subsequently react with metabolically liberated hydrogen peroxide through the Fenton reaction to produce extremely toxic hydroxyl radicals. If not properly buffered, hydroxyl radicals can stimulate protein oxidation and lipid peroxidation, which is thought to contribute to macromolecular injury and neuronal death. Iron is the most abundant metal in the brain and some degree of accessible reactive iron is necessary for brain viability as it serves as a cofactor in DNA, RNA, and protein synthesis and for heme and non-heme enzymes involved in both mitochondrial respiration and neurotransmitter synthesis (4). Although iron deficiencies early in life ...

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“…Azoles including imidazole, pyrazole and adenine, which are the central ingredients in many drugs, have been chosen as the objects for chemical modification by ferrocene. Ferrocene compounds, additionally to antitumor and antianemic [18,19] properties, also demonstrate membrane permeability, [20] and low toxicity. [2 -4,8,21,22] Ferrocene-modified heterocycles and also ferricenium salts were synthesized for biological tests.…”

Section: Introductionmentioning

confidence: 99%

Ferrocenylalkyl azoles: bioactivity, synthesis, structure

Snegur¹,

Nekrasov²,

Сергеева³

et al. 2008

Applied Organom Chemis

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aThe toxicity of ferrocenylethyl benzotriazole (1) and other ferrocene compounds including ferrocenylmethyl benzimidazoles (4,5,6,11), ferricenium salts (3,9,10) and ferrocenylmethyl adenine (7), was studied. All ferrocene complexes under investigation showed low or medium toxicities. On the basis of an earlier model of chemical carcinogenesis, the antitumor activity of ferrocenylalkyl azoles 1, 8 and ferricenium salts 9, 10 was studied in vivo in the so-called sub-capsular test on human tumors. This effectiveness was compared with that of cisplatin. A series of ferrocenylalkyl azoles were synthesized by interacting azoles either with α-hydroxyalkyl ferrocenes FcC(OH)R 1 R 2 in organic solvent in the presence of aqueous HBF 4 in quantitative yields or with trimethyl(aminomethyl)ferrocene iodide in an aqueous-basic medium in good yields. The X-ray determinations of molecular and crystal structures of α-(1-benzotriazolyl)ethylferrocene (1) and α-(1-naphthatriazolyl)ethylferrocene (12) were performed.

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Brain iron in the ferrocene-loaded rat: Its chelation and influence on dopamine metabolism

Cited by 63 publications

References 15 publications

Desferrioxamine and vitamin E protect against iron and MPTP-induced neurodegeneration in mice

Desferrioxamine and vitamin E protect against iron and MPTP-induced neurodegeneration in mice

Inhibition of Prolyl Hydroxylase Protects against 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Neurotoxicity

Ferrocenylalkyl azoles: bioactivity, synthesis, structure

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