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Biomedical subjects

C Gentsch

Publications and source records attributed to C Gentsch.

At least 19 recordsLinked to original sources
PubMed2002

[Scanning electron microscopic characterization of resorption lacunae and perforations in the cancellous bone of the human femoral head].

UNLABELLED: STAND: Light microscopic investigation of histologic and grinding sections indicates structural differences by resorption lacunae and perforations QUESTION: Is it possible to characterize different types of resorption lacunae and perforations on the basis of ultrastructural differences within them? AIM. Morphological characterization of resorption lacunae and perforations in cancellous bone of the human femoral head METHODS: Samples from the femoral head of 28 patients without skeletal diseases were macerated, dried, gold sputtered and analysed by scanning electron microscopy. RESULTS. We were able to distinguish two types of resorptions lacunae as well as two types of perforation: The longitudinal extended resorption (LER), the reticulate patched resorption (RPR), the lacunar perforation (LP), the tunneling perforation (TP). Moreover we demarcate perforations from blood vessel canals. CONCLUSION: The differentiated types of resorption lacunae and perforations suggest the influence of local factors which regulates osteoclastic activity or indicate different subspecies of osteoclasts.

Bone Diseases↗
PubMed2002

In vitro and in vivo characterization of MPEP, an allosteric modulator of the metabotropic glutamate receptor subtype 5: review article.

There is a need to identify subtype-specific ligands for mGlu receptors to elucidate the potential of these receptors for the treatment of nervous system disorders. To date, most mGlu receptor antagonists are amino acid-like compounds acting as competitive antagonists at the glutamate binding site located in the large extracellular N-terminal domain. We have characterized novel subtype-selective mGlu(5) receptor antagonists which are structurally unrelated to competitive mGlu receptor ligands. Using a series of chimeric receptors and point mutations we demonstrate that these antagonists act as inverse agonists with a novel allosteric binding site in the seven-transmembrane domain. Recent studies in animal models implicate mGlu(5) receptors as a potentially important therapeutic target particularly for the treatment of pain and anxiety.

Animals↗
PubMed2001

Current awareness.

In order to keep subscribers up-to-date with the latest developments in their field, John Wiley & Sons are providing a current awareness service in each issue of the journal. The bibliography contains newly published material in the field of NMR in biomedicine. Each bibliography is divided into 9 sections: 1 Books, Reviews ' Symposia; 2 General; 3 Technology; 4 Brain and Nerves; 5 Neuropathology; 6 Cancer; 7 Cardiac, Vascular and Respiratory Systems; 8 Liver, Kidney and Other Organs; 9 Muscle and Orthopaedic. Within each section, articles are listed in alphabetical order with respect to author. If, in the preceding period, no publications are located relevant to any one of these headings, that section will be omitted.

Magnetic Resonance Spectroscopy↗
PubMed2001

Non-invasive, quantitative assessment of the anatomical phenotype of corticotropin-releasing factor-overexpressing mice by MRI.

High resolution magnetic resonance imaging (MRI) was applied to quantify alterations in thymus and adrenal volumes, as well as body fat in genetically engineered corticotropin-releasing factor (CRF)-overexpressing mice. When compared to the organs in age-matched wild-type animals, the adrenals in CRF-overexpressing male mice were significantly enlarged and the thymus volume in females was significantly smaller. The fat content was significantly larger in CRF-overexpressing mice. The anatomical alterations observed in the MRI studies were in perfect line with post-mortem data (weights of organs). Furthermore, the observed interstrain differences are in agreement with recently published data on (i) the effect of continuous, intraventricular infusion of CRF in rats and (ii) the presence of atrophic adrenals in CRF-knockout mice. The present studies demonstrate that MRI can provide reliable measures of relatively small structures such as the adrenal glands and the thymus in mice. This makes MRI an attractive, non-terminal tool to monitor in laboratory animals, including transgenic mice, the consequence of continuous stress on relevant organs.

Adipose Tissue↗
PubMed2000

NKP608: a selective NK-1 receptor antagonist with anxiolytic-like effects in the social interaction and social exploration test in rats.

