Biomedical subjects
Publications and source records attributed to S Bischoff.
Potent antagonists at the glycine-binding site of NMDA receptors, as well as dual antagonists acting also at AMPA receptors have been identified in a series of 5-arylaminomethylquinoxaline-2,3-diones. A study of the structure-activity relationship of these compounds is reported here.
In an attempt to gain knowledge of the possible functions of kainate receptors, we have used in situ hybridization to examine the regional and cellular expression patterns of glutamate receptor subunits GluR5-7, KA1 and KA2 in the adult mouse basal ganglia, known to play a pivotal role in the translation of motivation into actions. Kainate receptor subunits were found to be differentially expressed in the circuitry forming the basal ganglia. They differ from each other in expression levels and their spatial localization. GluR6 appeared as the key subunit for the descending gamma-aminobutyric acid (GABA)ergic-glutamatergic pathways, with highest message levels in the caudate putamen, globus pallidus and subthalamic nucleus as well as in the nucleus accumbens and olfactory tubercle. GluR7 exhibited highest expression in the ascending nigrostriatal and mesolimbic dopaminergic neurons. GluR5 had a restricted distribution pattern, with high expression in the ventral pallidum, the islands of Calleja and pars compacta of the substantia nigra. KA2 was usually coexpressed with GluR6, although with a generally lower level of expression. Finally, KA1 mRNA was barely detectable in these neuronal circuits. These data suggest that kainate receptors in general may be involved in the functions associated with the basal ganglia, with a key role in the control of the central dopaminergic transmission. Thus, they might be implicated in the neurodegenerative and psychic disorders associated with an impairment of the basal ganglia.
GABA (gamma-amino-butyric acid), the principal inhibitory neurotransmitter in the brain, signals through ionotropic (GABA(A)/ GABA(c)) and metabotropic (GABA(B)) receptor systems. Here we report the cloning of GABA(B) receptors. Photoaffinity labelling experiments suggest that the cloned receptors correspond to two highly conserved GABA(B) receptor forms present in the vertebrate nervous system. The cloned receptors negatively couple to adenylyl cyclase and show sequence similarity to the metabotropic receptors for the excitatory neurotransmitter L-glutamate.
In addition to specific ligand binding elements, receptor assembly for interleukin(IL)-6, oncostatin-M, leukaemia inhibitory factor, ciliary neurotrophic factor and IL-11 includes an additional unit, gp130. This molecule is a transmembrane glycoprotein of 130 kDa. In this paper, reviewing molecular, biochemical and functional data on gp130, we describe the dissimilar action of IL-3 on the expression of the binding unit of the IL-6 receptor and that of gp130. According to FACS studies, resting basophils express only IL-6 receptors and no gp130 molecules on the plasma membranes. After incubation with IL-3, the surface appearance and de novo transcription of gp130 was shown by FACS and mRNA polymerase chain reaction analysis.
