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D Ben-Shachar

Publications and source records attributed to D Ben-Shachar.

At least 19 recordsLinked to original sources
PubMed2005

Antidepressants and prolonged stress in rats modulate CAM-L1, laminin, and pCREB, implicated in neuronal plasticity.

Previously, we reported an ability of NE to promote processes of plasticity in neuroblastoma cells, as observed by morphological changes such as an elongated granule-rich cell body and neuritegenesis, in addition to a progressive decrease in the pluripotent marker Oct4 and an increase in the growth cone marker GAP-43. This was accompanied by the induction of three plasticity genes forming a functional cluster, the cell adhesion molecule L1 (CAM-L1), laminin, and CREB, all involved in neuronal plasticity and neurite outgrowth. In the present study, we hypothesized that the regulation of CAM-L1, laminin, and CREB/pCREB by NE could mediate processes of plasticity in the mode of action of antidepressants, as well as in the long-term effects of stress, in rats, given the association of both with NE alterations and neuronal plasticity. In the first experiment, rats were chronically administered with antidepressants (21 days). In the second experiment, rats were exposed to chronic stress and examined 4 months later, a model shown to exhibit behavioral indices of stress. We found brain region-specific alterations in mRNA and protein levels of CAM-L1, laminin, and pCREB in rats chronically treated with the noradrenergic antidepressant desipramine and, to a lesser extent, in those treated with fluoxetine. Stressed rats presented a decrease in CAM-L1, laminin, and pCREB, specifically in brain areas implicated in stress. Our findings suggest that noradrenergic-regulated plasticity genes such as CAM-L1, laminin, and CREB play an important role both in stress and in the treatment of depression.

Animals↗
PubMed2004

Dopamine toxicity involves mitochondrial complex I inhibition: implications to dopamine-related neuropsychiatric disorders.

Dopamine, which is suggested as a prominent etiological factor in several neuropsychiatric disorders such as Parkinson's disease and schizophrenia, demonstrates neurotoxic properties. In such dopamine-related diseases mitochondrial dysfunction has been reported. Dopamine oxidized metabolites were shown to inhibit the mitochondrial respiratory system both in vivo and in vitro. In the present study, we suggest an additional mechanism for dopamine toxicity, which involves mitochondrial complex I inhibition by dopamine. In human neuroblastoma SH-SY5Y cells dopamine induced a reduction in ATP concentrations, which was negatively correlated to intracellular dopamine levels (r = - 0.96, P = 0.012), and was already evident at non-toxic dopamine doses. In disrupted mitochondria dopamine inhibited complex I activity with IC50 = 11.87 +/- 1.45 microm or 8.12 +/- 0.75 microM in the presence of CoQ or ferricyanide, respectively, with no effect on complexes IV and V activities. The catechol moiety, but not the amine group, of dopamine is essential for complex I inhibition, as is indicated by comparing the inhibitory potential of functionally and structurally dopamine-related compounds. In line with the latter is the finding that chelatable FeCl2 prevented dopamine-induced inhibition of complex I. Monoamine oxidase A and B inhibitors, as well as the antioxidant butylated hydroxytoluene (BHT), did not prevent dopamine-induced inhibition, suggesting that dopamine oxidation was not involved in this process. The present study suggests that dopamine toxicity involves, or is initiated by, its interaction with the mitochondrial oxidative phosphorylation system. We further hypothesize that this interaction between dopamine and mitochondria is associated with mitochondrial dysfunction observed in dopamine-related neuropsychiatric disorders, such as schizophrenia and Parkinson's disease.

Adenosine Triphosphatases↗
PubMed2004

ATF2, a member of the CREB/ATF family of transcription factors, in chronic stress and consequent to antidepressant treatment: animal models and human post-mortem brains.

