Search PubMed⌕ Search

Biomedical subjects

F Karege

Publications and source records attributed to F Karege.

At least 19 recordsLinked to original sources
PubMed2001

Differential changes of cAMP-dependent protein kinase activity and 3H-cAMP binding sites in rat hippocampus during maturation and aging.

The cyclic AMP-dependent protein kinase (PKA) has been involved in the brain aging process and recent papers have reported age-associated changes in enzyme activity in rat brain. The present study was undertaken to assess simultaneously PKA activity and regulatory (R) subunit levels during maturation and aging. Five cohorts of rats of different ages were used, namely pups of 1 week and 3 weeks old, mature rats (2 months), postmature rats (1 year) and old rats (2 years or more). PKA activity and 3H-cAMP binding sites were determined in cytosolic fractions of hippocampus. Results showed a low PKA activity in newborn rats which increased in mature and postmature rats and finally declined in old rats (ANOVA, P<0.001). The maximum binding sites (Bmax) of 3H-cAMP which measure the PKA R subunit levels were elevated in newborn rats and declined in mature and old rats (ANOVA; P<0.001). It is suggested the changes in PKA R subunit levels reflect an adaptative role in maturing process, a role which is lost in aging phase.

Aging↗
PubMed2001

A non-radioactive assay for the cAMP-dependent protein kinase activity in rat brain homogenates and age-related changes in hippocampus and cortex.

Cyclic AMP-dependent protein kinase (PKA) activity was involved in a number of brain functions such as cognitive process or aging. The measurement of PKA activity is traditionally based on the use of [(32)P]ATP in phosphorylation of specific protein. Recently non-isotopic PKA assays have been developed, but none has been tested on brain homogenates. This work aimed to adapt a fluorimetric method of PKA activity into a novel assay never applied before in brain homogenate, and to characterize the enzyme activity and ratio in hippocampus and cortex from rats of different ages. Optimal conditions of homogenization and enzyme protection were determined. The method was sensitive and reproducible (intra-assay and interassay variation was 5.0% and 9.0%, respectively). In hippocampal cytosol, PKA activity was 27+/-8 and 80+/-9 nmol/min per mg protein in basal and cAMP-stimulated activity, respectively, and accounted for 80% of total cell PKA activity. The non-PKA activity, assessed by the use of the PKA specific inhibitor (PKI) accounted for 49.0% and 65.0% of endogenous levels in cytosol and membrane, respectively. cAMP-augmenting drugs effects were measured and increase of 53%, 273% and 118% over basal by 10 microM isoproterenol, 100 microM forskolin, 1 microM Sp-AMP, respectively, was observed. With respect to the changes in animal age, PKA activity increased from newborn to the mature rats but decreased in older rats. The PKA ratio was higher in cytosol than in particulate fraction, and was decreased in hippocampal sample from old rats (P<0.05). This last result was interpreted as related to the loss of cognitive capacities in old animals.

Aging↗
PubMed1999

Lithium and haloperidol treatments differently affect the mononuclear leukocyte Galphas protein levels in bipolar affective disorder.

Despite numerous suggestions of the involvement of GTP-binding proteins in the mechanisms of action of psychoactive drugs in bipolar affective disorder, few studies have been conducted during the drug treatment of patients. The aim of the present study was to investigate the effects of a mood stabilizer and an antipsychotic drug on Galphas proteins. Patients with bipolar affective disorder under lithium treatment with or without haloperidol were assessed with respect to their mononuclear leukocyte (MNL) Galphas subunit protein. Galphas-45 protein subunit levels were analyzed by the Western immunoblot method. The subjects consisted of a group of 20 patients, all diagnosed as euthymic bipolars, and a comparison group of 15 drug-free healthy subjects. Results showed that Galphas levels were significantly decreased in the bipolar patients (BP) compared to drug-free healthy subjects (Mann-Whitney U test, p < 0.002). The drug effect was evaluated by a factorial analysis of variance and showed significant differences between groups (Kruskal-Wallis H test, p < 0.02). Lithium-treated patients displayed the most decreased Galphas levels (normalized mean values 53.2 +/- 31 vs. 122 +/- 45% for BP and controls, respectively, p < 0.001), while no change was observed in Galphas levels of haloperidol-treated patients compared to controls (mean values: 124.9 +/- 37%; NS). The data indicate that lithium and haloperidol affect the mechanism of Galphas protein signal transduction differently, consistent with previous animal studies.