N-(diethylamino-ethyl)-4-chloro-5-cyano-2-methoxy-benzamide-hydrochlo rid e (CGP 25454A) is a new benzamide derivative now in clinical trials in patients with major depression. Here we describe some basic neurochemical and behavioural properties in animal experiments. In vitro, CGP 25454A increased the field-stimulated [3H]- and [14C]-overflow from rat striatal slices preloaded with [3H]dopamine and [14C]choline, indicating that CGP 25454A was able to enhance the release of both dopamine (DA) and acetylcholine (ACh). However, CGP 25454A was 12.9 times more potent in increasing, by 1/6 of the apparent maximal increase, the release of [3H]DA than that of [14C]ACh. In vivo, CGP 25454A increased [3H]spiperone binding to receptors of the D2 family in rat striatum by 90-110% (ED50: 13 mg/kg i.p.). As a similar increase in [3H]spiperone binding was found with a variety of agents which increase the synaptic concentration of endogenous DA, the effect of CGP 25454A most probably reflects an enhanced release of DA under in vivo conditions. At 30-100 mg/kg, CGP 25454A inhibited [3H]spiperone binding in the pituitary of the same animals as a result of a blockade of postsynaptic DA receptors. This dual mode of action was also apparent in terms of behavioral changes. At doses as low as 5-10 mg/kg, CGP 25454A produced a weak stimulation, suggested by a trend of increased spontaneous rearing and corroborated by a significant potentiation of the elevated rearing induced by (+)-amphetamine. By contrast, at doses of 30-100 mg/kg, it exerted clear-cut sedative and neuroleptic-like properties.(ABSTRACT TRUNCATED AT 250 WORDS)
This article describes the conceptual basis, design, and intervention approach for a worksite-based heart disease risk reduction project. Baseline characteristics of the 26 moderate size worksites participating in the Take Heart Project are also described. The trial is designed to produce changes at both the organization and employee level on tobacco use, dietary fat intake, and serum cholesterol. A key feature of the intervention is creation of employee steering committees to enhance ownership and involvement. From a menu of brief, low-intensity health education and environmental change activities, these committees select activities best suited to their worksite. The baseline characteristics of organizations randomized to intervention and control conditions were similar, and indicated a relatively high level of worksite activity related to cholesterol and smoking.
The characteristics of dopamine (DA) D2 receptors were studied in rat hippocampus and for comparison in striatum using the [3H]spiperone radioreceptor assay in vitro. D2 receptors exhibit a bimodal distribution along the length of the hippocampus. Heterogeneity also exists in the transverse axis with high densities in the molecular layers of the subiculum and CA1 plus CA2. As in the striatum, D2 receptors in both dorsal and ventral hippocampus display high and low affinity states for agonists, but all three regions differ with regard to the percentage of receptors in these states. The modulation of these affinity states by GTP, Mg2+ and the iron-chelator, 1,1-O-phenanthroline, differs markedly between dorsal and ventral hippocampus, and between these regions and the striatum. A new model for the modulation of the affinity of D2 receptors for agonists is presented. These data suggest the presence of regional differences in the composition of the D2 receptor-regulatory protein complex.
Acute treatment of rats with the antidepressant bupropion increased [3H]spiperone binding to D2 receptors in vivo. This dose- and time-dependent effect was greatest in striatum and minimal in cerebellum and pituitary. A parallel behavioral stimulation occurred in the same rats. Among 21 antidepressants and CNS stimulants tested, only those that activate dopamine (DA) transmission had similar effects: nomifensine, amineptine, methylphenidate, D-amphetamine, amfonelic acid, cocaine, benztropine and GBR 12909. Decreasing DA transmission with reserpine plus alpha-methyl-p-tyrosine prevented the action of bupropion. Finally, bupropion was inactive in vitro and ex-vivo. Therefore, we propose that bupropion and other DA-enhancing agents modify the characteristics of [3H]spiperone binding through the intervention of a dynamic regulation of the D2 receptors by the neurotransmitter itself.
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[3H]spiperone (SPI) binding in vivo, biochemical parameters and behavior were measured after modulating DA levels by various drug treatments. DA releasers and uptake inhibitors increased SPI binding in rat striatum. In other brain areas, the effects were variable, but only the pituitary remained unaffected. Surprisingly, nomifensine decreased SPI binding in frontal cortex. The effects of these drugs were monitored by measuring DA, serotonin (5-HT) and their metabolites in the same rats. The increased SPI binding in striatum was parallel to the locomotor stimulation with the following rank order: amfonelic acid greater than nomifensine greater than D-amphetamine greater than or equal to methylphenidate greater than amineptine greater than bupropion. Decreasing DA levels with reserpine or alpha-methyl-para-tyrosine reduced SPI binding by 45% in striatum only when both drugs were combined. In contrast, reserpine enhanced SPI binding in pituitary. Thus, the amount of releasable DA seems to modulate SPI binding characteristics. It is suggested that in vivo, DA receptors are submitted to dynamic regulation in response to changes in intrasynaptic concentrations of DA.
