Search PubMed⌕ Search

Biomedical subjects

D Ben-Shachar

Publications and source records attributed to D Ben-Shachar.

52 records · Page 3Linked to original sources
PubMed1989

Is Parkinson's disease a progressive siderosis of substantia nigra resulting in iron and melanin induced neurodegeneration?

Razor sharp and high iron deposits are present in the substantia nigra (SN). Although the function of such high iron content is not known, the homeostasis of brain iron is important for normal brain function. The participation of free tissue iron in oxidative stress (OS), resulting in the formation of cytotoxic hydroxyl radical (.OH) from H2O2 (Fenton reaction) and promotion of membrane lipid peroxides by .OH can no longer be questioned as a biological phenomenon. The highly selective increase of Fe2+ and Fe3+ and lipid peroxidation observed in parkinsonian SN points to OS in such brains. Lipid peroxidation proceeds with either Fe2+ or Fe3+ provided a mechanism exists to facilitate the interconversion of iron between its redox states. Indeed H2O2 derived from MAO B reaction and autooxidation of dopamine to melanin in the SN can drive the iron dependent Fenton reaction. Furthermore, interaction of iron with melanin may be even more important considering that melanin avidly binds Fe3+ and reduce it to Fe2+, resulting in .OH generation. Thus, without evoking environmental neurotoxins, the excessive accumulation of free iron in the SN and "melanin-trap" could be the trigger for accelerated cell death and Parkinsonism.

Humans↗
PubMed1988

Enhancing effects of fluoride-containing ceramic implants on bone formation in the dog femur.

This study examined the enhancing effects of newly constructed ceramic implants, consisting of unidirectional macroporous (200 micron in diameter) material, upon in vivo bone formation in dogs' femurs. The implants comprised calcium phosphate salts that included 0.5% fluoride. The latter were introduced into bone defects in healthy dogs and were followed thereafter for a period of 8 months. Radiological and histological examinations indicated new bone formation at the implantation sites concurrent with the disappearance of the original implanted material. The rate of in situ degradation of these implants correlated to the overall size of the inserted implant. It became evident that this new kind of ceramic (that included fluoride in its basic composition) possessed a remarkable stimulating potential upon bone morphogenesis.

Animals↗
PubMed1988

Selective alteration in blood-brain barrier and insulin transport in iron-deficient rats.

Nutritional iron deficiency induced in rats causes a significant reduction in level of brain nonheme iron and is accompanied by selective reduction of dopamine D2 receptor Bmax. Our previous studies have clearly demonstrated that these alterations can be restored to normal by supplementation with ferrous sulfate; however, neither brain nonheme iron level nor dopamine D2 receptor Bmax can be increased beyond control values even after long-term iron therapy. The possibility that iron deficiency can induce the breakdown of the blood-brain barrier (BBB) was examined. A 70 and 100% increase in brain uptake index (BUI) for L-glucose and insulin, respectively, were noted in iron-deficient rats. However, the BUI for valine was decreased by 40%, and those for L-norepinephrine and glycine were unchanged. In addition, it was demonstrated that in normal rats insulin is transported into the brain. The data show that iron deficiency selectively affects the integrity of the BBB for insulin, glucose, and valine transport. Whether the effect of iron deficiency on the BBB is at the level of the capillary endothelial cell tight junction is not yet known. However, this study has shown that an important nutritional disorder (iron-deficiency anemia) has a profound effect on the BBB and brain function.

Anemia, Hypochromic↗
PubMed1988

Picrotoxin, a gamma-aminobutyric acid-receptor antagonist, retards craniofacial development in the weaning rat: I. Effect on mandibular bone growth.

The in vivo effects of elevated doses of picrotoxin, a gamma-aminobutyric acid (GABA) A-receptor antagonist, were studied in the skulls of weaning rats. Twenty-one-day-old male rats were treated daily with 2 mg/kg of pictroxin for a period of 3 weeks. This study revealed that chronic administration of the agent caused a reduction in bone formation in various growth sites in the skull along with a significant decrease in the calcium content and alkaline phosphatase activity in the mandible. Serum levels of calcium were unchanged, but the activity of alkaline phosphatase decreased. The decrease in bone alkaline phosphatase was accompanied by structural changes in the developing mandible. The latter was manifested by qualitative changes in the structure of ossification sites, in the appearance of the osteoblasts, and in the pattern of bone mineralization. These findings indicate that picrotoxin affects the normal growth of the craniofacial skeleton in an intact growing animal, probably because of central changes in GABA-ergic control on motor function along with possible alteration in corticosteroid secretion.

