Biomedical subjects

Dorit Ben-Shachar

Publications and source records attributed to Dorit Ben-Shachar.

9 recordsLinked to original sources

PubMed2006

Increased mRNA levels of the mitochondrial complex I 75-kDa subunit. A potential peripheral marker of early onset schizophrenia?

Recently, the dopamine D3-receptor mRNA on blood lymphocytes and platelet mitochondrial complex I were suggested as biological markers of schizophrenia in adults. We investigated the mRNA level of the dopamine D3-receptor and complex I subunits in whole blood cells of early-onset schizophrenic patients compared to healthy controls using quantitative real-time PCR. We found an increased mRNA expression of the complex I 75-kDa subunit (referred to beta-actin in schizophrenic patients (0.57 +/- 0.24 versus 0.23 +/- 0.18 in controls, P < 0.01)), but were unable to analyse the dopamine D3-mRNA expression. This increase appears to be inherent to schizophrenia, because it was found in neuroleptic-naive patients and it was not affected by neuroleptic treatment. Our preliminary findings suggest the mitochondrial complex I as a potential peripheral marker of schizophrenia and its involvement in the pathophysiology of this illness.

Actins↗

PubMed2005

Alterations in cell adhesion molecule L1 and functionally related genes in major depression: a postmortem study.

BACKGROUND: Current research in depression aims to delineate genes involved in neuronal plasticity that are altered in the disease or its treatment. We have shown antidepressant induced increases in three interrelated genes, cell adhesion molecule L1 (CAM-L1), laminin, and cAMP response element binding protein (CREB), and a reciprocal decrease in these genes consequent to stress. Presently we hypothesized that CAM-L1, CREB, and laminin may be altered in post mortem brains of depressed subjects. METHODS: Studies were performed in the prefrontal and in the ventral parieto-occipital cortices, of 59 brains from depressed, bipolar, and schizophrenic subjects, and normal controls, obtained from the Stanley Foundation Brain Collection. mRNA and protein levels were determined by RT-PCR and Western blot analysis, respectively. RESULTS: Levels of CAM-L1 and of phosphorylated CREB (pCREB) were increased in the prefrontal cortex of the depressed group, while CAM-L1, laminin and pCREB were decreased in the parieto-occipital cortex. Depressed subjects receiving antidepressants differed from subjects not receiving antidepressants in the expression of CAM-L1 and laminin in the parieto-occipital cortex, and in the expression of pCREB in the prefrontal cortex. CONCLUSIONS: The present findings of specific alterations in depression and antidepressant treatment particularly in CAM-L1 suggest that this gene may play an important role in the pathophysiology and treatment of depression.

Adult↗

PubMed2004

Mitochondria, synaptic plasticity, and schizophrenia.

The conceptualization of schizophrenia as a disorder of connectivity, i.e., of neuronal?synaptic plasticity, suggests abnormal synaptic modeling and neuronal signaling, possibly as a consequence of flawed interactions with the environment, as at least a secondary mechanism underlying the pathophysiology of this disorder. Indeed, deficits in episodic memory and malfunction of hippocampal circuitry, as well as anomalies of axonal sprouting and synapse formation, are all suggestive of diminished neuronal plasticity in schizophrenia. Evidence supports a dysfunction of mitochondria in schizophrenia, including mitochondrial hypoplasia, and a dysfunction of the oxidative phosphorylation system, as well as altered mitochondrial-related gene expression. Mitochondrial dysfunction leads to alterations in ATP production and cytoplasmatic calcium concentrations, as well as reactive oxygen species and nitric oxide production. All of the latter processes have been well established as leading to altered synaptic strength or plasticity. Moreover, mitochondria have been shown to play a role in plasticity of neuronal polarity, and studies in the visual cortex show an association between mitochondria and synaptogenesis. Finally, mitochondrial gene upregulation has been observed following synaptic and neuronal activity. This review proposes that mitochondrial dysfunction in schizophrenia could cause, or arise from, anomalies in processes of plasticity in this disorder.

Animals↗

PubMed2003

Iron-binding characteristics of neuromelanin of the human substantia nigra.