The regulation of gene expression has been implicated in the etiology and treatment of depression. Transcription factors serve as the intermediates between intracellular cascades and gene expression, and may therefore be involved in the pathophysiology and pharmacotherapy of depression. We and others have previously reported an increase in the phosphorylation of the transcription factor cAMP response element binding protein (CREB) by antidepressants, alongside brain region-specific alterations in pCREB by stress. In the present study, we examined the expression of another member of the CREB/ATF family of transcription factors, ATF2, in the brains of rats chronically treated with two different antidepressants, and in rats 4 months after their exposure to prolonged stress. ATF2 phosphorylation was decreased by antidepressants and increased at the aftermath of prolonged stress, specifically in the frontal cortex. We also examined ATF2 expression in the ventral parieto-occipital region of post-mortem human brains of normal controls, depressed, bipolar, and schizophrenic patients, obtained from the Stanley Foundation Brain Consortium. No alterations were observed in the levels of ATF2. However, in the depressed group, the pATF2 levels were higher in unmedicated compared to medicated patients, suggesting an antidepressant-induced reduction in pATF2. We discuss the possible role of ATF2 in depression, and propose that an interplay between ATF2 and CREB, and possibly other transcription factors, determines the final gene expression pattern in the etiology and treatment of depression.

Activating Transcription Factor 2↗
PubMed2002

State-dependent alterations in mitochondrial complex I activity in platelets: a potential peripheral marker for schizophrenia.

Schizophrenia, the most severe psychiatric disorder, is characterized by heterogeneity of clinical signs, often categorized into positive and negative symptoms. Among a wide array of competing biological mechanisms, altered cerebral energy metabolism and mitochondrial dysfunction have been suggested to play an important role in the pathophysiology of schizophrenia. In this study we investigated mitochondrial complex I in platelets of 113 schizophrenic patients divided into three groups (acute psychotic episode, chronic active state and residual schizophrenia) and 37 control subjects. Complex I was analysed at the level of enzymatic activity, mRNA and protein levels by enzyme kinetics, RT-PCR and Western blot analyses, respectively. Complex I activity in platelets of schizophrenic patients altered with disease state presenting high specificity and sensitivity. Thus, increased activity was associated with psychotic symptomology, while its decrease was observed in patients with residual schizophrenia. The relationship between the clinical state and complex I activity in schizophrenia was further supported by its positive correlation with the severity of patients' positive symptoms assessed by clinical ratings. In addition, similar alterations were observed at the levels of mRNA and protein of the 24- and 51-kDa iron-sulfur flavoprotein subunits of the complex. Taken together these results point to the potential of platelet complex I to turn into a reliable novel marker for schizophrenia. At present, definitive diagnosis depends only on descriptive behavioral and symptomatic information, therefore a peripheral measurable specific marker will contribute to diagnosis and monitoring of the disease.

Adolescent↗
PubMed2001

A peripheral marker for schizophrenia: Increased levels of D3 dopamine receptor mRNA in blood lymphocytes.

Dopamine is a major neurotransmitter in the central nervous system, and its receptors are associated with a number of neuropathological disorders such as Parkinson's disease and schizophrenia. Although the precise pathophysiology of schizophrenia remains unknown, the dopaminergic hypothesis of the illness assumes that the illness results from excessive activity at dopamine synapses in the brain. Because, at present, the diagnosis of schizophrenia relies on descriptive behavioral and symptomatic information, a peripheral measurable marker may enable a simpler, more rapid, and more accurate diagnosis and monitoring. In recent years, human peripheral blood lymphocytes have been found to express several dopamine receptors (D(3), D(4), and D(5)) by using molecular biology techniques and binding assays. It has been suggested that these dopamine receptors found on lymphocytes may reflect receptors found in the brain. Here we demonstrate a correlation between the D(3) dopamine receptor on lymphocytes and schizophrenia and show a significant elevation of at least 2-fold in the mRNA level of the D(3), but not of the D(4), dopamine receptor in schizophrenic patients. This increase is not affected by different antipsychotic drug treatments (typical or atypical). Moreover, nonmedicated patients exhibit the same pattern, indicating that this change is not a result of medical treatment. We propose the D(3) receptor mRNA on blood lymphocytes as a marker for identification and followup of schizophrenia.

