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Biomedical subjects

G Agam

Publications and source records attributed to G Agam.

At least 19 recordsLinked to original sources
PubMed2006

Elevated urinary ADAM12 protein levels in lithium-treated bipolar patients.

ADAM (A Disintegrin And Metalloprotease)12 is a member of a family of integral membrane and secreted glycoproteins. ADAM12 has recently been detected in urine. In the present study we measured ADAM12 protein levels in urine from bipolar patients vs. healthy controls. Nineteen bipolar patients and 22 matched-control subjects were studied. Urine samples were concentrated and Western-blot analysis used to determine ADAM12 protein levels. The 92 kDa form of urine ADAM12 protein levels were highly elevated in Li-treated bipolar patients compared with normal controls. The 68 kDa form of urine ADAM12 protein levels did not differ. Future experiments are needed to explore a potential link between ADAM12 protein level elevation and lithium response.

ADAM Proteins↗
PubMed2006

Behavioural phenotyping of sodium-myo-inositol cotransporter heterozygous knockout mice with reduced brain inositol.

Inositol plays a key role in dopamine, serotonin, noradrenaline and acetylcholine neurotransmission, and inositol treatment is reported to have beneficial effects in depression and anxiety. Therefore, a reduction in brain intracellular inositol levels could be a cause of some psychiatric disorders, such as depression or anxiety. To determine the behavioural consequences of inositol depletion, we studied the behaviour of sodium-dependent myo-inositol cotransporter-1 heterozygous knockout mice. In heterozygous mice, free inositol levels were reduced by 15% in the frontal cortex and by 25% in the hippocampus, but they did not differ from their wild-type littermates in cholinergic-mediated lithium-pilocarpine seizures, in the apomorphine-induced stereotypic climbing model of dopaminergic system function, in the Porsolt forced-swimming test model of depression, in amphetamine-induced hyperactivity, or in the elevated plus-maze model of anxiety. Reduction of brain inositol by more than 25% may be required to elicit neurobehavioural effects.

Analysis of Variance↗
PubMed2005

CSF homocysteine is not elevated in schizophrenia.

Homocysteine is a neurotoxic amino acid originally found to be an independent risk factor for cardiovascular and cerebral vascular disease and more recently suggested to be a risk factor for Alzheimer's disease. Several authors have observed high plasma homocysteine levels among schizophrenia patients. We reported that such high levels characterize young male schizophrenia patients. We now studied two groups of schizophrenia patients (N=41) and controls (N=29) for CSF homocysteine levels. No difference was found for CSF homocysteine levels between schizophrenia patients and controls (p=.041 for Study A and p=.52 for Study B).

Adolescent↗
PubMed2004

Reduced GSK-3beta mRNA levels in postmortem dorsolateral prefrontal cortex of schizophrenic patients.

Glycogen Synthase Kinase (GSK)-3 is a ubiquitous serine/threonine protein kinase highly abundant in brain which plays a key role in neural development and neuron survival. We have previously reported that GSK-3beta protein levels and GSK-3 activity are reduced by over 40% in postmortem prefrontal cortex of schizophrenic patients compared to patients with bipolar illness, unipolar depression and to normal controls, and Emamian et al. have recently presented convergent evidence for impaired AKT1-GSK-3beta signaling in schizophrenia. Using specimens of dorsolateral prefrontal cortex tissue obtained from The Stanley Medical Research Institute's Brain Collection, from the same subjects used previously, we now show that GSK-3beta, but not GSK-3alpha, mRNA levels are 36% lower in the patients with schizophrenia compared to all other comparison groups. The present study lends further support to the finding of low GSK-3beta levels in schizophrenia and extends this observation by suggesting that the decrease in GSK-3beta may be due to reduced protein synthesis possibly due to altered transcriptional drive of the GSK-3beta gene.

Adult↗
PubMed2004

GSK-3beta in cerebrospinal fluid of schizophrenia patients.