The effects of dopamine D1 and D2 receptor agonists and antagonists on the rate of GABA synthesis in four regions of mouse brain (corpus striatum, cerebellum, cortex and hippocampus) were examined after irreversible inhibition of 4-aminobutyrate: 2-oxoglutarate aminotransferase (EC 2.6.1.19; GABA-T) by gabaculine. The dopamine D2 receptor agonists PPHT, LY 171555 and RU 24213 exerted a dose-related inhibitory effect on GABA synthesis in these four regions. The decreases in the rate of GABA formation were prevented by the dopamine D2 receptor antagonist S(-)-sulpiride. The dopamine D1 receptor agonists SKF 77434 and SKF 38393 augmented gabaculine-induced GABA accumulation in the corpus striatum only, and this effect was blocked by the dopamine D1 receptor antagonist SCH 23390. However, SKF 81297 and SKF 82958, two other dopamine D1 receptor agonists, did not affect or only marginally altered the rate of GABA synthesis. Stimulation of D2 receptors thus induces a decrease in the rate of GABA formation in the four brain areas examined, whereas stimulation of D1 receptors either increases GABA synthesis in the corpus striatum or does not alter it. This effect appears to be independent of the degree of receptor occupancy.
CGP 28014 (N-(2-pyridone-6-yl)-N',N'-di-n-propylformamidine) or its methanesulfonate salt CGP 28014 A was suspected to be a catechol-O-methyl-transferase (COMT) inhibitor because it was found to reduce the levels of homovanillic acid (HVA) and to increase those of 3,4-dihydroxyphenylacetic acid (DOPAC) in the rat striatum, after oral or intraperitoneal administration. These effects were maintained after repeated administration. The compound was only weakly active as a COMT inhibitor in vitro. However, its effect on striatal HVA and DOPAC was not prevented by pretreatment with the inhibitor of microsomal drug metabolizing enzymes in the liver, proadifen, indicating that, if CGP 28014 acts as a prodrug, its conversion to the active compound is not by oxidative metabolism in the liver. Also, there was no evidence that conversion to 2-amino-6-hydroxypyridine could explain its effects. The in vivo effect of CGP 28014 was substantiated in two additional in vivo test systems. Thus, it inhibited the accumulation of 3-methoxytyramine in the rat striatum after MAO inhibition by clorgyline, and the formation of O-methyl-DOPA from exogenously administered DOPA. It proved to be equipotent or nearly so with tropolone, and also showed a similar duration of action. Similar to tropolone, it increased S-adenosylmethionine levels in the striatum. Pyrogallol, on the other hand, decreased them, because being a substrate of COMT, it consumes methyl groups. This suggests that CGP 28014 does not inhibit COMT because it is a substrate of the enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)
The course of endocrine ophthalmopathy was investigated on the basis of clinical and biochemical parameters and in relation to different therapeutic strategies. A retrospective appraisal was made of 297 patients (44 +/- 14 yr, 249 women) with inclusion of anamnestic and clinical data as well as the results of computer tomography. At the beginning of therapy, 253 patients were hyperthyroid, 36 were euthyroid and eight were hypothyroid. The HLA typing carried out in 89 patients showed the phenotypes B8 and DR3 in 32% and 42% of the cases, respectively. Raised microsomal antibodies were present in 56% of the patients and there were raised thyroglobulin antibodies in 19%. Sixty-three % of the patients received immunosuppressants in the course of therapy: glucocorticoids in all cases, nonsteroid immunosuppressants in 15%. Eight % of the patients were irradiated retrobulbarly. The inflammatory parameters could be favorably affected, whereas eye muscle involvement and bulbar protrusion proved to be more resistant to therapy. In patients with combined immunosuppressant therapy or steroids + retrobulbar radiation, there were unequivocal successes with regard to the proptosis, vision and intraocular pressure. None of the strategies applied constitutes an optimal treatment with regard to the long-term course. Following therapy, there is an improvement of endocrine ophthalmopathy, but not complete healing.
