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D Ben-Shachar

Publications and source records attributed to D Ben-Shachar.

At least 37 records · Page 2Linked to original sources
PubMed1993

The possible role of iron in the etiopathology of Parkinson's disease.

The identification of 6-hydroxydopamine (6-OHDA) and N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as dopaminergic neurotoxins that can induce parkinsonism in humans and animals has contributed to a better understanding of Parkinson's disease (PD). Although the involvement of similar neurotoxins has been implicated in PD, the etiology of the disease remains obscure. However, the recently described pathology of PD supports the view for a state of oxidative stress in the substantia nigra (SN), resulting as a consequence of the selective accumulation of iron in SN zona compacta and within the melanized dopamine neurons. Whether iron is directly involved cannot be ascertained. Nevertheless, the biochemical changes due to oxidative stress resulting from tissue iron overload (siderosis) are similar to those now being identified in parkinsonian SN. These include the reduction of mitochondrial electron transport, complex I and III activities, glutathione peroxidase activity, glutathione (GSH) ascorbate, calcium-binding protein, and superoxide dismutase and increase of basal lipid peroxidation and deposition of iron. The participation of iron-induced oxygen free radicals in the process of nigrostriatal dopamine neuron degeneration is strengthened by recent studies in which the neurotoxicity of 6-OHDA has been linked to the release of iron from its binding sites in ferritin. This is further supported by experiments with the prototype iron chelator, desferrioxamine (Desferal), a free-radical inhibitor, which protects against 6-OHDA-induced lesions in the rat. Indeed, intranigral iron injection in rats produces a selective lesioning of dopamine neurons, resulting in a behavioral and biochemical parkinsonism.

Animals↗
PubMed1993

Iron, melanin and dopamine interaction: relevance to Parkinson's disease.

1. Interaction between iron and melanin may provide a reasonable explanation for the vulnerability of the melanin containing dopaminergic neurons in the substantia nigra (SN) to neurodegeneration in Parkinson's disease (PD). 2. Scatchard analysis of the binding of iron to synthetic dopamine melanin revealed a high-affinity (KD = 13 nM) and a lower affinity (KD = 200 nM) binding sites. 3. The binding of iron to melanin is dependent on the concentration of melanin and on pH. 4. Iron chelators, U74500A, desferrioxamine and to a lesser extent 1,10-phenanthroline and chlorpromazine could displace iron from melanin. In contrast, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its metabolite 1-methyl-4-phenyl-pyridinium (MPP+), which cause Parkinsonism, were unable to displace iron. 5. Melanin alone reduced lipid peroxidation in rat cortical membrane preparations. However, iron induced lipid peroxidation, which could be inhibited by desferrioxamine, was potentiated by melanin. 6. Iron bound to neuromelanin in melanized dopamine neurons was detected only in parkinsonian brains and not in controls. The interaction of iron with neuromelanin as identified by x-ray defraction technique was identical to iron interaction with synthetic dopamine melanin. 7. In the absence of an identified exogenous or endogenous neurotoxin in idiopathic Parkinson's disease, iron-melanin interaction in the SN may serve as a candidate for the oxygen-radical induced neurodegeneration of the melanin containing dopaminergic neurons.

Animals↗
PubMed1993

Iron modulates neuroleptic-induced effects related to the dopaminergic system.

Long-term neuroleptic medication to schizophrenic patients is often associated with extrapyramidal side effects, of which tardive dyskinesia is the most severe. The mechanism by which neuroleptics induce these side effects is unclear. The dopaminergic system is the main target with which the neuroleptics interact in the brain. Intact dopaminergic function is dependent on normal iron metabolism. Thus, the relationship between iron and the neuroleptics may elucidate some new aspects of their mechanism of action. Indeed, peripheral iron status plays a crucial role in neuroleptic-induced dopamine supersensitivity. Moreover, neuroleptics such as haloperidol and chlorpromazine, alter the blood brain barrier (BBB) of the rat and enhance the normally restricted iron transport into the brain. Increased brain iron levels may be related to the toxic effects of these drugs since clozapine, an atypical neuroleptic with a low incidence of extrapyramidal side effects, prohibits iron uptake into the brain but causes sedimentation of iron in brain blood vessels. The demonstration that peripheral iron concentrations affect neuroleptic-induced dopamine receptor supersensitivity as well as iron transport into the brain may have therapeutic significance. In addition, the different potentials of typical and atypical neuroleptics to increase iron transport into the brain may be related to the severity of the side effects they induce and to the pathophysiology of tardive dyskinesia.

Animals↗
PubMed1992

Role of iron and iron chelation in dopaminergic-induced neurodegeneration: implication for Parkinson's disease.