Adult↗
PubMed1998

The effect of clinical outcome on platelet G proteins of major depressed patients.

Platelet G protein subunits (G alpha i2, G alpha q and Gbeta) were measured in 15 non-treated depressed patients (recurrent major depression) and 15 age- and sex-matched healthy controls by using the Western immunoblot method. The depression severity was measured by the AMDP depression rating scale before start of treatment. The AMDP score ranged between 12 and 44. Patients were then treated with different antidepressant drugs (ATD) for 1 month, after which G protein and depression were reassessed. Results indicated that drug-free depressed patients displayed increased levels of G proteins subunits, in comparison to healthy controls. Antidepressant drug administration resulted in decrease of depression severity but only seven patients showed a net response to drugs (AMDP depression score less than 12). These drug-responding patients have also reduced G protein levels, while patients without significant improvement continued to display either the same levels of G proteins or higher, whatever the class of the drug administered. These results suggest that depression is associated to increase in G protein subunit levels and that the clinical outcome seemed to be the determining factor in further decrease occurring in G protein levels.

Adult↗
PubMed1996

Platelet phosphoinositide signaling system: an overstimulated pathway in depression.

In order to test a possible depression-associated defect in signal transduction, platelet alpha 2-adrenergic-mediated phosphoinositide (PI) hydrolysis was measured, both in drug-free major depressed patients and in control healthy subjects. Results that express phospholipase C activity have shown significant increase in the metabolites of epinephrine-stimulated tritiated phosphatidyl-4,5-biphosphate (3H-PIP2) with respect to basal activity (saline-stimulated). Thrombin (2 units) and 10 mM sodium fluoride (NaF) also induced an increase in 3H-PIP2 metabolites. These increases were potentiated in drug-free depressed patients both in epinephrine-and thrombin-stimulated platelets. In contrast, sodium fluoride, which directly stimulates G protein without receptor interaction, did not differentiate between patients and controls with respect to PI hydrolysis. This result suggests a possible depression-associated defect in heterologous receptor-G protein interaction.

Adrenergic alpha-2 Receptor Antagonists↗
PubMed1994

Platelet serotonin and plasma tryptophan in depressed patients: effect of drug treatment and clinical outcome.

Platelet serotonin and plasma tryptophan were studied in healthy subjects and in depressed patients before and during their antidepressant drug treatment. Before treatment, mean platelet serotonin level was normal in depressed patients compared with healthy subjects while a significant decrease in patients' plasma TRP was noted (t = 6.0, p < .001). The concentrations of platelet 5-HT level did not correlate with either plasma TRP or with clinical variables, that is, AMDP depression and AMDP anxiety scores. Antidepressant drugs treatment decreased platelet 5-HT level (ANOVA F = 8.27, p < .001) whatever the clinical outcome of the patient, whereas the changes observed in plasma TRP were positively related to the mood state change. These results suggest that platelet serotonin could be a good pharmacological model but has no relevance concerning the mood state.

Affect↗
PubMed1993

Lack of effect of anxiety on total plasma MHPG in depressed patients.

This report was undertaken to test the noradrenergic deficiency hypothesis of depression and the postulated increase in noradrenergic activity associated to anxiety states. A possible dual effect of both depression and anxiety on total plasma MHPG levels was hypothesized and assessed in anxious and non-anxious depressed patients. The findings show a decrease in plasma MHPG levels in depressed patients whatever their degree of anxiety. There was no difference in total plasma MHPG levels either between anxious and non-anxious depressed patients or between low and high anxiety to depression ratio (ADR) depressed patients. Following antidepressant drug-treatment, a decrease in plasma MHPG was found. A positive correlation between the drug-induced decrease in NA activity and the severity of depression was observed, and suggested a relationship between the severity of depression and the instability of the NA system. No correlation between the drug-induced decrease in plasma MHPG and the degree of anxiety was found. The results do not suggest out an effect of anxiety on total plasma MHPG levels in depressed patients.

Adult↗
PubMed1993

Adrenaline-induced platelet aggregation in depressed patients and control subjects.

