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Biomedical subjects

S Avissar

Publications and source records attributed to S Avissar.

At least 19 recordsLinked to original sources
PubMed2005

Dynamics of beta-arrestin1 protein and mRNA levels elevation by antidepressants in mononuclear leukocytes of patients with depression.

BACKGROUND: Beta-arrestins interfere in G protein-receptor interaction leading to desensitization of G protein-mediated receptor signaling. G protein-receptor signaling and its desensitization were previously implicated in the pathophysiology, diagnosis and treatment of mood disorders. The present study aims at evaluating alterations in beta-arrestin1 protein and mRNA levels in mononuclear leukocytes of untreated patients with major depression and the effects and time course of antidepressant treatments on these alterations. METHODS: Repeated beta-arrestin1 protein and mRNA measurements, through immunoblot analyses using monoclonal antibodies against beta-arrestin1 and reverse transcriptase polymerase chain reaction, respectively, were carried in mononuclear leukocytes of 18 patients with major depression and compared with 18 healthy subjects. Each patient was examined while untreated and after 1, 2, and 4 weeks of antidepressant treatment. RESULTS: Beta-arrestin1 protein and mRNA levels in mononuclear leukocytes of untreated patients with major depression were significantly lower than those of healthy subjects. The low beta-arrestin1 protein and mRNA levels were alleviated by antidepressant treatment. Normalization of beta-arrestin1 measures preceded, and thus predicted clinical improvement. CONCLUSIONS: These findings support the implication of beta-arrestin1 in the pathophysiology of major depression and in the mechanism underlying antidepressant-induced receptor down-regulation and therapeutic effects. Beta-arrestin1 measurements in patients with depression may potentially serve for biochemical diagnostic purposes and for monitoring and predicting response to antidepressants.

Adult↗
PubMed2001

Elevated dopamine receptor-coupled G(s) protein measures in mononuclear leukocytes of patients with schizophrenia.

Heterotrimeric G proteins play a pivotal role in post-receptor information transduction and were previously implicated in the pathophysiology and treatment of mood disorders. Changes previously detected in G protein levels in post-mortem brain of patients with schizophrenia could reflect effects of antipsychotic medication. The present study aims at quantitatively and functionally evaluating receptor-coupled G proteins in mononuclear leukocytes obtained from 23 untreated patients with schizophrenia and 30 healthy subjects in an attempt to unravel a pattern of G protein measures in schizophrenia distinctive from patterns previously obtained in mood disorders. Dopamine-enhanced guanine nucleotide binding capacity to G(s) protein through D1/D5 receptor in mononuclear leukocytes of untreated patients with schizophrenia was significantly increased in comparison with healthy subjects, and positively correlated with both the total PANSS score and the positive subscale. beta-Adrenergic and muscarinic receptor-coupled G protein functions, as well as G(s)alpha, G(i)alpha and Gbeta immunoreactivities, were similar to healthy subjects. These findings, distinctive for schizophrenia, unrelated to drug treatment, and differential from previous findings in mania and depression, may potentially help to differentially diagnose, after the first psychotic episode, between the major psychoses: schizophrenia and manic-depressive illness.

Acute Disease↗
PubMed2001

Differential effects of the antipsychotics haloperidol and clozapine on G protein measures in mononuclear leukocytes of patients with schizophrenia.