Cerebrospinal fluid contains proteins and metabolites of brain origin and was extensively studied in psychiatry in the 1970's with few definitive results. We have recently found 40% reduced protein levels of GSK-3beta in schizophrenia in postmortem prefrontal cortex, but our attempt to develop a diagnostic marker using peripheral lymphocyte GSK-3beta was not successful. In this study we aimed to find whether the reduction in brain GSK-3beta is reflected in CSF of schizophrenia patients. We report a significant reduction in CSF GSK-3beta protein levels in six schizophrenia patients compared to seventeen healthy subjects. Our results corroborate other studies in which CSF protein levels reflect the alteration found in these proteins in schizophrenia patients' postmortem brain.

Adult↗
PubMed2004

A molecular cell biology of lithium.

Lithium (Li(+)), a mood stabilizer, has profound effects on cultured neurons, offering an opportunity to investigate its cellular biological effects. Here we consider the effect of Li(+) and other psychotropic drugs on growth cone morphology and chemotaxis. Li(+) inhibits GSK-3 (glycogen synthase kinase-3) at a therapeutically relevant concentration. Treated cells show a number of features that arise due to GSK-3 inhibition, such as altered microtubule dynamics, axonal branching and loss of semaphorin 3A-mediated growth cone collapse. Li(+) also causes growth cones to spread; however, a similar effect is seen with two other mood stabilizers, valproic acid and carbamazepine, but without changes in microtubules or axon branching. This common effect of mood stabilizers is mediated by changes in inositol phosphate signalling, not GSK-3 activity. Given the presence of neurogenesis in the adult brain, we speculate that changes in growth cone behaviour could also occur during treatment of mental disorders.

Animals↗
PubMed2004

Genetic correlational analysis of glycogen synthase kinase-3 beta and prepulse inhibition in inbred mice.

In humans, GSK-3 beta activity is diminished in schizophrenic patients as is prepulse inhibition of the startle response (PPI). We performed a genetic correlational analysis between published PPI values and frontal cortex GSK-3 activity analyzed in our laboratory in 10 inbred mouse strains. This methodology could indicate relevant parameters for study in an animal model. Indeed, we obtained significant correlations between the enzyme's activity and PPI measured by two different methods. This may indicate that investigation of the genetics of GSK-3 beta regulation holds promise for understanding some of the biochemical underpinnings of schizophrenia.

Animals↗
PubMed2002

Reduced inositol content in lymphocyte-derived cell lines from bipolar patients.

OBJECTIVES: The study aimed to determine whether low inositol content and uptake previously reported in brain and peripheral tissue of bipolar patients are also reflected in lymphocyte-derived cell lines from these patients. METHODS: Inositol content and uptake were studied in lymphocyte-derived cell lines grown in vitro for at least five generations to eliminate influences of drug treatment. Inositol content was studied gas chromatographically and inositol uptake by following 3H-inositol incorporation at various concentrations. RESULTS: Inositol levels of cell lines derived from bipolar patients were significantly lower than those of cell lines from controls. CONCLUSIONS: Low inositol content in lymphocyte-derived cell lines from bipolar patients corroborates previous findings in frontal cortex and in lymphoblastoid cell lines and are consistent with the notion that the phosphatidylinositol signaling system is involved in the pathophysiology of this disorder.

Bipolar Disorder↗
PubMed2002

3'(2')-phosphoadenosine 5'-phosphate phosphatase is reduced in postmortem frontal cortex of bipolar patients.

OBJECTIVE: 3'(2')-Phosphoadenosine 5'-phosphate (PAP) phosphatase is a novel lithium (Li) inhibitable enzyme. Thus the enzyme seemed an important candidate for studies of the molecular etiology of bipolar disorder. METHODS: RT-PCR, Western-blot analysis and Pi liberation were used to measure PAP phosphatase mRNA levels, protein levels and enzyme activity (respectively) in postmortem frontal cortex specimens of bipolar patients versus normal subjects. RESULTS: The PAP phosphatase protein levels were 24% significantly lower in bipolar patients than in normal subjects. PAP phosphatase mRNA levels and enzymatic activity did not differ between normal controls and bipolar patients. CONCLUSIONS: Abnormality of PAP phosphatase in bipolar patients offers a new direction for study of bipolar disorder etiology.

Adult↗
PubMed2001

Low GSK-3 activity in frontal cortex of schizophrenic patients.