NKP608 is a non-peptidic derivative of 4-aminopiperidine which acts as a selective, specific and potent antagonist at the neurokinin-1 (NK-1) receptor both in vitro and in vivo. In vitro, the binding of NKP608 to bovine retina was characterized by an IC50 of 2.6+/-0.4 nM, whereas the compound's affinity to other receptor binding sites, including NK-2 and NK-3, was much lower. Species differences in IC(50) values with NKP608 were less pronounced than with previously described NK-1 receptor antagonists, being 13+/-2 and 27+/-2 nM in gerbil midbrain and rat striatum, respectively. In vivo, using the hind foot thumping model in gerbils, NKP608 exhibited a potent NK-1 antagonistic activity following oral administration (ID(50)=0.23 mg/kg; 2 h pretreatment), supporting a central activity of NKP608. The compound had a long duration of action with an ID(50) value of 0. 15 mg/kg p.o. and 0.38 mg/kg p.o. following a pretreatment of 5 and 24 h, respectively. Following a subchronic administration for 7 consecutive days (once daily) there was no evidence for the development of tolerance or accumulation. In the social interaction test performed in a highly illuminated, unfamiliar test arena, NKP608 specifically increased the time the two rats spent in social contact, and there was no concomitant increase in parameters reflecting general activity, i.e. ambulation (number of square entries) or the number of rearings. Active social time was maximally increased at a dose range of 0.01-1 mg/kg p.o. NKP608, the effect being weaker or absent at both lower (0.001 mg/kg p.o.) and higher (10 mg/kg p.o.) doses. A comparable bell-shaped dose-response relation was seen in the social exploration test in rats. In this modified resident/intruder paradigm, maximal increase in social contact of the intruder rat directed towards the resident rat was seen at a similar dose range (0.03-3 mg/kg p.o.) The effects observed following an acute oral administration of NKP608 were comparable to those seen following a treatment with the well-known benzodiazepine, chlordiazepoxide, in both these tests. These findings indicate that NKP608 exhibits an anxiolytic-like effect and that this effect, as concluded from the observed antagonism of the hind foot thumping induced by i.c.v. administration of the NK-1 receptor agonist SPOMe, is centrally mediated. This makes this compound a potentially promising candidate for treating anxiety-related disorders in humans.

Administration, Oral↗
PubMed2000

The NK1-receptor antagonist NKP608 has an antidepressant-like effect in the chronic mild stress model of depression in rats.

The chronic mild stress (CMS) model of depression was used to study the potential antidepressant-like activity of NKP608, a non-peptidic, specific, potent and orally active NK1 receptor antagonist. In this model, a substantial decrease in consumption of a 1% sucrose solution is observed in rats continously subjected to a variety of mild stressors. This effect can be reversed by chronic administration of various classes of antidepressant drugs. Chronic, oral treatment with NKP608 (once daily for 5 weeks) gradually reversed CMS-induced reductions in sucrose consumption and, the magnitude of this effect was comparable to that observed following administration of imipramine (10 mg/kg). The time-course of action of NKP608 in the CMS model was dose-dependent. At the dose of 0.03 mg/kg, NKP608 caused a full reversal of the CMS-induced deficit in sucrose consumption after 4 weeks of treatment (comparable to 5 weeks required for imipramine), while only 1 week of treatment was required in the group receiving the dose of 0.1 mg/kg NKP608. Lower (0.003 mg/kg) and higher (1.0 mg/kg) doses of the compound were ineffective. These results suggest that NKP608 has antidepressant-like properties in the CMS model in rats; the effect was comparable to conventional drugs, but the onset of action was faster than with the representative tricyclic antidepressant imipramine.

Animals↗
PubMed2000

Anxiolytic-like effects of the prototypical metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine in rodents.