AIMS: Heterotrimeric G proteins play a pivotal role in postreceptor information transduction. These proteins were previously implicated in the pathophysiology and treatment of mood and other neuropsychiatric disorders. Recently we showed that untreated patients with schizophrenia have a significantly elevated dopamine-induced Gs protein function which is correlated with the severity of the psychotic symptoms. In contrast, an inverse picture with reduction in the function and the immunoreactivity of Gs protein was detected in patients with Parkinson's disease. The present study aims at investigating the effect of antipsychotic medications on dopamine-induced Gs protein hyperfunction in schizophrenia comparing the classical antipsychotic haloperidol and the newer antipsychotic clozapine, which is devoid of extrapyramidal side effects, on G protein measures. METHODS: G protein functional measurements coupled to beta-adrenergic, muscarinic, and dopamine receptors were undertaken through bacterial toxin sensitive, agonist enhanced [3H]-Gpp(NH)p binding capacity, substantiated by quantitative measures of Gs alpha, Gi alpha, and G beta subunit proteins through immunoblot analysis in mononuclear leukocytes obtained from patients with schizophrenia under haloperidol, or clozapine treatments in comparison with untreated patients with schizophrenia and healthy volunteers. RESULTS: Dopamine-induced Gs hyperfunction characteristic of untreated patients with schizophrenia was not detected under antipsychotic treatment with either haloperidol or clozapine. Haloperidol caused a significant decrease in Gs function and immunoreactivity below normal levels. The extend of reduction in Gs function was found to be correlated with the intensity of extrapyramidal side effects. The pattern of G protein subunits levels in patients with schizophrenia under haloperidol treatment resembles the one obtained in patients with Parkinson's disease. CONCLUSIONS: In the present study it is shown that G protein measurements in patients with schizophrenia under antipsychotic treatments can be used to biochemically monitor effects of antipsychotic medications in living patients. Moreover, these measurements may be used also for monitoring parkinsonian side effects induced by antipsychotic medications.

Adult↗
PubMed2001

Dynamic analysis of inter-words time intervals: a method to analyze the structure of communicative signals.

Speech analyses are usually focused on words as signifiers ignoring inter-words time intervals (IWIs), which are related to the 'form' of speech, rather than to its 'content'. Applying the method of power spectrum analysis to inter-vocalizations time intervals of bird singing, underlying periodic processes were detected. In contrast, human IWIs revealed non-periodicity, which may be random or chaotic. To differentiate between these two possibilities, the non-linear dynamic methods of unstable periodic orbits and correlation dimension were applied to show that IWIs are characterized by a low dimensional chaotic attractor. Its correlation dimension of 3.2 +/- 1.1 suggests a minimum number of four variables underlying the system. The methods developed in the present communication can be further applied: (a) for the measurement of specific alterations in the processes underlying the form of speech in human disorders, i.e., schizophrenia, (b) for the assessment of normal and pathological developmental aspects of speech processes in children; (c) for comparing communicative signals between humans and other species.

Adult↗
PubMed2000

G protein levels and function as an objective measure of depression in patients with functional bowel disorders.

Heterotrimeric G proteins play a pivotal role in postreceptor information transduction. These proteins have been implicated in the pathophysiology, diagnosis, and treatment of mood disorders and proposed as a state-dependent biochemical mood marker in mononuclear leukocytes. Irritable bowel syndrome (IBS) is associated with changes in mood, affecting patients' illness perceptions and behavior. We examined whether mononuclear leukocytes of patients with IBS have altered G protein measures. We undertook G protein functional measurements through agonist-enhanced [3H]Gpp(NH)p binding capacity and quantitative measures by immunoblot analysis using anti-Galpha antibodies in mononuclear leukocytes obtained from 19 IBS patients (Rome criteria) and 19 healthy matched subjects. The study groups were similar in age, gender, and years of education. Mononuclear leukocyte functions of G(s) (21.3+/-8.3%) and G(i) (22.2+/-6.7%) proteins in IBS patients were similar to healthy subjects (24.8+/-4.7 and 25.2+/-4.0%, respectively). The relative immunoreactivities of the G(sa) (98.9+/-10.2%) and the G(ia) (104.2+/-11.5%) subunit proteins in mononuclear leukocytes of IBS patients were also similar to those in healthy subjects. Two patients clinically diagnosed as depressed were detected by the G protein assay. The results lend objective support to the contention that major depression is not a causative factor in IBS, nor associated with its severity. The G protein assay may provide an objective biochemical tool for detecting depression in IBS, differentiating it from psychological distress that is commonly diagnosed by subjective tests.

Adult↗
PubMed2000

G proteins as a biochemical tool for diagnosis and monitoring treatments of mental disorders.

