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Biomedical subjects

R Rupprecht

Publications and source records attributed to R Rupprecht.

At least 91 records · Page 5Linked to original sources
PubMed1996

Molecular and functional evidence for in vitro cytokine enhancement of human and murine target cell sensitivity to glucocorticoids. TNF-alpha priming increases glucocorticoid inhibition of TNF-alpha-induced cytotoxicity/apoptosis.

Cytokine-induced glucocorticoid secretion and glucocorticoid inhibition of cytokine synthesis and pleiotropic actions act as important safeguards in preventing cytokine overreaction. We found that TNF-alpha increased glucocorticoid-induced transcriptional activity of the glucocorticoid receptor (GR) via the glucocorticoid response elements (GRE) in L-929 mouse fibroblasts transfected with a glucocorticoid-inducible reporter plasmid. In addition, TNF-alpha also enhanced GR number. The TNF-alpha effect on transcriptional activity was absent in other cell lines that express TNF-alpha receptors but not GRs, and became manifest when a GR expression vector was cotransfected, indicating that TNF-alpha, independent of any effect it may have on GR number, has a stimulatory effect on the glucocorticoid-induced transcriptional activity of the GR. Moreover, TNF-alpha increased GR binding to GRE. As a functional biological correlate of this mechanism, priming of L-929 cells with a low (noncytotoxic) dose of TNF-alpha significantly increased the sensitivity to glucocorticoid inhibition of TNF-alpha-induced cytotoxicity/apoptosis. TNF-alpha and IL-1 beta had the same stimulatory action on glucocorticoid-induced transcriptional activity of the GR via the GRE, in different types of cytokine/glucocorticoid target cells (glioma, pituitary, epithelioid). The phenomenon may therefore reflect a general molecular mechanism whereby cytokines modulate the transcriptional activity of the GR, thus potentiating the counterregulation by glucocorticoids at the level of their target cells.

Animals↗
PubMed1996

Functional antagonistic properties of clozapine at the 5-HT3 receptor.

The atypical neuroleptic clozapine is thought to exert its psychopharmacological actions through a variety of neurotransmitter receptors. It binds preferentially to D4 and 5-HT2 receptors; however, little is known on it's interaction with the 5-HT3 receptor. Using a cell line stably expressing the 5-HT3 receptor, whole-cell voltage-clamp analysis revealed functional antagonistic properties of clozapine at low nanomolar concentrations in view of a binding affinity in the upper nanomolar range. Because the concentration of clozapine required for an interaction with the 5-HT3 receptor can be achieved with therapeutical doses, functional antagonistic properties at this ligand-gated ion channel may contribute to its unique psychopharmacological profile.

Antipsychotic Agents↗
PubMed1996

Steroid receptor-mediated effects of neuroactive steroids: characterization of structure-activity relationship.

Neuroactive steroids rapidly alter neuronal excitability through their action via the cell surface. The 3 alpha-hydroxy ring A-reduced pregnane steroids enhance gamma-aminobutyric acid (GABA)-mediated Cl- currents while pregnenolone sulfate and dehydroepiandrosterone sulfate may exert functional antagonistic properties. Based on our previous findings that the 3 alpha-hydroxy ring A-reduced pregnane steroids allotetrahydroprogesterone and allotetrahydrodeoxycorticosterone may regulate gene expression via the progesterone receptor after intracellular oxidation, we have characterized the effects of a series of natural and synthetic neuroactive steroids at the genomic level using a cotransfection system with various steroid receptor expression vectors and a reporter gene in a human neuroblastoma cell line. Pregnanolone and pregnenolone were able to activate both the chicken and the human progesterone receptor while the synthetic 3 alpha-hydroxylated derivative alphaxalone and dehydroepiandrosterone were active via the chicken progesterone receptor but devoid of transcriptional activity via the human progesterone receptor. Moreover, the antiglucocorticoid activity of dehydroepiandrosterone reported at the systemic level could not be reconstituted in the cellular cotransfection system. None of the neuroactive steroids bound directly to steroid receptors. Thus, their genomic activity appears to be mediated via intracellular metabolization. This study provides evidence for differential genomic effects of neuroactive steroids in a structure-specific and species-specific way that may have impact on the development of these steroids for therapeutic application.

Animals↗
PubMed1996

Oxidative stress-resistant cells are protected against haloperidol toxicity.

The neuroleptic drug haloperidol is cytotoxic to cells of different origin in high doses. The mechanism of haloperidol toxicity may involve oxidative stress resulting in necrosis. In the present study, we show that rat pheochromocytoma PC12 cell clones which were selected for resistance to the toxicity of the oxidative stressor amyloid beta-protein (A beta), were also resistant to haloperidol toxicity. This data strongly supports the causative involvement of free radicals in haloperidol-induced cell death.