Recently, selective and systemically active antagonists for the metabotropic glutamate 5 receptor (mGlu(5)) were discovered, and the most potent derivative was found to be MPEP (2-methyl-6-(phenylethynyl)pyridine). Given the high expression of mGlu(5) receptors in limbic forebrain regions, it was decided to evaluate the anxiolytic potential of MPEP. After an acute oral administration, MPEP attenuated the anxiety-dependent variable in a variety of well established anxiety test paradigms. In rats, MPEP (10, 30, and 100 mg/kg) increased punished responses in the Geller-Seifter test, but none of these effects reached statistical significance. MPEP significantly increased the ratio (open/total arm entries; 0.1, 1, and 10 mg/kg), the number of open arm entries (0.1, 1, and 10 mg/kg), as well as time spent on open arm (0.1 and 1 mg/kg) in the elevated plus maze test. Furthermore, MPEP (0.3 and 1 mg/kg) significantly increased the time spent in social contact in the social exploration test. In mice, MPEP attenuated stress-induced hyperthermia (15 and 30 mg/kg) and decreased the number of buried marbles in the marble burying test (7.5 and 30 mg/kg). Finally, MPEP (0.01, 0.1, 1, 10, and 100 mg/kg) was tested on spontaneous locomotor activity in mice, and only a dose of 100 mg/kg significantly reduced vertical activity; no effect was seen on horizontal activity. MPEP (7.5, 15, and 30 mg/kg) was ineffective on d-amphetamine-induced (2.5 mg/kg) locomotor activity in mice and prepulse inhibition in rats (1, 3, or 10 mg/kg). Thus, these findings indicate that MPEP exhibits anxiolytic-like effects and low risks for sedation and psychotomimetic side-effects in rodents.

Animals↗
PubMed1999

The effect of a subchronic post-lesion treatment with (-)-deprenyl on the sensitivity of 6-OHDA-lesioned rats to apomorphine and d-amphetamine.

The effects of a subchronic post-lesion treatment of 14 days with (-)-deprenyl or its solvent on the rotational response to apomorphine (0.1 mg/kg) and d-amphetamine (2.5 mg/kg) in 6-OHDA- and SHAM-lesioned rats were investigated. Rats received a local injection of 6-OHDA (9 microg/0.7 microl) or its solvent into the medial forebrain bundle. Following the (SHAM or 6-OHDA) lesion the animals were randomly assigned to one of the two post-lesion treatment groups, viz. vehicle or (-)-deprenyl (0.1 mg/kg, 2 x day, i.p.) and treated for 14 days. After a wash out period of 6 weeks the number of rotations in response to apomorphine (0.1 mg/kg) and d-amphetamine (2.5 mg/kg) were compared. Seven days following the final behavioural experiments the animals were sacrificed and the striatal dopamine, DOPAC and HVA levels were determined. The (-)-deprenyl-treated 6-OHDA-lesioned rats responded with a reduced number of rotations in response to apomorphine but not to d-amphetamine as compared to vehicle-treated 6-OHDA-lesioned rats. However the two lesion groups did not differ in striatal dopamine, DOPAC and HVA concentrations; the levels were below or close to the detection limit ipsilateral to the 6-OHDA injections. Thus a post-lesion treatment with (-)-deprenyl reduced the dopaminergic supersensitivity without a concomitant increase in striatal dopamine content. The data are discussed in the light of the previously described neurorescue properties of (-)-deprenyl.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Differences in pre- and post-synaptic sensitivity to apomorphine between saline and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated C57BL/6 mice as reflected in climbing activity.