Alkaline Phosphatase↗
PubMed1988

Picrotoxin, a gamma-aminobutyric acid-receptor antagonist, retards craniofacial development in the weaning rat: II. Effect on mandibular condylar cartilage.

The in vivo effects of picrotoxin, a gamma-aminobutyric acid (GABA)-receptor antagonist, were studied in the mandibular condyles of weaning rats. Male rats 21 days old were treated daily with 2 mg/kg of picrotoxin for a period of 3 weeks. This study revealed that chronic administration of the agent caused a reduction in bone formation in various sites in the mandible, along with significant changes in the structure of the condylar cartilage and its ossification front. The length of the chondroblastic zone increased, yet the length of the hypertrophic zone was reduced. The latter phenomenon was manifested by qualitative changes in the overall structure of various cellular zones, in the appearance of the osteoblasts, and in the pattern of cartilage mineralization. The changes in the condylar cartilage cannot be attributed to a direct effect of picrotoxin; in vitro studies indicated no significant change in the incorporation of 3H-thymidine and 35S-sulfate in picrotoxin-treated cultures. These findings indicate that picrotoxin affects the normal growth of the mandible in an intact, growing animal, probably through an indirect route involving neurons in the central nervous system.

Animals↗
PubMed1986

Characterization of the hepatic prolactin receptors induced by chronic iron deficiency and neuroleptics.

Nutritional iron deficiency (ID), like neuroleptic treatment, results in a reduction in dopaminergic activity and a rise in serum prolactin (PRL). Since PRL has been shown to regulate its own receptors, we studied PRL binding sites during the above treatments. ID induced in 21 day old male rats for 28 days, or treatment with either chlorpromazine (10 mg/kg per day i.p.) or fluphenazine (5 mg/kg per day i.p.) for 21 days or haloperidol (5 mg/kg per day i.p.) for 9 days, caused significant increases (3- to 8-fold) in [125I]oPRL specific binding to the liver membranes. The combined treatment with haloperidol and ID, as above, resulted in an additive effect on hepatic PRL receptors, suggesting that the actions of neuroleptics and ID may be either submaximal or mediated by two different mechanisms. After 7 days or recovery from ID, the induced PRL receptors were completely reduced to the control values. In vitro desaturation of the induced PRL binding sites with MgCl2 caused a further increase (1.57-fold) in PRL binding. Characterization of the hepatic PRL binding sites induced by ID showed properties similar to those reported for the classical PRL receptors, including specificity for the lactogenic hormones, a high affinity constant (2.38 X 10(10) M-1) and inhibition of PRL binding to the induced receptors by an anti-PRL receptor antibody. The results of this study further support the suggested role of endogenous PRL in inducing its own receptors.

Animals↗
PubMed1986

Long-term consequence of early iron-deficiency on dopaminergic neurotransmission in rats.

Nutritional iron-deficiency (ID) induced in rats caused a reduction in peripheral as well as central iron metabolism. This effect was markedly greater in the liver than the brain. Although the decrease in the rate of brain non-haem iron was slower than that of serum and liver, significant diminutions of behavioral response to apomorphine (2 mg/kg) and maximum [3H]spiperone binding (Bmax) in caudate nucleus were noted in these animals. These effects of ID can be reserved by iron supplementation in young (21-day-old) and adult (48-day-old) rats. In contrast, if ID is induced in new born (10-day-old) animals, the diminished brain non-haem iron, behavioral response to apomorphine and [3H]-spiperone binding in caudate nucleus will not recover even after 6 weeks of iron supplementation. However, these animals have normal serum iron, haemoglobin and liver iron. These data point to the profound effect early ID can have on the development of dopaminergic neurotransmission, since brain iron concentration increases its maximum in the 4-5 weeks after birth. The implications of the present finding is that the prevalence of ID in children occurs in the first decade of life, when brain iron accumulation reaches values observed in adults. The profound cognitive changes associated with ID in children is thought to be dopamine-dependent and is not always reversible with iron therapy.

Aging↗
PubMed1985

Increased hepatic and reduced prostatic prolactin (PRL) binding in iron deficiency and during neuroleptic treatment: correlation with changes in serum PRL and testosterone.