Adult↗
PubMed2000

The effects of bile acids on beta-adrenoceptors, fluidity, and the extent of lipid peroxidation in rat cardiac membranes.

Bile acids have been proposed as a causative factor for the cardiomyopathy of cholestatic liver disease, since they cause negative inotropism and chronotropism and attenuate cardiac responsiveness to sympathetic stimulation. Bile acids can also modify membrane fluidity and generate reactive oxygen species (ROS). The effects of 10(-6)-10(-3) M deoxycholic acid (DCA) and chenodeoxycholic acid (CDCA) and their taurine conjugates, TDCA and TCDCA, on (1) the binding characteristics of beta-adrenoceptors, (2) membrane fluidity, and (3) the extent of lipid peroxidation in rat cardiac membranes were assessed. The results were compared to the effects of the oxidant, 10(-4)-10(-3) M hydrogen peroxide (H(2)O(2)), and the membrane-fluidizing compound, 5 x 10(-5) M 2-(2-methoxyethoxy)ethyl 8-(cis-2-n-octylcyclopropyl)octanoate (A(2)C). Cardiac beta-adrenoceptor density alone was reduced at 10(-4) M bile acid concentration while, at 10(-3) M bile acids, reductions in both receptor density and affinity were seen. At 10(-4) M H(2)O(2), receptor number and affinity were reduced, whereas A(2)C increased receptor affinity without affecting receptor density. Bile acids (10(-3) M) and 10(-4) M H(2)O(2) reduced membrane fluidity. H(2)O(2) caused a concentration-dependent increase in the extent of lipid peroxidation, whereas the bile acids and A(2)C had no effect. Bile acids (10(-4) M) reduced beta-adrenoceptor density in the absence of variations in membrane fluidity and in the extent of membrane lipid peroxidation. This result suggests that bile acids, at concentrations equivalent to the plasma/serum total or estimated free bile acid concentration, may have a possible role in the etiology of cardiomyopathy of cholestatic liver disease. At 10(-3) M bile acid concentration, beta-adrenoceptor number and affinity were adversely affected, accompanied by a decrease in membrane fluidity but without any significant increase in the extent of membrane lipid peroxidation. Although cardiac beta-adrenoceptor density and affinity and membrane fluidity were adversely affected by bile acids, the relevance of these findings to our understanding of the etiological basis of hepatic cardiomyopathy is questionable, since such concentrations exceeded the highest concentrations seen in the plasma and/or tissues of patients with cholestatic liver disease.

Animals↗
PubMed2000

Paroxetine binding in aggressive schizophrenic patients.

Decreased central serotonergic activity has been associated with aggressive behavior in humans and animals. Whether or not this phenomenon is related to current aggression or to aggressive tendency is debatable. [3H]paroxetine binding in blood platelets represents the activity of serotonin peripheral binding sites. We investigated a possible association between [3H]paroxetine binding in blood platelets and current aggression or homicidal history in schizophrenic patients. Blood platelets of 11 aggressive schizophrenic patients were assayed for [3H]paroxetine binding in blood platelets and compared to findings in 15 non-aggressive schizophrenic patients, 15 presently non-aggressive schizophrenic patients with homicidal history, and 15 healthy volunteers. Clinical evaluation was performed using the Positive and Negative Syndrome Scale, the Hamilton Rating Scale for Depression and the Clinical Global Impression scale. B(max) of [3H]paroxetine binding in blood platelets of currently aggressive schizophrenic patients was significantly higher than that in platelets of non-aggressive schizophrenic patients, presently non-aggressive patients with homicidal history and healthy volunteers. No difference was found between the last three study groups. No significant correlation was found between scores of all rating scales and the investigated biochemical parameters. An association was found between current aggression among schizophrenic patients and high B(max) values of [3H]paroxetine binding in blood platelets. This association is probably related to present state of aggression rather than to tendency towards aggression.

Adult↗
PubMed2000

Structural characteristics of human substantia nigra neuromelanin and synthetic dopamine melanins.