Recent studies in Parkinson's disease suggest that the degeneration of the nigrostriatal melanin-containing dopaminergic neurons results from toxic effects of free radicals, which are generated during dopamine metabolism in the substantia nigra (SN). This has been linked to the selective accumulation of iron, a known catalyst of radical formation, in the zona compacta of the SN. We have shown that interaction of iron with melanin may result in a high affinity binding of iron to melanin (KD = 13.0 +/- 0.15 nM). Indeed, x-ray analysis of melanized dopamine neurons of parkinsonian SN has shown an interaction of iron with melanin that is absent in control brains. In the presence of excess Fe3+, melanin potentiates iron-induced lipid peroxidation. Since iron chelators prevent lipid peroxidation, we have ascertained the ability of the iron chelator deferoxamine to prevent the lesion of the nigrostriatal dopamine neuron induced by 6-hydroxy dopamine (6-OHDA). Our results demonstrated that intraventricular injection of 130 ng deferoxamine to rats prior to 250 micrograms of 6-OHDA partially prevented the decrease in striatal dopamine content caused by 6-OHDA (56% reduction vs 90%, respectively). This protection was sufficient to produce normal dopamine-related behavioral responses. These results suggest that iron and iron chelators play a crucial role in the process of dopaminergic neurodegeneration and neuroprotection. The latter is further supported by our recent findings that intranigral injection of iron (50 micrograms) resulted in a substantial selective decrease of striatal dopamine (95%) and impaired dopamine-related responses.

Animals↗
PubMed1992

Iron-melanin complex in substantia nigra of parkinsonian brains: an x-ray microanalysis.

Using energy-dispersive x-ray analysis on an electron microscope working in the scanning transmission electron microscopy mode equipped with a microanalysis system, we studied the subcellular distribution of trace elements in neuromelanin-containing neurons of the substantia nigra zona compacta (SNZC) of three cases of idiopathic Parkinson's disease (PD) [one with Alzheimer's disease (AD)] and of three controls, in Lewy bodies of SNZC, and in synthetic dopamine-melanin chemically charged or uncharged with Fe. Weak but significant Fe peaks similar to those of a synthetic melanin-Fe3+ complex were seen only in intraneuronal highly electron-dense neuromelanin granules of SNZC cells of PD brains, with the highest levels in a case of PD plus AD, whereas a synthetic melanin-Fe2+ complex showed much lower iron peaks, indicating that neuromelanin has higher affinity for Fe3+ than for Fe2+. No detectable Fe was seen in nonmelanized cytoplasm of SNZC neurons and in the adjacent neuropil in both PD and controls, in Lewy bodies in SNZC neurons in PD, and in synthetic dopamine-melanin uncharged with iron. These findings, demonstrating for the first time a neuromelanin-iron complex in dopaminergic SNZC neurons in PD, support the assumption that an iron-melanin interaction contributes significantly to dopaminergic neurodegeneration in PD and PD plus AD.

Aged↗
PubMed1991

Prevention of neuroleptic-induced dopamine D2 receptor supersensitivity by chronic iron salt treatment.

The ability of neuroleptics to induce dopamine D2 receptor supersensitivity has been linked to the onset of tardive dyskinesia, the major side-effect of these drugs. Brain iron metabolism has been shown to be involved in the regulation of dopamine D2 receptors. We now examined the effect of chronic treatment with FeCl2 on chlorpromazine-induced D2 receptor supersensitivity. The results show that FeCl2 (5 mg/kg per day for 21 days) given to rats treated with chlorpromazine (10 mg/kg per day, for 21 days) prevented the onset of supersensitive biochemical and behavioral (apomorphine) expressions of DA D2 receptor. Inclusion of iron did not affect the chlorpromazine-induced sedation or hypothermia. Moreover, the combined chronic iron-chlorpromazine treatment produced the same net effects as chronic chlorpromazine on striatal amounts of dopamine, DOPAC (dihydroxyphenylacetic acid) and HVA (homovanillic acid). Chlorpromazine medication caused a decrease in liver non-haem iron levels (40%) but not in brain iron. The effect of the neuroleptic drug on iron stores and the involvement of iron in the neuroleptic-induced dopamine supersensitivity suggest that mobilization of iron from the periphery into the brain may play an important role in the mechanism of action of the neuroleptics.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Iron-melanin interaction and lipid peroxidation: implications for Parkinson's disease.