CGP 31358, a novel triazole, inhibited the binding of L-[3H]glutamate and [3H]MK-801 to the N-methyl-D-aspartate (NMDA) receptor complex in rat brain synaptic membrane fractions, and showed anticonvulsant activity in mice. It had no effect on the strychnine-insensitive binding of [3H]glycine. Saturation and Hill analyses indicated that CGP 31358 binds to a site on the NMDA receptor which is separate from, but coupled to, both the transmitter recognition site and the channel domain. Available data indicate that this site is distinct from those with which tricyclic antidepressants and ifenprodil interact. CGP 31358 is a new chemical entity with a novel mechanism of action at the NMDA receptor, and as such may form a tool for understanding the molecular pharmacology of this receptor-channel complex.
The arrhythmia profile and heart rate (HR) were analyzed by 24-hour Holter monitoring in 37 hyperthyroid patients before (triiodothyronine [T3] hormone level = 331 +/- 108 ng/dl), during (T3 level = 202 +/- 98 ng/dl) and after an antihyperthyroid therapy of 8 to 89 weeks' duration (T3 level = 149 +/- 41 ng/dl). The data were compared with those of 50 control subjects free from cardiac disease. Only 12 hyperthyroid patients (32%) had complex ventricular arrhythmias (Lown grade 3 or 4) as compared with 6 normal subjects (12%, p greater than 0.05). Three patients (8%) had repetitive ventricular arrhythmias (Lown grade 4A/B) as compared with 4 normal subjects (8%, p greater than 0.05). Supraventricular premature complexes occurred more often in hyperthyroid patients than in normal subjects before and after therapy (p less than 0.001). The prevalence of supraventricular tachycardia decreased from 8 patients to 1 during therapy (p less than 0.002). The HR decreased from 95 +/- 13 to 79 +/- 9 beats/min after therapy, but was still increased as compared with the normal subjects (72 +/- 8 beats/min, p less than 0.001). A day/night difference in HR greater than 10% was found in 32 patients (86%) and was more pronounced than in the normal group (p less than 0.001). Compared with the normal HR profile, the HR curve of hyperthyroid patients was shifted to a higher level (about 20 beats/min). Serum T3 level correlated best with HR at night in hyperthyroid patients (r = 0.74, p less than 0.001). Thus, hyperthyroid patients show frequent supraventricular arrhythmias that might be reversible during therapy.(ABSTRACT TRUNCATED AT 250 WORDS)
Arrhythmia profiles and heart rates, obtained by 24-hour ECG monitoring, were analysed in 48 patients with hyperthyroidism before (T3 level: 331 +/- 108 ng/100 ml, heart rate: 95 +/- 13/min), during (T3 level: 202 +/- 98 ng/100 ml, heart rate: 85 +/- 11/min) and after (T3 level: 149 +/- 41 ng/100 ml, heart rate: 79 +/- 9/min) antithyroid treatment. 50 persons in whom organic heart disease has been excluded by invasive and noninvasive tests served as controls. Only 6% of patients had repetitive ventricular arrhythmias (Lown group IV) before treatment (controls: 4%; P greater than 0.05). Supraventricular extrasystoles were common both before and after treatment (P less than 0.001), especially in elderly patients. The number of patients with supraventricular tachycardias decreased in the course of treatment from eleven to two. There was a clear correlation between the T3 level and nocturnal heart rate (r = 0.74; P less than 0.001). A day-night difference in heart rate (a ratio of greater than or equal to 1.10) was present in 43 patients and higher than in the controls (P less than 0.001). Thus with respect to ventricular arrhythmias hyperthyroid patients had a normal profile, but a marked tendency towards supraventricular arrhythmias which was partly age-related. Antithyroid treatment affected only the incidence of supraventricular tachycardias, while day-night differences in heart rate remained unchanged.