Neuromelanin (NM) is a complex polymer pigment found primarily in the dopaminergic neurons of the human substantia nigra. The structure of NM is only partially characterized, and its synthesis pathway remains unknown. We used nuclear magnetic and infrared spectroscopy to examine the structure of human NM isolated from the substantia nigra compared with synthetic dopamine melanins. Biochemical analyses were used to investigate proteinaceous and dopaminergic components in these samples. Following acid hydrolysis of NM samples, small amounts of DOPA, dopamine, and a variety of amino acids were measured. These findings suggest a peptide component in NM structure. NM also appears to contain a variety of unidentified structural components possibly derived from the oxidation of dopamine. Human NM differs structurally from synthetic dopamine melanin, but both human and synthetic NM include an aromatic backbone. It is interesting that both human NM and synthetic melanin also contain a large proportion of aliphatic structures. Our results suggest that NM is a more complex pigment than synthetic dopamine melanin formed via dopamine autoxidation alone.

Adult↗
PubMed1999

Chronic repetitive transcranial magnetic stimulation alters beta-adrenergic and 5-HT2 receptor characteristics in rat brain.

Repetitive transcranial magnetic stimulation (rTMS) has been shown to affect mood in health and disease. Evidence to date has demonstrated an antidepressant potential for low- and high-frequency rTMS treatment. In animal behavioral models of depression magnetic stimulation of the brain induced similar effects to those of electroconvulsive shock (ECS). In this study the effects of repeated rTMS on rat brain noradrenaline, dopamine, serotonin and their metabolites levels, as well as on beta-adrenergic and 5-HT2 receptor characteristics were studied. After 10 days of treatment, beta-adrenergic receptors were significantly up regulated in the frontal cortex, down regulated in the striatum and were unchanged in the hippocampus. 5-HT2 receptors were down regulated in the frontal cortex and were not changed in the other brain areas. No change in benzodiazepine receptors in the frontal cortex and cerebellum were demonstrated. These findings demonstrate specific and selective alterations induced by repeated rTMS, which are distinct from those induced by other antidepressant treatments. TMS therapeutic effects in humans and behavioral and biochemical effects in animal, suggest that TMS has a unique mechanism of action which requires further investigation.

Animals↗
PubMed1999

Therapeutic efficacy of right prefrontal slow repetitive transcranial magnetic stimulation in major depression: a double-blind controlled study.

BACKGROUND: Transcranial magnetic stimulation (TMS), a noninvasive technique for stimulation of the brain, has recently been suggested to be effective for the treatment of major depression. We conducted a double-blind, placebo-controlled study to assess the efficacy of slow repetitive TMS (rTMS) in patients with major depression. METHODS: Seventy patients with major depression (53 women, 17 men; mean age, 58.7 years; SD, 17.2 years) were randomly assigned to receive rTMS or sham rTMS in a double-blind design. Treatment was administered in 10 daily sessions during a 2-week period. Severity of depression was blindly assessed before, during, and after completion of the treatment protocol. RESULTS: All patients completed the first week of treatment and 67 completed the entire protocol. Patients who received rTMS had a significantly greater improvement in depression scores compared with those who received sham treatment. At the end of 2 weeks, 17 of 35 patients in the rTMS group, but only 8 of 32 in the sham-treated group, had an improvement of greater than 50% in their depression ratings. CONCLUSIONS: This controlled study provides evidence for the short-term efficacy of slow rTMS in patients with recurrent major depression. Additional studies will be necessary to assess the efficacy of rTMS as compared with electroconvulsive therapy as well as the long-term outcome of this treatment in major depression and possibly other psychiatric disorders.

Adolescent↗
PubMed1999

Rat brain monoamines after acute and chronic myo-inositol treatment.

Inositol was reported to have effects in depression, panic disorder and OCD, and in animal models of depression and anxiety. The present study tested whether inositol treatment alters monoamine systems. Brain areas of rats pre-treated with acute or chronic inositol were analysed by HPLC for monoamines and their metabolites and compared to control animals. Inositol treatment had no significant effect on levels of monoamines, their metabolites, or turnover rates compared to controls.