The vulnerability of substantia nigral (SN) melaninized dopamine neurons to neurodegeneration in Parkinson's disease and the selective increases of iron and basal lipid peroxidation in SN indicate that iron-melanin interaction could be crucial to the pathogenesis of this disease. The present study describes, for the first time, the identification and characterization of a high-affinity (KD = 13 nM) and a lower affinity (KD = 200 nM) binding site for iron on dopamine melanin. The binding of iron to melanin is dependent on pH and the concentration of melanin. Iron chelators, U74500A, desferrioxamine, and to less extent 1,10-phenanthroline and chlorpromazine, but not the Parkinson-inducing neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, can inhibit the binding of iron to melanin and iron-induced lipid peroxidation. Although melanin alone diminishes basal lipid peroxidation in rat cortical homogenates, it can also potentiate that initiated by iron, a reaction inhibited by desferrioxamine. In the absence of an identifiable exogenous or endogenous neurotoxin in idiopathic Parkinson's disease, iron-melanin interaction in pars compacta of SN may be a strong candidate for the cytotoxic component of oxygen radical-induced neurodegeneration of melaninized dopamine neurons.

Animals↗
PubMed1991

Intranigral iron injection induces behavioral and biochemical "parkinsonism" in rats.

Elevated iron concentrations in the substantia nigra (SN) pars compacta have been implicated in the development of idiopathic Parkinson's disease. Because, as a transitional metal, iron promotes free radical formation, the role of iron in the degeneration of the nigrostriatal dopamine neurons in Parkinson's disease has received much attention. This study further investigates the cytotoxic effects of iron in the SN. Various concentrations of FeCl3 (1, 5, and 50 micrograms of Fe3+ in 5 microliters) were unilaterally injected into the SN of adult rats. The two lower doses of iron had no effect on striatal dopamine levels or on the behavioral responses of the rats. However, injection of 50 micrograms of Fe3+ resulted in a substantial selective decrease of striatal dopamine (95%), 3,4-dihydroxyphenylacetic acid (82%), and homovanillic acid (45%), without any change in norepinephrine concentration. Dopamine-related behavioral responses, such as spontaneous movements in a novel space and rearing, were significantly impaired, whereas amphetamine administration induced ipsilateral rotation in the iron-treated rats. The present study indicates that the nigrostriatal dopamine neurons are susceptible to the presence of ionic iron and thus supports the assumption that iron initiates dopaminergic neurodegeneration in Parkinson's disease.

Animals↗
PubMed1991

The iron chelator desferrioxamine (Desferal) retards 6-hydroxydopamine-induced degeneration of nigrostriatal dopamine neurons.

A selective increase in content of iron in the pars compacta of the substantia nigra has been implicated in the biochemical pathology of Parkinson's disease. Iron is thought to induce oxidative stress by liberation of oxygen free radicals from H2O2. Because 6-hydroxydopamine (6-OHDA) is thought to induce nigrostriatal dopaminergic neuronal lesions via metal-catalyzed free radical formation, the effect of the iron chelator desferrioxamine was investigated on 6-OHDA-induced dopaminergic neuron degeneration in the rat. Intracerebroventricular injection of 6-OHDA (250 micrograms) caused a 88, 79, and 70% reduction in striatal tissue content of dopamine (DA), 3,4-dihydroxyphenylacetic acid, and homovanillic acid (HVA), respectively, and a 2.5-fold increase in DA release as indicated by the HVA/DA ratio. Prior injection of desferrioxamine (130 ng i.c.v.) resulted in a significant protection (approximately 60%) against the 6-OHDA-induced reduction in striatal DA content and a normalization of DA release. Dopaminergic-related behavioral responses, such as spontaneous movements in a novel environment and rearing, were significantly impaired in the 6-OHDA-treated group. By contrast, the desferrioxamine-pretreated rats exhibited almost normal behavioral responses. The ability of iron chelators to retard dopaminergic neurodegeneration in the substantia nigra may indicate a new therapeutic strategy in the treatment of Parkinson's disease.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1991

Iron in brain function and dysfunction with emphasis on Parkinson's disease.

Metals such as lead, zinc, copper, aluminum and manganese have been implicated in neuropsychiatric disorders. However, until fairly recently the role of iron in brain function was rather obscure, because little attention was paid to its metabolism in the brain. It is now apparent that maintenance of brain iron homoeostasis is important for the normal functioning of his organ. Most of the studies have been directed towards the cognitive and attentional deficit resulting from nutritional iron deficiency. Evidence so far suggests subsensitivity of striatal dopamine neurotransmission. By contrast the selective increase in free iron in the substantia nigra pars compacta of parkinsonian brains is thought to initiate oxidative stress, from iron-induced liberation of cytotoxic oxygen free radicals. Such radicals are known to promote membrane fluidity, alteration in cellular calcium homoeostasis, lipid peroxidation and finally cell death in systemic organs. Evidence supporting similar processes being responsible for nigrostriatal dopamine neuron degeneration in Parkinson's disease is now becoming available. Such possibilities afford the development of neuroprotective drugs as a means to retard the progression of this disorder. These include other selective monoamine oxidase B inhibitors, iron chelators with the ability to cross the blood-brain barrier, selective calcium channel antagonists and mitochondrial electron transport system protectors.