Glycogen synthase kinase-3 (GSK-3) (EC 2.7.1.37) is a protein kinase highly abundant in brain and involved in signal transduction cascades of multiple cellular processes, particularly neurodevelopment. Two forms of the enzyme, GSK-3alpha and -3beta have been previously identified. We have previously reported reduced GSK-3beta protein levels in postmortem frontal cortex of schizophrenic patients. In an attempt to explore whether reduction of GSK-3beta levels is brain region specific we examined it in occipital cortex. In order to find out if the reduction in frontal cortex is reflected in altered activity we measured GSK-3 enzymatic activity in this brain region. Western-blot analysis of GSK-3beta was carried out in postmortem occipital cortex of 15 schizophrenic, 15 bipolar, and 15 unipolar patients, and 15 normal controls. GSK-3 activity was measured by quantitating the phosphorylation of the specific substrate phospho-CREB in the frontal cortex specimens. GSK-3beta levels in occipital cortex did not differ between the four diagnostic groups. GSK-3 activity in the frontal cortex of schizophrenic patients was 45% lower than that of normal controls (0.196+/-0.082 and 0.357+/-0.084 pmol/mg proteinxmin, respectively; Kruskal-Wallis analysis: chi-square=8.27, df=3, p=0.04). The other two diagnostic groups showed no difference from the control group. Our results are consistent with the notion that schizophrenia involves neurodevelopmental pathology.

Bipolar Disorder↗
PubMed2001

Characterization of two genes, Impa1 and Impa2 encoding mouse myo-inositol monophosphatases.

The enzyme myo-inositol monophosphatase (Impa) catalyzes the synthesis of free myo-inositol from various myo-inositol monophosphates in the phosphatidylinositol signaling system. Impa is a lithium-blockable enzyme that has been hypothesized to be the biological target for lithium-salts used as mood-stabilizing drugs in the treatment of manic-depressive (bipolar) illness. As an initial step to explore the functional consequences of reduced or absent Impa activity in an animal model we here report the isolation of two Impa-encoding mouse genes, Impa1 and Impa2. Impa1 spans approximately 17.5 kb and contains nine exons of 46--1354 bp encoding a protein of 277 amino acids. Impa2 spans at least 19.5 kb and contains eight exons of 46--444 bp size encoding a protein of 290 amino acids. The genomic structure including the positions of the exon-intron splice sites seems to be conserved among myo-inositol monophosphatase genes in mammalian species. One or more Impa-like genes do also exist in evolutionary more distant species like invertebrates, plants and bacteria. The proteins encoded by the non-vertebrate genes seem to be equally related to Impa1 and Impa2. We therefore suggest that the Impa1 and Impa2 genes duplicated from a common ancestral gene after the evolutionary divergence of vertebrates.

Animals↗
PubMed2001

The mechanism of lithium action: state of the art, ten years later.

Lithium is an effective drug for both treatment and prophylaxis of bipolar disorder. However, the mechanism of lithium action is still unknown. The inositol depletion hypothesis is supported by biochemical and behavioral data in rats, but primate inositol levels are higher than in rodents and may obviate the effects of depletion. Inhibition of 5HT autoreceptors by lithium is supported by biochemical and behavioral data in rats but would seem more related to lithium's antidepressant than to its antimanic or prophylactic effects. Lithium induces increases in levels of the anti-apoptotic factor Bcl-2. This effect could be most relevant for treatment of neurodegenerative disorders. Lithium inhibits glycogen synthase kinase-3, which is involved in a wide range of signal transduction pathways. However, this lithium effect occurs at high concentrations and may be more relevant for its toxic effect. Lithium in low concentrations induces accumulation of PAP, which affects several cellular processes including RNA processing. However, PAP phosphatase is present more in peripheral tissues than in brain. This lithium effect could explain some of its peripheral side effects. Chronic lithium administration upregulates glutamate reuptake and thus decreases glutamate availability in synapse. Glutamate is an excitatory neurotransmitter and its reduction could exert an antimanic effect. Biochemical and clinical experiments are necessary to determine the key mechanism of lithium efficacy in treatment and prophylaxis of affective disorders.

5'-Nucleotidase↗
PubMed2001

Inositol monophosphatase activity in brain and lymphocyte-derived cell lines of bipolar patients.