Iron deficiency (ID) induced in 21 day old male rats for 28 days caused a 7 fold increase in hepatic prolactin (PRL)-specific binding and a parallel 3 fold rise in serum PRL, as expected from both the reported reduction in central dopaminergic (DA) activity and PRL's up-regulating effect on its own liver receptors. Similarly, serum testosterone was increased by 80%. Prostatic PRL binding was slightly reduced (by 27%), possibly because of masking by the raised hormone levels, although more likely by a more generalized reduction in proliferation during ID, as indicated by the 50% prostatic weight loss. Chronic treatment with neuroleptics also increased hepatic PRL binding in accord with their anti DA activity: chlorpromazine (10 mg/kg) or fluphenazine (5 mg/kg) injected daily (i.p.) for 21 days followed by a 3 day drug-free period resulted in 26 and 10 fold increases, respectively. The parallel reductions of serum levels of PRL (by 40%) and of testosterone (by 70%) by both drugs is indicative of the drug withdrawal supersensitivity normally observed in the caudate nucleus DA receptor. A testicular peripheral effect of the neuroleptics probably further accounted for the reduction in testosterone synthesis, reinforcing the induction of liver PRL binding by these drugs and explaining their negative effects on prostate PRL binding and weight. These findings stress the importance of monitoring hormone levels in ID and during treatment with neuroleptics, in order to avoid endocrine side-effects.

Animals↗
PubMed1985

Effect of iron chelators on dopamine D2 receptors.

Nutritional iron deficiency induced in rats causes a selective reduction of [3H]spiperone binding in caudate nucleus. This effect can be reversed by iron supplementation in vivo. The possibility that iron may be involved in the dopamine D2 receptor was investigated by examining the effect of various iron and noniron chelators on the binding of [3H]spiperone in rat caudate nucleus. Iron chelators 1,10-phenanthroline, 2,4,6-tripyridyl-s-triazine, alpha, alpha'-dipyridyl, and desferrioxamine mesylate inhibited the binding of [3H]spiperone. The inhibition by 1,10-phenanthroline was noncompetitive and reversible. In the presence of FeCl2 or FeCl3, the inhibitory effect of 1,10-phenanthroline was potentiated. Iron salts or chelators were without effect on the binding of [3H]dihydroalprenolol to beta-adrenoreceptors in caudate nucleus; thus the action of iron chelators on the dopamine D2 receptor tends to be selective. Incubation of caudate nucleus membrane prepared from iron-deficient rats with FeCl2 or FeCl3 did not reverse the diminished binding of [3H]spiperone. The present study indicates that if iron is involved in the physiological regulation of dopamine D2 agonist-antagonist binding sites, it is more complex than hitherto considered.

2,2'-Dipyridyl↗
PubMed1984

Modulation of dopamine receptor in the striatum by iron: behavioral and biochemical correlates.

The present study has shown that in the rat brain iron is unevenly distributed and may be associated with the dopaminergic neuron. The function of the large amounts of iron in certain brain areas, such as the pallidum, caudate nucleus, substantia nigra, nucleus accumbens, and olfactory tubercule, is not known. But it is obvious that by reduction of brain iron, as in the case of nutritional iron deficiency, certain dopamine-mediated behavioral phenomena and biochemical reactions are altered. These changes have been attributed to the selective reduction in dopamine D2 receptors and function in brain areas rich in dopamine neurons and iron. If iron is especially important to dopaminergic modulatory systems in the brain, its deficit might explain the increasing number of reports on behavioral disturbances, EEG, and event-related potentials (ERPs) associated with nutritional iron deficiency in children.

Animals↗
PubMed1983

Brain iron and dopamine receptor function.