Anemia, Hypochromic↗
PubMed1990

Selectivity of melaninized nigra-striatal dopamine neurons to degeneration in Parkinson's disease may depend on iron-melanin interaction.

The recent studies on the chemical pathology of Parkinson's disease show selective increases of iron and lipid peroxidation and decreased glutathione (GSH) oxidizing capacity in the substantia nigra (SN). These changes are indicative of oxidative stress, possibly due to the accumulation of iron in the SN. It is the melaninized dopamine neurons that are vunerable to degeneration. The investigation of the interaction of iron with dopamine melanin demonstrates the presence of two relatively high affinity binding sites for 59Fe3+ on dopamine melanin. Interaction of Fe3+ with dopamine melanin results in potentiation of lipid peroxidation of rat cerebral cortex as compared to that induced by Fe3+. Only compounds with the ability to chelate iron are able to inhibit the binding of Fe3+ to melanin and the resultant lipid peroxidation. Therapeutic use of iron chelators, with the ability of crossing the blood brain barrier, as agents for retarding the oxidative stress and Parkinson's disease is envisaged.

Dopamine↗
PubMed1990

The role of monoamine oxidase, iron-melanin interaction, and intracellular calcium in Parkinson's disease.

Recent evidence suggests that iron accumulates in substantia nigra pars compacta of patients with Parkinson's disease (PD). This finding is compatible with changes in the respiratory chain activity, increase of malondialdehyde concentration (a measure of lipid peroxidation), decrease of enzyme activity of enzymes involved in detoxication of hydrogen peroxide and oxygen radical species, increased MAO-B-activity in this brain area etc. All these data suggest that oxidative stress may play a certain role in the pathobiochemistry of PD. In addition to the description of the neuroprotective mechanism of the MAO-B-inhibitor L-deprenyl a new aspect focuses the role of the endogenous MAO-B substrates "polyamines" which occur both in neurons and glia. A further aspect of this review deals with the role of calcium as cellular toxin. Although of major importance it is not decided yet whether these biochemical changes are primary or secondary importance to the pathogenesis of PD.

Animals↗
PubMed1990

Neuroleptic-induced supersensitivity and brain iron: I. Iron deficiency and neuroleptic-induced dopamine D2 receptor supersensitivity.

Previous studies have shown that nutritional iron deficiency in rats reduces brain iron content, resulting in dopamine D2 receptor subsensitivity, as indicated by a decrease in [3H]spiperone binding in caudate nucleus and in behavioral responses to apomorphine. Both phenomena can be reversed by iron supplementation. The possibility that neuroleptic-induced dopamine D2 receptor supersensitivity involves an alteration in brain iron content was investigated in nutritionally iron-deficient and control rats chronically treated with haloperidol (5 mg/kg daily for 14 or 21 days). Neuroleptic treatment was initiated either (a) concurrently with iron deficiency or (b) 2 weeks after the start of iron deficiency. The results show that dopamine D2 receptor subsensitivity, a feature of iron deficiency, is absent in haloperidol-treated, iron-deficient groups. On the contrary, these animals demonstrated biochemical and behavioral dopamine D2 receptor supersensitivity that is relatively greater than that observed with control, haloperidol-treated animals. Haloperidol (5 mg/kg daily for 21 days) as well as chlorpromazine (10 mg/kg daily for 21 days) caused a significant reduction (20-25%) in liver nonheme iron stores as compared with values in control rats. However, in iron-deficient rats, in which liver iron stores were almost totally depleted, haloperidol had no effect. The ability of chronic haloperidol treatment to prevent the reduction of dopamine D2 receptor number during iron deficiency may be associated with alteration of body iron status. Thus, less iron may result in an increase in free haloperidol available to the dopamine D2 receptor.

Animals↗
PubMed1989

Putative biological mechanisms of the effect of iron deficiency on brain biochemistry and behavior.

An animal model of nutritional iron deficiency (ID) is described that demonstrates a reduction of brain nonheme iron. The most prominent feature of ID is the significant and selective diminution of central dopamine neurotransmission resulting from the decreased number of dopamine D2 receptors in the caudate nucleus, nucleus accumbens, pituitary, and in all probability the frontal cortex. The consequences of diminished dopaminergic neurotransmission is a modification of dopamine-dependent behaviors and biochemical reactions, the most important of which is the reduction in learning processes. The role of iron in maintaining the homeostasis of normally functioning dopamine neurons and their involvement in cognitive processes cannot be excluded. An interference with iron metabolism at an early age can result in irreversible damage to developing dopamine neurons, with consequences that may manifest themselves in adult life.

Animals↗