The climbing behaviour after low doses (0.05, 0.1 and 0.2 mg/kg) or a high dose (1.5 mg/kg) of apomorphine was studied in saline or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated C57BL/6 mice. Following a 3-week recovery from two injections of saline or MPTP (50 mg/kg inter-injection period: 72 h), mice were randomly selected for determinations of contents of neurotransmitters and metabolites (dopamine, homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC), serotonin (5-hydroxytryptamine, 5-HT) and 5-hydroxyindole-3-acetic acid (5-HIAA)) or the apomorphine-induced climbing paradigm. For the climbing experiment, the animals were habituated for 60 min to metal climbing cylinders after which they received a subcutaneous injection of apomorphine or its solvent. Subsequently, the animals were placed back in the cylinders and their climbing scores were recorded every 5 min for 60 min. The biochemical data indicated that striatal levels of dopamine, DOPAC and HVA were significantly reduced following MPTP-treatment whereas striatal 5-HT and 5-HIAA levels were unaffected. In the climbing paradigm saline and MPTP-treated C57BL/6 mice responded diametrically opposite to low doses of apomorphine: 0.1 and 0.2 mg/kg apomorphine reduced the climbing score in saline-treated mice as compared to saline injections whereas 0.2 mg/kg apomorphine increased the climbing score in MPTP-treated mice. A relatively high dose of apomorphine (1.5 mg/kg) increased the climbing score in both saline- and MPTP-treated mice. However, the climbing score was significantly higher in MPTP-treated mice than in saline-treated mice. These data suggest that MPTP-treated mice lack pre-synaptic dopamine receptors and have an increased post-synaptic sensitivity for apomorphine which is in agreement with the fact that MPTP selectively affects the dopaminergic nigro-striatal pathway which then results in an up-regulation of post-synaptic receptors.

Animals↗
PubMed1996

The memory-facilitating effects of the competitive NMDA-receptor antagonist CGP 37849 are steroid-sensitive, whereas its memory-impairing effects are not.

The retention performance of mice in a passive-avoidance task was facilitated by low doses (0.3 mg/kg) of the competitive NMDA-receptor blocker CGP 37849, but impaired by high doses (30 mg/kg). The facilitatory effect was selectively suppressed by elevation of the plasma levels of aldosterone or corticosterone, or by blockade of steroid biosynthesis or the mineralocorticoid receptors. The impairment of memory, on the other hand, was not steroid sensitive. Accordingly, the data are in line with the hypothesis that drug induced memory facilitation is dependent on steroid sensitive processes.

2-Amino-5-phosphonovalerate↗
PubMed1995

Phosphinic acid analogues of GABA. 1. New potent and selective GABAB agonists.

The antispastic agent and muscle relaxant baclofen 1 is a potent and selective agonist for bicuculline-insensitive GABAB receptors. For many years efforts to obtain superior GABAB agonists were unsuccessful. We describe the syntheses and biological properties of two new series of GABAB agonists, the best compounds of which are more potent than baclofen in vitro and in vivo. They were obtained by replacing the carboxylic acid group of GABA or baclofen derivatives with either the phosphinic acid or the methylphosphinic acid residue. Surprisingly, ethyl- and higher alkylphosphinic acid derivatives of GABA yielded novel GABAB antagonists, which are described in part 2 of this series. Structure-activity relationships of the novel GABAB agonists are discussed with respect to their affinities to GABAB receptors as well as to their effects in many functional tests in vitro and in vivo providing new muscle relaxant drugs with significantly improved side effect profiles.

Animals↗
PubMed1994

Synergistic interactions between NMDA-antagonists and L-dopa on activity in MPTP-treated mice.

Four experiments were performed to investigate whether or not coadministration of NMDA-antagonists potentiate the effect of an ineffective dose of L-Dopa on motor activity in hypoactive MPTP-treated mice. Motor activity was measured in an automated system recording both locomotion (horizontal) and rearing (vertical) activity. L-Dopa alone, at doses of 10 and 20 mg/kg, but not 5 mg/kg, expressed an anti-akinesia effect in MPTP-treated mice. The non-competitive NMDA-antagonist MK-801 (0.03, 0.1, and 0.3 mg/kg) increased by itself both locomotion (0.1 and 0.3 mg/kg) and rearing (0.03 mg/kg) in control (saline-treated) mice whereas no effect was seen in the MPTP-treated mice. Combined with 5 mg/kg L-Dopa, MK-801 (0.1 mg/kg) increased locomotion in MPTP-treated mice. There was no interaction seen between L-Dopa and MK 801 in the control mice. CGP40116 and CGP40117, the active D- and the inactive L-stereoisomer of the competitive NMDA-inhibitor CGP37849, respectively, were also administered together with 5 mg/kg L-Dopa. Both doses (0.003 and 0.03 mg/kg) of CGP40116 in contrast to CGP40117, produced anti-akinesia effect in MPTP-treated mice. CGP40116 (0.0001 to 0.1 mg/kg) together with 5 mg/kg L-Dopa did not affect behaviour in control mice but produced (0.01 mg/kg CGP40116 and 5 mg/kg L-Dopa) in the MPTP-treated mice an anti-akinesia effect. Our findings indicate that the non-competitive NMDA-antagonist MK-801, at doses with reported side-effects, only increase locomotion while rearing remained unaltered in MPTP-treated mice when combined with 5 mg/kg L-Dopa. Only the active stereoisomer CGP40116 in contrast to CG40117, at doses far below reported side-effects, dose-dependently modulated the anti-akinesia effect of a subthreshold dose of L-Dopa. Such data thus support the notion that this behavioural modulation was regulated via NMDA-receptors. The synergism between L-Dopa and the competitive NMDA-antagonist CGP40116 has a potential in treatment of Parkinson's disease to reduce the side-effects of doses of L-Dopa that are used today.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1994