There is a significant gap between advances in medication for mental disorders and the present static situation of diagnosis and monitoring treatments of these disorders. Heterotrimeric G proteins play a pivotal role in postreceptor information transduction. These proteins were previously implicated by us in the biochemical mechanism underlying lithium action, and in the pathophysiology of mood disorders. We aimed at quantitatively and functionally evaluating G proteins in patients with major mental disorders in an attempt to unravel a differential pattern of G protein measures characterizing each disorder. We undertook G protein functional measurements coupled to beta-adrenergic, muscarinic or dopamine receptors through bacterial toxin-sensitive, agonist-enhanced [3H]-Gpp(NH)p binding capacity, substituted by quantitative measures of G alpha s, G alpha i, and G beta subunit proteins through immunoblot analysis using polyclonal anti-G submit antibodies in mononuclear leukocytes obtained from patients with major mental disorders in comparison with healthy volunteers. A differential pattern of receptor coupled G protein function and of their immunoreactive levels were detected in mononuclear leukocytes of patient s for the following mental disorders: mania, depression, schizophrenia, and panic. Normalization of altered G protein measures in mood-disorder ed patients occurred under specific treatments. As state-dependent markers, G protein measures can potentially be used as an aid in both the biochemical diagnosis of mental disorders and in the biochemical monitoring of the response to a specific treatment.

GTP-Binding Proteins↗
PubMed1999

The effects of seasons and light therapy on G protein levels in mononuclear leukocytes of patients with seasonal affective disorder.

BACKGROUND: Information-transducing heterotrimeric G proteins have been implicated previously in the mechanism of action of mood stabilizers and in the pathophysiology of mood disorders. Mononuclear leukocytes of patients with unipolar and bipolar depression have been characterized by reduced measures of the stimulatory and inhibitory G proteins. In this study, patients with seasonal affective disorder (SAD) were measured for mononuclear leukocyte G protein levels while depressed during the winter, following light therapy, and in remission during the summer. METHODS: Twenty-six patients with SAD and 28 healthy subjects were assessed in the study. The immunoreactivities of Gs alpha, Gi alpha, and Gbeta subunit proteins were determined by Western blot analysis of mononuclear leukocyte membranes with selective polyclonal antibodies for the various G subunit proteins, followed by densitometric quantitation using an image analysis system. RESULTS: Untreated patients with SAD and winter, atypical-type depression showed significantly reduced mononuclear leukocyte immunoreactive levels of Gs alpha and Gi alpha proteins, similar to previous observations in patients with nonseasonal major depression. The reduced G protein levels were normalized with 2 weeks of light therapy. The same patients while in remission during the summer had G protein levels that were similar to those of healthy subjects. CONCLUSIONS: G protein-immunoreactive measures in patients with SAD are suggested as a state marker for winter depression, which is normalized by light treatment and during the summer. We speculate that light may exert its effects via normalization of transducin (Gt protein) levels, which are thought to be reduced in winter depression.

Adult↗
PubMed1999

The role of G proteins in the psychobiology and treatment of affective disorders and their integration with the neurotransmitter hypothesis.

Heterotrimeric G proteins are a crucial point of convergence in the transmission of signals from a variety of primary messengers and their membrane receptors to downstream intracellular second messenger effector enzymes and ionic channels. Thus, these proteins have raised increasing interest in the clinical perspective of altered G protein function. This article addresses the most recent significant findings regarding the role of G proteins in the pathophysiology of mood disorders and in the molecular mechanisms underlying the treatment of these disorders, with emphasis on biochemical and genetic approaches.

Antimanic Agents↗
PubMed1998

Dynamics of ECT normalization of low G protein function and immunoreactivity in mononuclear leukocytes of patients with major depression.

OBJECTIVE: Heterotrimeric G proteins were previously implicated in the biochemical mechanisms underlying the pathophysiology and treatment of mood disorders. Low function and immunoreactivity of G proteins were observed in patients with major depression. In the present study the authors evaluated the effects of ECT on the low measures of G proteins in patients with major depression. METHOD: Repeated G protein measurements in mononuclear leukocytes of 10 patients with major depression were made. Each patient was examined while untreated and after successive sessions of ECT; 14 normal subjects were also studied. G protein function was evaluated through beta-adrenergic- and muscarinic-agonist-enhanced guanine nucleotide binding capacity, substantiated by quantitative measures of G proteins through immunoblot analyses using polyclonal antibodies against Gs alpha, Gi alpha, and G beta proteins. RESULTS: Mononuclear leukocytes of patients with depression showed immunoreactive levels of Gs alpha and Gi alpha that were significantly lower than those of normal subjects; the depressed patients also had markedly hypofunctional Gs and Gi. The low levels of G protein function and immunoreactivity were alleviated by ECT. Repeated measurements in the same patients after successive ECT sessions showed that the normalization of G protein measures preceded, and thus predicted, clinical improvement. The function and quantity of Gs and Gi proteins in patients given ECT were significantly correlated. CONCLUSIONS: These findings support the implication of G proteins in the pathophysiology and treatment of mood disorders. G protein measurements in patients with depression may potentially serve not only as a biochemical marker for affective state but also for biochemical prediction and evaluation of responses to ECT.