The vulnerability of the dopaminergic neurons of the substantia nigra (SN) in Parkinson's disease has been related to the presence of the pigment neuromelanin (NM) in these neurons. It is hypothesised that NM may act as an endogenous storage molecule for iron, an interaction suggested to influence free radical production. The current study quantified and characterised the interaction between NM and iron. Iron-binding studies demonstrated that both NM and synthetically-produced dopamine melanin contain equivalent numbers of high and low-affinity binding sites for iron but that the affinity of NM for iron is higher than that of synthetic melanin. Quantification of the total iron content in iron-loaded NM and synthetic melanin demonstrated that the iron-binding capacity of NM is 10-fold greater than that of the model melanin. This data was in agreement with the larger iron cluster size demonstrated by Mössbauer spectroscopy in the native pigment compared with the synthetic melanin. These findings are consistent with the hypothesis that NM may act as an endogenous iron-binding molecule in dopaminergic neurons of the SN in the human brain. The interaction between NM and iron has implications for disorders such as Parkinson's disease where an increase in iron in the SN is associated with increased indices of oxidative stress.

Humans↗

PubMed2003

Neuromelanin and its interaction with iron as a potential risk factor for dopaminergic neurodegeneration underlying Parkinson's disease.

Neuromelanin (NM) is a granular, dark brown pigment produced in some but not all of the dopaminergic neurons of the human substantia nigra (SN). In Parkinson's disease (PD) the pigmented dopaminergic neurons of the SN degenerate, suggesting that this process is related to the presence of NM. As yet it is unknown whether NM in the parkinsonian brain differs from that found in healthy tissue and thus may fulfil a different role within this tissue. 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 direct inactivation of free radical species or via its ability to chelate transition metals, such as iron. NM has the ability to bind a variety of metals, seven per cent of isolated NM is reported to consist of Fe, Cu, Zn and Cr. Iron is of particular interest as this metal is highly concentrated within the SN. Up to 20 per cent of the total iron contained in the SN from normal subjects is bound within NM. Further, it was demonstrated that NM contains a protein component and that iron is bound to NM in the ferric form. Increased tissue iron found in the parkinsonian SN 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. It is hypothesized that this redox-active iron could be released and involved in a Fenton-like reaction leading to an increased production of oxidative radicals. The resultant radical-mediated cytotoxicity may contribute to cellular damage observed in PD.

Dopamine↗

PubMed2003

Modulation of frequency and duration of repetitive magnetic stimulation affects catecholamine levels and tyrosine hydroxylase activity in human neuroblastoma cells: implication for the antidepressant effect of rTMS.

Transcranial magnetic stimulation (TMS), which is produced by strong non-static magnetic fields, is a non-invasive means to stimulate the cerebral cortex. Studies from recent years show that TMS affects mood in healthy subjects and improves depressive symptoms in patients with major depression. However, the relationship between the clinical efficacy of TMS and stimulation parameters is still obscure. In the present study we have investigated the effects of different stimulation frequencies and number of treatments on catecholamine turnover in SH-SY5Y cell cultures. A single session of magnetic stimulation (1.7 T) caused a significant decrease in intracellular dopamine and L-DOPA and in noradrenaline (NE) release at a rate of 3 Hz for 10 s but increased NE release at a rate of 9 Hz. These alterations were associated with a reduction (47.8%) or an increase (48%) in tyrosine hydroxylase (TH) activity after 3 and 9 Hz magnetic stimulation, respectively. The latter may be related to the known sensitivity of TH to neuronal firing rates and NE concentrations. Higher stimulation frequencies (15, 20, 45 Hz) had no effect on catecholamine metabolism. Unlike 3 Hz acute treatment, chronic treatment (3 Hz, 11 sessions, for 4 d) had no effect on monoamines and TH activity was increased by 54.5% with no change in its protein level. The results of the present study demonstrate that in tissue culture system frequency and treatment duration of the magnetic stimulation are important factors in affecting catecholamine turnover. Considering the major role of catecholamine in the pathophysiology of depression, these findings may be of relevance to the application of rTMS in humans with major depression.