Animals↗
PubMed1996

Allopregnanolone acts as an inhibitory modulator on alpha1- and alpha6-containing GABA-A receptors.

Allopregnanolone, known so far to act as a gamma-aminobutyric acid (GABA) agonist, allosterically decreased the affinity of the GABA agonist muscimol for recombinant alpha1beta2gamma2 and alpha6beta2gamma2 GABA-A receptors. Pregnenolone sulfate, a GABA antagonist, had a similar effect. Both of these neuroactive steroids also reduced the time constant of desensitization (tau) of GABA-induced chloride currents. The effect on desensitization was demonstrated for native receptors of hypothalamic neurons as well as for the recombinant GABA-A receptors. Hence neuroactive steroids may differentially modulate distinct assemblies of GABA-A receptors and thus induce a more subtle modulation of GABAergic synaptic transmission than previously thought possible.

Animals↗
PubMed1996

The SIMA-project: effects of 1 year cognitive and psychomotor training on cognitive abilities of the elderly.

In an interdisciplinary project on maintaining and supporting independent living in old age, (a) competence training, (b) memory training and (c) psychomotor training as well as (d) combined competence and psychomotor training and (e) combined memory and psychomotor training was performed with n = 309 elderly of 75 to 89 years of age for 9 months. Regardless of treatment conditions, an age-related decline of health and subjective well-being was found 1 year after the end of the training. The specific training measures each led to highly significant specific improvements of the trained functions. A favorable influence of competence training on everyday coping and hence on active strategies for staying independent as well as of memory training on all cognitive functions and especially on memory performance was found. While global psychomotor performance was not significantly improved, effects of psychomotor training on specific functions were detected. In addition, the combined psychomotor and memory training led to an improvement of psychomotor performance and to a reduction of symptoms of dementia, even though neither psychomotor training alone nor memory training alone resulted in such effects. Neurophysiological changes leading to a provision of reserve-capacity of CNS-performance are among other effects assumed as an explanation.

Activities of Daily Living↗
PubMed1996

Neurosteroids: molecular mechanisms of action and psychopharmacological significance.

In addition to the well-known genomic effects of steroid molecules via intracellular steroid receptors, certain steroids rapidly alter neuronal excitability through binding sites on neurotransmitter-gated ion channels. Several of these steroids accumulate in the brain after local synthesis or after metabolization of adrenal steroids. The 3 alpha-hydroxy ring A-reduced pregnane steroids allopregnanolone and tetrahydrodeoxycorticosterone have been thought not to interact with intracellular receptors but enhance gamma-aminobutyric acid (GABA)-medicated chloride currents. When administered systematically in the rat, these neurosteroids display anxiolytic and hypnotic activities that suggest pronounced systemic effects as well as neuropsychopharmacological potential for modulation of sleep and anxiety. We demonstrated that these neurosteroids can regulate gene expression via the progesterone receptor. The induction of DNA-binding and transcriptional activation of the progesterone receptor requires intracellular oxidation of the neurosteroids into progesterone receptor-active 5 alpha-pregnane steroids. Thus, in physiological concentrations these neurosteroids regulate neuronal function through their concurrent influence on transmitter-gated ion channels and gene expression. These findings extend the concept of a "cross-talk" between membrane and nuclear hormone effects and provide a new role for the therapeutic application of these steroids in neurology and psychiatry.

Animals↗
PubMed1996

Progesterone induces changes in sleep comparable to those of agonistic GABAA receptor modulators.

There is much evidence that progesterone has hypnotic anesthetic properties. In this vehicle-controlled study, we examined the effects of three doses of progesterone (30, 90, and 180 mg/kg) administered intraperitoneally at light onset on sleep in rats. Progesterone dose dependently shortened non-rapid eye movement sleep (NREMS) latency, lengthened rapid eye movement sleep (REMS) latency, decreased the amount of wakefulness and REMS, and markedly increased pre-REMS, an intermediate state between NREMS and REMS. Progesterone also elicited dose-related changes in sleep state-specific electroencephalogram (EEG) power densities. Within NREMS, EEG activity was reduced in the lower frequencies (< or = 7 Hz) and was enhanced in the higher frequencies. Within REMS, EEG activity was markedly enhanced in the higher frequencies. The effects were maximal during the first postinjection hours. The concentrations of progesterone and the progesterone metabolites 3 alpha-hydroxy-5 alpha-pregnan-20-one and 3 alpha-hydroxy-5 beta-pregnan-20-one, both positive allosteric modulators of gamma-aminobutyric acid A (GABAA) receptors, were determined at different time intervals after vehicle and 30 or 90 mg/kg progesterone. Progesterone administration resulted in dose-dependent initially supraphysiological elevations of progesterone and its metabolites in the plasma and brain, which were most prominent during the first hour postinjection. The effects of progesterone on sleep closely resemble those of agonistic modulators of GABAA receptors such as benzodiazepines and correlate well with the increases in the levels of its GABAA agonistic metabolites. These observations suggest that the hypnotic effects of progesterone are mediated by the facilitating action of its neuroactive metabolites on GABAA receptor functioning.