Biomarkers↗
PubMed1997

Reduced Gs protein function and G alpha s levels in leukocytes of patients with Parkinson's disease.

Early events in signal information transduction beyond dopamine, beta-adrenergic, and muscarinic receptors, involving receptor-coupled G-protein function and G alpha subunit immunoreactive levels were measured in mononuclear leukocytes (MNLs) of 12 never-treated patients with Parkinson's disease in comparison with 10 age- and sex-matched healthy control subjects. Both beta-adrenergic and dopamine receptor-coupled Gs protein function as measured by cholera toxin-sensitive, isoproterenol- and dopamine-induced increases in Gpp(NH)p-binding capacity, in MNLs of patients with Parkinson's disease were found to be significantly reduced in comparison with those in the control group. Muscarinic receptor-coupled non-Gs (Gi or G(o)) protein function: pertussis toxin-sensitive, carbamylcholine-induced increase in Gpp(NH)p-binding capacity, was not found to be significantly different between patients with Parkinson's disease and control subjects. G protein alpha subunits were measured through immunoblotting analyses with specific polyclonal antibodies against G alpha s, G alpha i, and G alpha q subunits. MNL levels of the 45-kDa species of G alpha s were found to be significantly reduced in patients with Parkinson's disease in comparison with control subjects. Other non-Gs proteins (Gi, Gq) did not show any significant quantitative differences between patients with Parkinson's disease and control subjects. The reductions in G alpha s levels in MNLs of patients with Parkinson's disease may explain the beta-adrenergic and dopamine receptor-coupled Gs protein hypofunction detected in MNLs of these patients. As previous studies have failed to observe significant changes in receptor levels in MNLs of patients with Parkinson's disease, our findings of reduced dopaminergic and beta-adrenergic receptor-coupled Gs function and of G alpha s immunoreactive levels in MNLs of Parkinson's patients point to alterations distal to these receptors at the level of the signal-transducing Gs protein.

Adult↗
PubMed1997

Differential G protein measures in mononuclear leukocytes of patients with bipolar mood disorder are state dependent.

Quantitative and functional measurements of G proteins were undertaken in mononuclear leukocytes of bipolar disordered patients comparing bipolar depressed with manic patients groups in order to verify whether any alterations observed in G protein functional or immunoreactive measures in bipolar mood disorder are state- or trait-dependent characteristics. Compared with the control group of 30 subjects, isoproterenol- and carbamylcholine-enhanced Gpp(NH)p binding capacities were highly significantly increased in the group of 20 manic patients, while highly significantly reduced in the group of 11 bipolar depressed patients. While manic patients showed highly significant elevations in mononuclear leukocytes levels of G alpha s and G alpha i, evaluated through immunoblot analysis using specific polyclonal antibodies against the subunit proteins, mononuclear leukocytes of bipolar depressed patients show significant reductions in G alpha s and G alpha i immunoreactive levels. G beta subunit levels were found to be similar in all three groups. The changes in G protein measures observed in mononuclear leukocytes of mood disordered patients thus represent state characteristics of the disorder.

Adult↗
PubMed1997

Photoperiodicity and annual rhythms of wars and violent crimes.