Administration, Oral↗
PubMed1997

Transcranial magnetic stimulation induces alterations in brain monoamines.

Transcranial magnetic stimulation has been suggested as a possible therapeutic tool in depression. In behavioral models of depression, magnetic stimulation induced similar effects to those of electroconvulsive shock. This study demonstrates the effect of a single session of rapid TMS on tissue monoamines in rat brain. Alterations in monoamines were selective and specific in relation to brain areas and type of monoamine. The results imply on a biochemical basis to the suggested ECT-like treatment potential of TMS.

Animals↗
PubMed1995

Dopamine neurotoxicity: inhibition of mitochondrial respiration.

Dopamine, due to metabolism by monoamine oxidase or autoxidation, can generate toxic products such as hydrogen peroxide, oxygen-derived radicals, semiquinones, and quinones and thus exert its neurotoxic effects. Intracerebroventricular injection of dopamine into rats pretreated with the monoamine oxidase nonselective inhibitor pargyline caused mortality in a dose-dependent manner with LD50 = 90 micrograms. Norepinephrine was less effective with LD50 = 141 micrograms. The iron chelator desferrioxamine completely protected against dopamine-induced mortality. In the absence of pargyline more rats survived, indicating that the products of dopamine enzymatic metabolism are not the main contributors to dopamine-induced toxicity. Biochemical analysis of frontal cortex and striatum from rats that received a lethal dose of dopamine did not show any difference from control rats in lipid and protein peroxidation and glutathione reductase and peroxidase activities. Moreover, dopamine significantly reduced the formation of iron-induced malondialdehyde in vitro, thus suggesting that earlier events in cell damage are involved in dopamine toxicity. Indeed, dopamine inhibited mitochondrial NADH dehydrogenase activity with IC50 = 8 microM, and that of norepinephrine was twice as much (IC50 = 15 microM). Dopamine-induced inhibition of NADH dehydrogenase activity was only partially reversed by desferrioxamine, which had no effect on norepinephrine-induced inhibition. These results suggest that catecholamines can cause toxicity not only by inducing an oxidative stress state but also possibly through direct interaction with the mitochondrial electron transport system. The latter was further supported by the ability of ADP to reverse dopamine-induced inhibition of NADH dehydrogenase activity in a dose-dependent manner.

Animals↗
PubMed1994

Typical and atypical neuroleptics induce alteration in blood-brain barrier and brain 59FeCl3 uptake.

Long-term neuroleptic medication of schizophrenic patients induces extrapyramidal motor side effects, of which tardive dyskinesia (TD) is the most severe. The etiology of TD is still obscure. Recently, it was suggested that abnormal iron metabolism may play a crucial role in neuroleptic-induced dopamine D2 receptor super-sensitivity. The apparent relationship between neuroleptics and iron is further supported by the increase of iron in the basal ganglia of patients with TD. We now report on the ability of neuroleptic to alter the blood-brain barrier in the rat and to potentiate the normally limited iron transport into the brain. Thus, chronic treatment of rats with chlorpromazine and haloperidol facilitated 59Fe3+ uptake into brain cells. In contrast, clozapine, an atypical antipsychotic neuroleptic with little extrapyramidal motor side effects, caused iron sedimentation in brain blood vessels with no sign of detectable iron in the cells. Moreover, chronic treatment with chlorpromazine and haloperidol caused a 43% and 24% reduction, respectively, in liver nonheme iron, whereas clozapine induced an 81% increase. The apparent different potentials of chlorpromazine, haloperidol, and clozapine to increase iron transport into the brain from its peripheral stores may be linked to the severity of extrapyramidal motor side effects they induce and to the pathophysiology of TD.

Animals↗
PubMed1994

Altered brain metabolism of iron as a cause of neurodegenerative diseases?