Blotting, Western↗

PubMed2002

Norepinephrine alters the expression of genes involved in neuronal sprouting and differentiation: relevance for major depression and antidepressant mechanisms.

Recent research into depression has focused on the involvement of long-term intracellular processes, leading to abnormal neuronal plasticity in brains of depressed patients, and reversed by antidepressant treatment. Given a suggested decrease in noradrenergic transmission in depression, and an antidepressant induced increase in norepinephrine (NE) level, a possible role for NE in mediating alterations in neuronal morphology and plasticity was examined. Human neuroblastoma SH-SY5Y cells treated with 10-5 m NE presented an elongated granule-rich cell-body and increased number of neurites, when compared with non-treated cells. Moreover, cell survival was enhanced in the presence of NE, while proliferation was inhibited. The above effects suggest a role for NE in cell differentiation. Indeed similar effects on cell survival and neurite outgrowth were induced in SH-SY5Y cells by retinoic acid (RA), an established differentiating agent. Finally, NE treatment resulted in a progressive decrease in the pluripotent marker Oct4 and an increase in the neuronal growth cone marker, growth-associated-protein 43 (GAP-43). Alongside these effects, NE-treated cells presented alterations in the expression of 44 genes as observed in a neurobiology cDNA microarray. Among the altered genes, an increase in the expression level of two neurite-outgrowth promoting genes, neural cell adhesion molecule L1 and laminin, was confirmed by RT-PCR. Taken together, the results support a role for NE in processes of synaptic connectivity, and may point to a role for this neurotransmitter in mediating the suggested neuronal plasticity in depression and in antidepressant treatment.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2002

Mitochondrial dysfunction in schizophrenia: a possible linkage to dopamine.

Mitochondria are not only the principal source of high energy intermediates, but play an important role in intracellular calcium buffering, are main producers of reactive oxygen species, and are the source of pro- and antiapoptotic key factors. Moreover, the mitochondria are of a ubiquitous nature and the respiratory chain has a dual genetic basis, i.e. the mitochondrial and the nuclear DNAs. Thus mitochondrial impairment could provide an explanation for the tremendous heterogeneity of clinical and pathological manifestations in schizophrenia. This article reviews several independent lines of evidence that suggest an involvement of mitochondrial dysfunction in schizophrenia. Among them are altered cerebral energy metabolism, mitochondrial hypoplasia, dysfunction of the oxidative phosphorylation system and altered mitochondrial related gene expression. In addition, the interaction between dopamine, a predominant etiological factor in schizophrenia, and mitochondrial respiration is considered as a possible mechanism underlying the hyper- and hypo-activity cycling in schizophrenia. Understanding the role of mitochondria in schizophrenia may encourage novel treatment approaches, the identification of candidate genes and new insights into the pathophysiology and etiology of the disorder.

Animals↗

PubMed1999

Increased mitochondrial complex I activity in platelets of schizophrenic patients.

It is believed that dopamine and alterations of energy metabolism in cortical and subcortical structures are involved in the pathophysiology of schizophrenia. Recently, we and others have shown that dopamine may affect energy metabolism by interacting with mitochondrial complex I activity in rats both in vivo and in vitro. In this study activity of complexes I and IV was assessed in mitochondria isolated from blood platelet of schizophrenic patients and compared to patients with affective disorders and healthy control subjects. Seventy-seven in-patients who met DSM-IV criteria for schizophrenia (in acute exacerbation), bipolar disorder depressed type (BP), or recurrent major depressive disorder (MDD) and 24 control subjects participated in the study. A highly significant increase (240%, p < 0.001) in complex I activity but not in complex IV, was detected in medicated and unmedicated schizophrenic patients compared to controls. No such change was observed in patients with affective disorders. The data demonstrate a specific and selective, alteration in platelet complex I activity in schizophrenic patients, which is not related to medication. If this abnormality in platelet mitochondria reflects brain alterations, it may further support the relevance of alterations in energy metabolism to the pathophysiology of schizophrenia. Finally in the lack of any clinically relevant biological marker for schizophrenia, complex I activity in platelets might become a useful peripheral marker for this disorder.

Journal Article↗