Animals↗
PubMed1995

Haloperidol-induced cell death--mechanism and protection with vitamin E in vitro.

Haloperidol, a dopamine receptor antagonist and sigma-receptor-active neuroleptic drug, is cytotoxic to primary hippocampal neurones, C6 glioma cells and NCB20 cells. A 24 h challenge of these cells with haloperidol resulted in reduced cell viability and ultimately cell lysis. The most dramatic changes in cellular morphology were the retraction of cellular extensions, development of membrane blebs, and finally cell detachment from the culture dish. DNA isolated from haloperidol-treated cells was randomly degraded, indicating a necrotic rather than an apoptotic pathway of cell death. Vitamin E (alpha-tocopherol), a lipophilic free radical scavenger, prevented haloperidol-induced DNA fragmentation and ultimately cell death. These findings suggest that haloperidol induces necrotic cell death in which free radicals play a major role.

Animals↗
PubMed1995

Cortisol, corticotropin, and beta-endorphin responses to corticotropin-releasing hormone in patients with atopic eczema.

Alterations in the hypothalamic-pituitary-adrenal (HPA) system are well documented in affective disorders. In depression these include increased secretion of cortisol, an insufficient suppressibility of cortisol by dexamethasone, a blunted corticotropin (ACTH) response to corticotropin-releasing hormone (CRH) and a dysfunction of the glucocorticoid receptor. Patients with atopic eczema, a common chronic skin disease, show seasonal variations in disease activity, symptoms of minor depression and immunological disturbances similar to those seen in patients with depression. To explore the integrity of the HPA system integrity in individuals with atopic eczema we studied the 24-h cortisol secretion and the cortisol, ACTH and beta-endorphin responses to CRH in such individuals and in healthy controls matched for sex and age. The 24-h secretion of cortisol did not differ between the patients with atopic eczema and the controls. The net response to CRH administered as a 100 micrograms i.v. bolus was significantly attenuated for both cortisol (24,235 +/- 12,443 vs. 47,019 +/- 34,515 nmol.min/dl; p < .03) and for ACTH (546 +/- 205 vs. 727 +/- 310 pmol.min/l; p < .05) in the patient group, whereas the beta-endorphin response did not differ between the groups (1072 +/- 448 vs. 1603 +/- 421 nmol.min/l). The blunted response of cortisol and ACTH cannot be explained by hypercortisolism as it is the case in major depression. Rather, it may be related to a prolonged underexposure to hypothalamic CRH or to an increased sensitivity of glucocorticoid feedback inhibition.

Adolescent↗
PubMed1994

Heterodimerization between mineralocorticoid and glucocorticoid receptor: a new principle of glucocorticoid action in the CNS.

In the mammalian central nervous system, responsiveness to glucocorticoids is mediated by both the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). These pharmacologically distinct receptors are believed to bind to common response elements as homodimers. We provide evidence that MR and GR can form a heterodimeric complex with DNA-binding and transactivation properties different from those of the respective homodimers. There was a high degree of cooperativity of MR and GR in binding to a glucocorticoid response element. Transient transfection of a neuroblastoma cell line revealed a transcriptional response pattern of coexpressed MR and GR distinct from that obtained by MR or GR alone. Our findings demonstrate that heterodimerization of MR and GR is a hitherto unrecognized principle for the transcriptional regulation of glucocorticoid-responsive genes in tissue coexpressing these receptors.

Base Sequence↗
PubMed1993

Pharmacological and functional characterization of human mineralocorticoid and glucocorticoid receptor ligands.