We measured alpha 2-adrenoceptor-mediated platelet primary aggregation in depressed patients and healthy subjects. Both initial velocity and maximum amplitudes of platelet response to increasing concentrations of adrenaline were decreased in drug-free depressed patients as compared with controls. The EC50 of both initial slope and maximum amplitude were also increased in drug-free depressed patients. The results suggested a lowered platelet alpha 2-adrenoceptor function. Demographic factors (age and sex) and the time between blood collection and start of aggregation monitoring did not influence the results. This report is consistent with postsynaptic receptor desensitization in depressed patients. The precise molecular mechanism for this impairment remains to be elucidated.

Adolescent↗
PubMed1992

Platelet membrane alpha 2-adrenergic receptors in depression.

The platelet membrane was used as a model system to examine alpha 2-adrenergic receptors in 30 depressed patients and 30 healthy control subjects. The number of binding sites and their affinity for 3H-UK 14304 (5-bromo-6-(2-imidazoline-2-ylamino)-quinoxaline), a potent, highly selective alpha 2-adrenergic receptor agonist, was measured. Plasma magnesium and free 3-methoxy-4-hydroxyphenylglycol (MHPG) concentrations were assayed in the same sample. A decreased agonist-receptor affinity was found in depressed patients, whereas receptor density was not significantly altered compared with that in control subjects. In bipolar depressed and dysthymic patients, there was a tendency toward a higher density of alpha 2-adrenergic receptors. This trend was not apparent in unipolar, recurrent depressed subjects. Moreover, a positive correlation between Bmax and Kd values was observed in patients but not in control subjects--a finding that suggests that a compensatory phenomenon occurs in depression. After the patients were treated with antidepressant drugs, an increased affinity (decrease in Kd) was observed, together with a decrease in binding sites. Plasma magnesium concentrations were higher in drug-free depressed patients than in control subjects. In addition, magnesium concentrations were negatively correlated with the density of alpha 2-adrenergic receptor binding sites in depressed patients, both before and during treatment. Lastly, a trend toward a negative correlation between plasma MHPG concentration and the number of binding sites was also observed. These results suggest a complex multifactorial regulation of alpha 2-adrenergic receptors, which are probably hyposensitive in depressive syndromes.

Adrenergic alpha-Agonists↗
PubMed1992

Decrease in epinephrine-induced attenuation of platelet adenylate cyclase activity in depressed patients: relation with plasma electrolytes.

We have measured the alpha 2-adrenoceptor-mediated inhibition of platelet membrane adenylate cyclase in depressed patients and control subjects. The results showed a decrease in the forskolin-stimulated adenylate cyclase inhibition of depressed patients compared to the healthy subjects. This suggests a subsensitivity of alpha 2-adrenoceptor in depression. However, this subsensitivity was not correlated to the severity of depression as both severely and moderately depressed patients exhibited the same percent of adenylate cyclase inhibition. The antidepressant drugs treatment induced an increase in the percent of adenylate cyclase inhibition with a trend towards the control values. However, this increase did not equal control value, and moreover both remitted and unremitted patients presented a similar change in their alpha 2-adrenoceptor-mediated adenylate cyclase inhibition. This result raises the question about a simple and direct relation between the clinical status of depression and the power of alpha 2-adrenoceptor-mediated adenylate cyclase inhibition. Plasma magnesium and sodium yielded correlations to this alpha 2-adrenoceptor-mediated adenylate cyclase inhibition suggesting a relation between the platelet adrenergic function and plasma electrolytes.

Adenylyl Cyclase Inhibitors↗
PubMed1992

Evolution of blood magnesium, sodium and potassium in depressed patients followed for three months.

No consensus has been obtained about blood electrolyte status, especially about magnesium, in affective disorders. This is mainly due to the lack of information about the distribution of the patients in clinical subgroups, sex, type of treatment and about the severity of their illnesses. Most of these studies concerned treated patients. We confirmed in this study that drug-free depressed patients have higher erythrocyte and plasma magnesium than controls, as shown in previous reports. Significant differences are observed in as shown in previous reports. Significant differences are observed in patients for sex and between clinical subgroups. Low plasma potassium levels are described in both male and female depressed patients. The erythrocyte magnesium level tends to normalize in parallel with clinical improvement, depending on sex and clinical subgroup, and seems then to be related to the intensity of the depression. Plasma magnesium in male and female patients, except for female unipolars, remains higher than controls in all conditions and might be related to the diagnosis of affective disorders.