BACKGROUND: Inositol monophosphatase (IMPase) activity was reported to be low in lymphocyte-derived cell lines of bipolar patients. METHODS: IMPase activity was measured spectrophotometrically as inorganic phosphate liberated from inositol-1-phosphate. RESULTS: The previously reported reduction was replicated in a new, small group of bipolar patients. The reduction is not present in cell lines of unipolar or schizophrenic patients. IMPase activity in postmortem frontal and occipital cortical samples of unipolar, bipolar and schizophrenic patients was not different from controls. CONCLUSIONS: A reduction in lymphocyte-derived IMPase activity without a parallel reduction in cortical IMPase activity could be due to the fact that most leukocyte IMPase activity is the product of the IMPA-2 gene.

Adult↗
PubMed2000

Scyllo-inositol in post-mortem brain of bipolar, unipolar and schizophrenic patients.

Inositol levels measured in postmortem brain of unipolar, bipolar and schizophrenic patients, suicide victims and normal controls showed no difference in scyllo-inositol levels in frontal or occipital cortex between any of the groups. We could not replicate previous reports of low myo-inositol levels in the frontal cortex of unipolar, bipolar and schizophrenic patients and suicide victims. There was no correlation between myo-inositol levels and estimated chlorpromazine equivalents in neuroleptic-treated subjects, and no effect of chronic haloperidol treatment on rat brain myo-inositol levels.

Adolescent↗
PubMed2000

Low GSK-3beta immunoreactivity in postmortem frontal cortex of schizophrenic patients.

OBJECTIVE: Glycogen synthase kinase-3 (GSK-3) is a protein kinase that is highly abundant in the brain. It is involved in signal transduction cascades of multiple cellular processes, particularly neurodevelopment. In an attempt to explore possible involvement of GSK-3beta in psychiatric disorders, the authors examined its levels in postmortem brain tissue. METHOD: Western blot analysis was performed to measure GSK-3beta in the frontal cortex of 14 schizophrenic patients, 15 patients with bipolar disorder, 15 patients with unipolar depression, and 14 normal comparison subjects. RESULTS: GSK-3beta levels were 41% lower in the schizophrenic patients than in the comparison subjects. Other diagnostic groups did not differ from the comparison subjects. CONCLUSIONS: These results are consistent with the notion that schizophrenia involves neurodevelopmental pathology. It remains to be investigated whether the active fraction of GSK-3beta, or its activity, is also low in frontal cortex of schizophrenic patients and if this is also reflected in other brain regions.

Adult↗
PubMed1998

Inositol levels are decreased in postmortem brain of schizophrenic patients.

BACKGROUND: A previous study reported decreased levels of inositol in frontal cortex of postmortem brain from bipolar patients and suicide victims. The aim of the present study was to test the specificity of this finding. METHODS: Inositol and the enzyme that synthesizes it, inositol monophosphatase, were measured in postmortem brain tissue from frontal and occipital cortex and cerebellum from 10 schizophrenic patients and the previously reported controls. Inositol levels were assayed gas-chromatographically as trimethylsilyl derivatives with mannitol as an internal standard. Inositol monophosphatase activity in brain homogenates was measured as the difference between phosphate release from inositol-l-phosphate in the absence and in the presence of Li+. RESULTS: Inositol was significantly reduced in all three areas in the schizophrenic patient' brains: inositol monophosphatase was unchanged. Postmortem interval did not correlate with inositol levels and did not differ between control group and schizophrenic patients. CONCLUSIONS: These results suggest an abnormality of second messenger precursor availability in common with schizophrenia and affective psychopathology.

Aged↗
PubMed1998

Chronic dietary inositol enhances locomotor activity and brain inositol levels in rats.

myo-Inositol has been found to be clinically effective in depression, obsessive compulsive disorder (OCD) and panic disorder when given chronically per os. The present study examined the effects of chronic dietary inositol in rats on locomotor behaviour. Regional brain levels of inositol were analyzed by gas chromatography. Chronic dietary inositol significantly enhanced locomotion and rearing in rats and elevated inositol levels by 36% in the cortex and 27% in hippocampus. No differences in inositol levels were found in the striatum or cerebellum. The stimulatory effects of inositol may be related to its effects as an atypical antidepressant in depressed patients.

Analysis of Variance↗