We characterized the pharmacological profiles of the human mineralocorticoid and glucocorticoid receptor for 11 natural and synthetic steroids regarding binding pharmacology, intracellular localization of hormone-receptor complexes, and agonistic or antagonistic properties at the gene expression level. The sex steroid progesterone bound with an affinity (ki < 0.01 nM) even higher than that of aldosterone to the human mineralocorticoid receptor and effectively antagonized the effect of aldosterone via the human mineralocorticoid receptor in functional co-transfection assays. This indicates that progesterone has potent antimineralocorticoid properties, while its antiglucocorticoid effects were less pronounced. The partial agonistic activities of antihormones in this assay suggest a direct interaction of antihormone-receptor complexes with the response elements on the DNA. These results are supported by immunofluorescence studies, in which both unliganded human mineralocorticoid and glucocorticoid receptors were distributed throughout the cytoplasm and nucleus, whereas agonist- as well as antagonist-receptor complexes showed an exclusively nuclear localization. These results contribute to the understanding of antihormone pharmacology and increase our understanding of the role of human mineralocorticoid and glucocorticoid receptors in physiological processes during different endocrine states.

Aldosterone↗
PubMed1993

Neurosteroid pregnenolone induces sleep-EEG changes in man compatible with inverse agonistic GABAA-receptor modulation.

The steroid pregnenolone (P) and its sulfate (PS) can accumulate in the central nervous system independent of peripheral sources. Pharmacologically, the sulphated form of P interacts with the GABAA receptor complex, and functional assays show that this steroid behaves as an allosteric GABAA receptor antagonist. The present study explored the effect of a single dose of P upon the sleep-EEG and concurrent secretion of growth hormone and cortisol in male volunteers. P increased the amount of time spent in slow wave sleep and depressed EEG sigma power. Sleep-associated nocturnal cortisol and growth hormone secretion remained unchanged, ruling out the possibility that P exerted its effect via altered regulation of these hormones. Furthermore, results from in vitro studies on the potency of P to activate gene transcription via corticosteroid receptors made a genomic action of P via hormone receptor-sensitive DNA sequences unlikely. We conclude that P acts in a non-genomic fashion at or in the vicinity of the benzodiazepine binding site, modulating allosterically the GABAA receptor like a partial inverse.

Adult↗
PubMed1993

Progesterone receptor-mediated effects of neuroactive steroids.

Several 3 alpha-hydroxysteroids accumulate in the brain after local synthesis or after metabolization of steroids that are provided by the adrenals. The 3 alpha-hydroxy ring A-reduced pregnane steroids allopregnanolone and tetrahydrodeoxycorticosterone are believed not to interact with intracellular receptors, but enhance GABA-mediated chloride currents. The present study shows that these neuroactive steroids can regulate gene expression via the progesterone receptor. The induction of DNA binding and transcriptional activation of the progesterone receptor requires intracellular oxidation of the neuroactive steroids into progesterone receptor active 5 alpha-pregnane steroids. Thus, at physiological concentrations, these neuroactive steroids regulate neuronal function through their effects on both transmitter-gated ion channels and steroid receptor-regulated gene expression.

Base Sequence↗
PubMed1993

Transactivation and synergistic properties of the mineralocorticoid receptor: relationship to the glucocorticoid receptor.

The human mineralocorticoid (hMR) and glucocorticoid (hGR) receptors mediate biological responses to adrenal corticosteroids and synthetic ligands. In transient transfection studies, corticosteroid-responsive promoters were used to monitor the hormone-dependent transcriptional regulatory properties of both receptors. The hMR mediates a lower stimulation of the transcription rate than the hGR and does not show cooperative activity on promoters containing multiple palindromic glucocorticoid-responsive elements. The functional importance of the amino-terminus in this differential response was demonstrated by hMR/hGR hybrid receptors in which this region was exchanged or deleted. These experiments revealed that the hMR amino-terminus does not provide the strong transactivation function present in the equivalent hGR domain and, in contrast to the hGR amino-terminus, interferes with the synergistic activity mediated by the DNA- and ligand-binding domains of both receptors.

Base Sequence↗
PubMed1992

Cell-mediated immunity and its glucocorticoid-sensitivity after clinical recovery from severe major depressive disorder.

This follow-up study investigated lymphocyte blastogenesis induced by concanavalin A, phytohemagglutinin A, and pokeweed mitogen and their sensitivity to in vitro dexamethasone administration in 12 patients clinically recovered from severe major depression. Although cortisol-levels at 4.00 p.m. decreased significantly after clinical remission, mitogen-driven lymphocyte proliferative responses were unchanged when assessed intra-individually. No impairment of in vitro glucocorticoid-sensitivity of lectin-induced lymphocyte blastogenesis could be observed in clinically recovered patients. The inhibitory potency of in vitro dexamethasone was found to be inversely correlated with in vivo adrenal cortical hormone levels. There were no correlations with age, weight, sex, antidepressant medication, severity or duration of depression. No differences from age- and sex-matched healthy individuals were found. These results indicate that reduced glucocorticoid receptor sensitivity occurs only during the acute depressive illness.

Adrenocorticotropic Hormone↗