Iron is the most abundant metal in the human body (Pollitt and Leibel, 1982; Youdim, 1988), and the brain, like the liver, contains a substantially higher concentration of iron than of any other metal (Yehuda and Youdim, 1988). Within the brain, iron shows an uneven distribution, with high levels in the basal ganglia (substantia nigra, putamen, caudate nucleus, and globus pallidus), red nucleus, and dentate nucleus (Spatz, 1922; Hallgren and Sourander, 1958; Hill and Switzer, 1984; Riederer et al., 1989). Iron deposition in the brain is mainly in organic storage forms such as ferritin but not hemosiderin (Hallgren and Sourander, 1958; Octave et al., 1983), with relatively little in a free and reactive form. Although the function of a regionally high brain iron content is unknown, the homeostasis of brain iron is thought to be necessary for normal brain function, especially in learning and memory (Youdim et al., 1989; Yehuda and Youdim, 1989; Pollit and Metallinos-Katsaras, 1990; Youdim, 1990). Thus, a high content of brain iron may be essential, particularly during development, but its presence means that injury to brain cells may release iron ions that can lead to oxidative stress via formation of oxygen free radicals. Such radicals are thought to be involved in lipid peroxidation of the cell membrane, leading to increased membrane fluidity, disturbance of calcium homeostasis, and finally cell death (Youdim et al., 1989; Halliwell, 1992). Iron is an essential participant in many metabolic processes, including (a) DNA, RNA, and protein synthesis, (b) as a cofactor of many heme and nonheme enzymes, (c) the formation of myelin, and (d) the development of the neuronal dendritic tree (Ben-Shachar et al., 1986; Youdim et al., 1991b). A deficiency of iron metabolism would therefore be expected to alter some or all of these processes (Jacobs and Worwood, 1980; Youdim, 1985, 1988). Studies of iron distribution in the human brain have demonstrated that the degree of iron deposition, primarily in the basal ganglia (a predominantly dopamine structure), increases with age (Hallgren and Sourander, 1958) and in certain disorders, most notably the basal ganglia disorders (Seitelberger, 1964). This review will present some of the experimental evidence indicating a role of disturbed iron metabolism as a cause of the neurodegenerative disorder Parkinson's disease and possibly other neurodegenerative disorders such as Alzheimer's disease.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Oxidoreductases↗
PubMed1994

The enigma of neuromelanin in Parkinson's disease substantia nigra.

The function of neuromelanin accumulation in the nigrostriatal dopamine neurons remains uncertain. Nevertheless, it is recognized that neuromelanin disappearance parallels the loss of dopamine neurons in Parkinson's disease, suggesting its participation in nigral cell death. It has been well known for some years that in systemic tissues melanin is a double-edged sword. On the one hand it can act as an antioxidant, but in the presence of transitional metals (primarily, iron) and drugs it promotes the formation of reactive oxygen free radicals. It is now apparent that synthetic dopamine-melanin and neuromelanin exhibit similar properties in vitro and nigrostriatal dopamine neuron co-culture studies. Thus, the identification of ionic iron in dopamine neurons of Parkinson's disease zona compacta and its association with neuromelanin has conferred a cytotoxic property to neuromelanin. This may explain the reported vulnerability of substantia nigra dopamine neurons in Parkinson's disease.

Antioxidants↗
PubMed1994

Blood to brain iron uptake in one rhesus monkey using [Fe-52]-citrate and positron emission tomography (PET): influence of haloperidol.

Iron is highly concentrated in the basal ganglia of the brain. The involvement of cerebral iron and its handling systems in neurodegenerative brain diseases like Parkinson's disease and tardive dyskinesia is currently under close investigation. There is evidence from animal studies that neuroleptics can increase iron uptake into brain. This effect appeared to be due to alteration of blood-brain barrier transport by the neuroleptics, particularly chlorpromazine and haloperidol, but not clozapine. We have investigated one Rhesus monkey using positron emission tomography (PET) and [Fe-52]-citrate before and during haloperidol administration. After drug withdrawal during a period of 1.5 year the investigation procedure was repeated. The results show that in the investigated monkey haloperidol induces a reversible marked increase of iron transport across the blood brain barrier concomitant with a large increase in elimination rate of the tracer from the blood.

Animals↗