The seasonal variations of individual violent crimes, i.e. sexual offenses and aggravated assaults, and non-violent offenses, i.e. burglary, in Israel, the USA, Denmark and New South Wales, Australia, representing four continents, were analyzed. Seasonal variations in the opening dates of wars were similarly analyzed. In northern hemisphere countries, although non-violent offenses are distributed equally throughout the year, individual violent crimes and collective acts of hostility are characterized by an annual rhythm of incidence, with a peak in the months of July-August and a nadir in December-February. Inverse rhythms were obtained in southern hemisphere countries. These rhythms were found to be correlated in a statistically significant manner with the duration of the daily photoperiod. The existence of similar patterns of annual variations in violent crimes and in the opening dates of wars indicate similarities between individual and collective aggressiveness with respect to the underlying mechanisms and probably also to the means of their prevention.

Aggression↗
PubMed1997

Reduced G protein functions and immunoreactive levels in mononuclear leukocytes of patients with depression.

OBJECTIVE: Heterotrimeric G proteins play a pivotal role in postreceptor information transduction. These proteins were previously implicated in the biochemical mechanism underlying lithium action and in the pathophysiology of mood disorders. The present study sought to quantitatively and functionally evaluate G proteins in patients with major depression. METHOD: G proteins were measured in mononuclear leukocytes of 37 untreated patients with major depression and 31 comparison subjects. Receptor-coupled G protein function was evaluated through beta-adrenergic and muscarinic-agonist-induced increases in guanine nucleotide binding capacity, which were substantiated by quantitative measures of G proteins through immunoblot analyses that used polyclonal antibodies against stimulatory (Gs alpha) and inhibitory (Gi alpha) G proteins. RESULTS: Mononuclear leukocytes of depressed patients showed significantly reduced immunoreactive quantities of Gs alpha and Gi alpha together with markedly hypofunctional Gs and Gi. The reductions in both function and quantity of Gs and Gi were significantly correlated with the severity of depressive symptoms. Moreover, simultaneous quantitative and functional measurements in a large number of patients showed significant correlations between the function and the quantity of mononuclear leukocyte Gs and Gi proteins: CONCLUSIONS: These findings lend further support to the implication of G proteins in the pathophysiology of mood disorders. G protein functional and quantitative measurements in mononuclear leukocytes of patients with mood disorders may potentially serve as a biochemical marker for the affective state of these patients.

Adult↗
PubMed1996

Reduced beta-adrenergic receptor-coupled Gs protein function and Gs alpha immunoreactivity in mononuclear leukocytes of patients with depression.

beta-Adrenergic receptor-coupled Gs protein function was measured in 26 depressed patients through cholera toxin-sensitive, isoproterenol-induced increases in 3H-Gpp(NH)p binding capacity to mononuclear leukocytes (MNL). Highly significant reductions in receptor-coupled Gs protein function were observed in the depressed patients: 2.0 +/- 1.3% increases in guanine nucleotide-binding capacity, in comparison with the control group values of 28.3 +/- 6.9%. Similar reductions in Gs protein function were detected in both uni- and bipolar depressed patients. A significant negative correlation was found between receptor-coupled Gs protein measures and the severity of depression. Adding semiquantitative measures of MNL Gs alpha through immunoblot analysis by use of polyclonal antibodies against Gs alpha subunit, it was found that Gs alpha relative immunoreactivity was reduced from 100 +/- 2.0% in the control group of subjects to 75.9 +/- 2.3% in the depressed patients. We have previously described hyperfunctional Gs proteins in leukocytes of patients with mania. The present findings of reduced function of Gs in depressed patients suggests receptor-coupled Gs protein activity as a biochemical parameter indicatory of the affective state. Reduced receptor-coupled Gs protein function may reflect reduced levels of the beta-adrenergic receptor previously shown in leukocytes of depressed patients; however, our complementary immunoblot studies suggest a direct, postreceptor, quantitative, and functional reduction in Gs protein in MNL of depressed patients.

Adult↗
PubMed1996

Measurement of early events in signal transduction beyond receptors involving G proteins function in mononuclear leucocytes.