It has been demonstrated that nutritional iron-deficiency induced in rats results in the reduction of DA D2 receptor binding sites, leading to down-regulation of dopaminergic activity similar to that observed in neuroleptic-treated animals. The following observations are common to both conditions: (a) Decreased behavioural response to pre- and post-synaptically DA and serotonin acting drugs, amphetamine, apomorphine and 5-methoxy-N,N-dimethyltryptamine. (b) Inhibition of amphetamine or apomorphine induced hypothermia in rats kept at an ambient temperature of 4 degrees C. (c) Increased sleeping time to phenobarbitone which cannot be attributed to the rate of drug metabolism (5,38). (d) Upregulation of prolactin binding sites in the liver as a result of increased serum prolactin. Additionally, nutritional iron-deficiency lowers brain iron and interferes with protein synthesis in this organ, which could explain the reduction of DA D2 receptor number and function. Given the fact that the highest brain concentrations of iron are found in dopaminergic structures (see 42 for review), and the essential role of intact dopaminergic systems to attentional and learning processes (15b,30), the resultant behavioural changes due to the reduction of dopaminergic activity in iron-deficient animals may go some way to explain the adverse effects on cognition, behavioural patterns, learning and attention, event-related potentials (ERPs) and EEG changes reported in iron-deficient children (19-28,30).

Anemia, Hemolytic↗
PubMed1982

Nutritional iron and dopamine binding sites in the rat brain.

Iron-deficiency (ID) anemia in man is associated with neurological disorders and abnormal behavior. Rats made nutritionally iron-deficient have markedly diminished behavioral responses to centrally-acting drugs (amphetamine and apomorphine) which affect monoaminergic systems. ID has no effect on either the levels of monoamines or on the activities of monoamine-metabolizing enzymes in the brain. We have investigated the possibility that ID may affect postsynaptic events at the level of receptor by measuring the specific binding sites of several neurotransmitters in different brain areas. The results clearly show that ID causes a significant (40-60%) reduction of the DA D2 binding sites in the caudate. DA-sensitive adenylate cyclase, alpha- and beta-adrenergic, muscarinic cholinergic and the benzodiazepine binding sites were not affected by ID. The effects of ID on DA D2 binding sites and the behavioral responses to apomorphine can be reversed when iron-deficient rats are placed for 8 days on an iron-deficient diet supplemented with iron. Chronic hemolytic anemia produced by repeated phenylhydrazine injections caused no change in serum iron and had no effect on either apomorphine-induced hyperactivity or 3H-spiroperidol binding in the caudate. Since the highest concentration of iron is found in DA-rich brain areas, it is possible that iron may be crucial to either the synthesis or coupling of the DA D2 binding site. The possibility that the DA supersensitivity induced by neuroleptics may be related to iron metabolism in the brain has been investigated.

Anemia, Hemolytic↗
PubMedDate not supplied

Influence of neuromelanin on oxidative pathways within the human substantia nigra.

Neuromelanin (NM) is a dark-coloured pigment produced in the dopaminergic neurons of the human substantia nigra (SN). The function of NM within the pigmented neurons is unknown but other melanins are believed to play a protective role via attenuation of free radical damage. Experimental evidence suggests that NM may also exhibit this characteristic, possibly by directly inactivating free radical species or via its ability to chelate transition metals, such as iron. Increased tissue iron, however, may saturate iron-chelating sites on NM and a looser association between iron and NM may result in an increased, rather than decreased, production of free radical species. The death of NM-pigmented neurons in Parkinson's disease (PD) is associated with both a measurable increase in tissue iron concentrations and indices of free radical mediated damage, suggesting that NM is involved in the aetiology of this disorder. As yet, it is unknown whether NM in the parkinsonian brain differs to that found in healthy tissue and thus may fulfil a different role within this tissue.

Binding Sites↗
PubMedDate not supplied

Minimal brain damage induced by early iron deficiency: modified dopaminergic neurotransmission.

The reports that iron-deficiency anemia in human subjects induces behavioral changes was investigated in rats made nutritionally iron-deficient. The most prominent features of these animals were: the unchanged metabolism of the neurotransmitters noradrenaline, dopamine and serotonin, profound reduction of brain nonheme iron, the selective diminution of dopamine D2 receptor number (measured by Bmax), modification of dopamine-dependent behaviors and reduction of learning processes. The induction of these changes and their recovery with iron supplementation are age- and time-dependent phenomena. In newborn rats, however, the consequences of iron deficiency are irreversible, even after long-term iron supplementation. The results point to the profound effect iron metabolism can have on the long-term development and function of dopaminergic neurotransmission. These findings may not be totally unexpected, since iron distribution in the brain is highly localized in dopaminergic-peptidergic regions, such as the globus pallidus, substantia nigra, red nucleus, thalamus, caudate nucleus and nucleus accumbens. In some regions its concentration is higher than that found in the liver, the site of iron metabolism.

Animals↗