Oxcarbazepine: preclinical anticonvulsant profile and putative mechanisms of action.

Oxcarbazepine (OCBZ, Trileptal) and its main human monohydroxy metabolite (MHD) protected mice and rats against generalized tonic-clonic seizures induced by electroshock with ED50 values between 13.5 and 20.5 mg/kg p.o. No tolerance toward this anticonvulsant effect was observed when rats were treated with OCBZ or MHD daily for 4 weeks. The therapeutic indices were 4 (OCBZ) and > 6 (MHD) for sedation (observation test, mice and rats) and 8 (MHD) or 10 (OCBZ) for motor impairment (rotorod test, mice). Both compounds were less potent in suppressing chemically induced seizures and did not significantly influence rat kindling development. At doses of 50 mg/kg p.o. and 20 mg/kg i.m. and higher, OCBZ and, to a lesser extent, MHD protected Rhesus monkeys from aluminum-induced chronically recurring partial seizures. In vitro, OCBZ and MHD suppressed sustained high-frequency repetitive firing of sodium-dependent action potentials in mouse neurons in cell culture with equal potency (medium effective concentration 5 x 10(-8) M/L). This effect is probably due in part to a direct effect on sodium channels. Patch-clamp studies on rat dorsal root ganglia cells revealed that up to a concentration of 3 x 10(-4) M, MHD did not significantly interact with L-type calcium currents, whereas OCBZ diminished them by about 30% at the concentration of 3 x 10(-4) M. In biochemical investigations, no brain neurotransmitter or modulator receptor site responsible for the anticonvulsant mechanism of action of OCBZ and MHD was identified.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Pretreatment with aldosterone or corticosterone blocks the memory-enhancing effects of nimodipine, captopril, CGP 37,849, and strychnine in mice.

Oral pretreatment with aldosterone or corticosterone blocked the memory-enhancing effects of the calcium antagonist nimodipine, the ACE inhibitor captopril, the NMDA blocker CGP 37,849, and the glycine antagonist strychnine in a passive-avoidance test in mice. The memory-disturbing effects of phenobarbitone, diazepam, CGP 37,849 and scopolamine were not influenced by the hormonal pretreatment. These findings could indicate the involvement of a steroid-sensitive mechanism in drug-induced improvement of memory. In the light of clinical observations showing elevated cortisol levels in Alzheimer patients, the results might also explain why only a limited number of these patients respond to therapy with memory enhancers.

2-Amino-5-phosphonovalerate↗
PubMed1991

Genetic and environmental influences on reactive and spontaneous locomotor activities in rats.

Paired groups of rats (derived from divergent, selective breeding or living in divergent environmental conditions) were compared with regard to locomotor activities. Intrapair differences were found to vary non-systematically, depending upon whether the rats were initially exposed to a test-environment with or without a slight environmental modification (reactive activities), or were allowed to habituate extensively to the environment (spontaneous activity). Since the behavioral patterns were found to represent distinct entities, this pointed to the necessity of differentiating clearly between spontaneous and reactive activities and indicated, once again, that both genetic and environmental influences are important in these behaviors and must be taken into account. Accepting and controlling for these variables makes it possible to use the factor of individual differences in laboratory animal behavior to advantage.

Animals↗