G protein function in human mononuclear leucocytes was measured through isoproterenol, carbamylcholine and dopamine-enhanced 3H-Gpp(NH)p binding. Dopamine and carbamylcholine exerted their effects through D5 and M2 receptors, respectively. ADP-ribosylation by bacterial toxins indicates that dopamine and isoproterenol affected Gs, while carbamylcholine affected Gi. Quantitative G proteins measures were conducted through immunoblot analyses with specific polyclonal antibodies against G alpha s, and G alpha i subunits. Simultaneous functional and quantitative measures of G proteins showed significant correlations between function and immunoreactivities. Agonist-enhanced guanine nucleotide exchange is thus suggested as a method for measurement of early events in signal transduction beyond receptors in leucocytes, which can potentially serve for detecting alterations in G proteins measures in human disease.

Adenylyl Cyclases↗
PubMed1992

Ziskind-Somerfeld research Award. The involvement of guanine nucleotide binding proteins in the pathogenesis and treatment of affective disorders.

Guanine nucleotide binding (G) proteins play a pivotal role in postreceptor information transduction. An important characteristic of G proteins is their increased guanine nucleotide binding following agonist stimulation, which in turn leads to their activation. We have developed a method that enables the measurement of early events in signal transduction beyond receptors, through activated receptor-coupled guanine nucleotide exchange on G proteins. Using this method, lithium was recently demonstrated to inhibit the coupling of both muscarinic cholinergic and beta-adrenergic receptors to pertussis toxin-sensitive and cholera toxin-sensitive G proteins, respectively, thus suggesting alteration of the function of G protein by lithium, as the single site for both the antimanic and antidepressant effects of this drug. One of the most puzzling aspects of the ability of lithium to ameliorate the manic-depressive condition is its relatively selective action upon the central nervous system (CNS). It was previously shown that lithium selectively attenuated the function of Gs proteins in the CNS. In the present study, we show that inhibition by lithium of muscarinic receptor-coupled G protein function is also selective to the CNS. The clinical profile of lithium, carbamazepine, and electroconvulsive treatment (ECT), agents that are effective in the prevention and treatment of bipolar affective disorder, differs from that of purely antidepressant drugs. Antidepressant drugs are effective in the acute treatment and prevention of depression only, and can even precipitate hypomanic or manic "switches," or "rapid cycling" between mania and depression. We have investigated and compared the effects of chronic antibipolar and antidepressant treatments on receptor-coupled G protein function. Antibipolar treatments (lithium, carbamazepine, ECT) attenuate both receptor-coupled Gs and non-Gs (i.e., Gi, Go) proteins function; in contrast, only Gs protein function is inhibited by antidepressant drugs [either tricyclics or monoamine oxidase (MAO) inhibitors]. Moreover, an integral adrenergic neuronal system is required for antidepressant inhibition of Gs protein function, as pretreatment with the noradrenergic neurotoxin DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine) specifically abolishes the effects of antidepressant drugs on Gs protein, whereas antibipolar drug effects on G protein function are unaffected by DSP-4. Our results suggest that attenuation of beta-adrenergic receptor-coupled Gs protein function, which is common to both antidepressant and antibipolar treatments, may be the mechanism underlying their antidepressant therapeutic efficacy.(ABSTRACT TRUNCATED AT 400 WORDS)

Antidepressive Agents↗
PubMed1991

Hyperfunctional G proteins in mononuclear leukocytes of patients with mania.

In a recent study, we found that lithium inhibits the function of guanine nucleotide-binding proteins, implicating G proteins as the common site for both the antimanic and antidepressant therapeutic effects of lithium. These findings may also suggest that an altered G protein function is of pathophysiological importance in bipolar affective disorder. In the present study, the coupling of both muscarinic-cholinergic receptors and beta-adrenergic receptors to pertussis toxin-sensitive G proteins or cholera toxin-sensitive G proteins was compared among untreated manic patients, lithium-treated euthymic bipolar patients, and healthy volunteers using mononuclear leukocyte (MNL) membrane preparations. Hyperactive function of G proteins was detected in untreated manic patients. Both isoproterenol-induced and carbamylcholine-induced increases in Gpp(NH)p binding capacity were twofold to threefold higher than the increases observed in healthy volunteers. On the other hand, lithium-treated euthymic bipolar patients showed G protein responses to agonist activation that were no different from the healthy volunteers. Altered G protein function may be of pathophysiological importance in bipolar affective disorder.

Adenosine Diphosphate↗