Adult↗
PubMed1991

High-performance liquid chromatographic determination of phenylacetic acid in human plasma extracted with ethyl acetate.

This paper describes a high-performance liquid chromatographic method with ultraviolet detection for measuring plasma phenylacetic acid. This simple and reliable method consists of an acid hydrolysis of conjugated phenylacetic acid before extraction with an organic solvent: washed ethyl acetate saturated in sodium chloride. The recovery of extraction was estimated by internal standardization with phenylpropionic acid, and validated by addition of phenylacetic acid standards. A preliminary application to plasma phenylacetic acid in patients suffering from depression is described.

Acetates↗
PubMed1989

The heterogeneity of 3-methoxy-4-hydroxyphenylglycol levels among depressed patients.

A previous report by our group and results published by other research groups have indicated a dichotomy in MHPG levels in depressed patients. This study attempted to characterize phenomena associated with this dichotomy in plasma MHPG levels. First, we have noted, at least in female patients, that homogeneity of MHPG levels, as tested by fitting with a normal curve, can be ruled out. In contrast, in the total population, a dichotomy was less evident in this study; the 2 subgroups, high and low levels of MHPG, partially overlap, and this results in a gaussian distribution. However, based on the hypothesis of a bimodal distribution, as shown by others and not excluded here, it was possible to find some factors associated with heterogeneity. Thus, polarity of depression, sex and age of the patients, age of disease onset and depression score affect MHPG levels. On the other hand, other elements suspected to modify MHPG values, such as the different lengths of the washout period (minimum 10 days), or some medication (chloralhydrate or levomepromazine) required during the washout period, did not show any effect. The aim of this study was to better characterize this peripheral index for its possible use in clinical application.

Adult↗
PubMed1988

Plasma 3,4-dihydroxyphenylethyleneglycol and 3-methoxy-4-hydroxyphenylethyleneglycol as indicators of central noradrenergic activity. A comparative study on control subjects and depressed patients.

Animal studies have suggested interspecies differences in brain norepinephrine (NE) metabolism, especially with regard to the relative proportions of 3,4-dihydroxyphenylethyleneglycol (DOPEG) compared to 3-methoxy-4-hydroxyphenylethyleneglycol (MOPEG). In order to question the value of both glycol metabolites as peripheral indices of central noradrenergic activity, a comparative study of plasma DOPEG and MOPEG (measured by HPLC) related to depression, sex, age and diagnostic categories (DSM-III) was carried out on depressed and control subjects. In addition, two groups of 8 patients were randomly submitted to a desipramine 150 mg/day, or a metapramine 450 mg/day antidepressant treatment influencing the formation of DOPEG and MOPEG in a different way. The study did not demonstrate any difference between DOPEG and MOPEG for most of the experimental factors. We found also a significant positive correlation between plasma levels of DOPEG and MOPEG. Our results support the idea that each of these two biological indices can be used in the assessment of central noradrenergic activity.

Adult↗
PubMed1987

Determination of 3,4-dihydroxyphenylglycol (DHPG) by HPLC with coulometric detection, and correlation with 3-methoxy-4-hydroxyphenylglycol (MHPG) in human plasma.

A method for determining plasma 3,4-dihydroxyphenylethyleneglycol (DHPG), a central noradrenaline (NA) metabolite, is described. The method used HPLC with dual coulometric detection set in screen mode of operation. The isolation of DHPG and related catecholamines (noradrenaline, dopamine and dihydroxybenzylamine) was performed on acid washed alumina extracted with 0.2 M HCIO4 containing EDTA (0.2%), and reduced glutathione as stabilizer. A reversed phase column with an eluting system containing 0.025 M citric acid-sodium hydrogen phosphate buffer in the ratio 3:2 (v:v) and 5% methanol was used. The experimental results of plasma DHPG levels compared favourably with the results from the literature, and a positively significant correlation with plasma MHPG was found. This method could be used as an alternative in central NA assessment.

Catecholamines↗