Biomedical subjects

T Klockgether

Publications and source records attributed to T Klockgether.

207 records · Page 12Linked to original sources

PubMed1986

The rat ventromedial thalamic nucleus and motor control: role of N-methyl-D-aspartate-mediated excitation, GABAergic inhibition, and muscarinic transmission.

The rat ventromedial thalamic nucleus (VM) is a point of convergence of several pathways that are supposed to be involved in motor control. Cortical fibers terminating within this nucleus use an excitatory amino acid, possibly L-glutamate, as their transmitter. Excitatory amino acids are known to interact with N-methyl-D-aspartate (NMDA), kainate, and quisqualate receptors, the presence of which has been demonstrated within the thalamus, gamma-Amino-butyrate (GABA) has been identified as the transmitter of the basal ganglia afferents to the VM, whereas cerebellar afferents to the VM are supposed to release ACh acting on muscarinic receptors. The present study investigates the behavioral and motor consequences of local injections of drugs into the VM, which specifically interact with NMDA, GABA, and muscarine receptors. Both the NMDA antagonist (-)2-amino-7-phosphonoheptanoate [(-)AP7], and the GABA agonist muscimol, but not the muscarinic antagonist scopolamine, induced catalepsy and limb rigidity. Both the (-)AP7- and muscimol-induced catalepsy were antagonized by coadministration of NMDA and the GABA antagonist bicuculline. The (-)AP7-induced catalepsy was characterized as an akinetic-rigid syndrome, in which the ability to induce a phasic activation of a set of muscles is lost and replaced by exaggerated tonic muscular responses. NMDA, bicuculline, and the muscarinic agonist bethanechol induced an increase in locomotor activity. The present study provides evidence that an imbalance between NMDA-mediated excitation and GABAergic inhibition within the rat VM leads to disturbances of motility, whereas muscarinic transmission within this nucleus appears to be of minor importance.

Animals↗

PubMed1985

Effects of methyl beta-carboline-3-carboxylate, Ro 15-1788 and CGS 8216 on muscle tone in genetically spastic rats.

Genetically spastic rats were used for studying the effect on muscle tone of beta-carboline-3-carboxylic acid methylester (beta-CCM), an inverse benzodiazepine (BDZ) agonist, and that of Ro 15-1788 and CGS 8216, both putative antagonists of pharmacological actions of BDZs. These animals exhibit pathologically increased muscle tone, which can be recorded and quantified in the electromyogram (EMG) of the gastrocnemius (GS) muscle. beta-CCM, 2.5 and 3.0 mg/kg i.p., augmented the tonic activity in the EMG of GS muscle in spastic rats while it did not modify muscle tone at doses of 1.0 and 2.0 mg/kg. Diazepam, 0.4 mg/kg i.p., and Ro 15-1788, 5 mg/kg i.p., but not CGS 8216, 5 mg/kg i.p., antagonised the effect of the beta-carboline on muscle tone. Ro 15-1788, at doses of 0.1-5 mg/kg i.p., did not affect muscle tone in the genetically spastic rats, whilst at doses of 25-200 mg/kg the imidazodiazepine dose dependently increased the tonic activity in the EMG. The action of Ro 15-1788, 50 mg/kg i.p., was reversed by diazepam, 0.4 mg/kg i.p., and beta-CCM, 2 mg/kg i.p., while CGS 8216, 5 mg/kg i.p., facilitated the effect of Ro 15-1788 on muscle tone. CGS 8216 at doses of 5 and 25 mg/kg i.p. was devoid of any effect on muscle tone, whilst at doses of 50 and 200 mg/kg the pyrazoloquinoline increased the tonic activity recorded in the EMG from the GS muscle of the spastic rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1985

ZK 91296, an anticonvulsant beta-carboline which lacks muscle relaxant properties.

ZK 91296, a newly synthesised beta-carboline with partial agonistic activity at the benzodiazepine receptor raised the threshold current necessary to elicit electroconvulsions in mice. This effect was dose-dependent and could be reversed by Ro 15-1788. ZK 91296 antagonised the anticonvulsant action of diazepam, but potentiated that of phenobarbitone. ZK 91296 protected mice from DMCM-induced seizures with high potency, this effect being benzodiazepine specific. In mutant rats exhibiting an increased muscle tone of the hindlimbs, ZK 91296 was devoid of muscle relaxant effect and antagonised the muscle relaxant action of both diazepam and phenobarbitone. The latter effect could be blocked by Ro 15-1788. The results suggest that the actions of ZK 91296 are only partly due to its partial agonistic properties at the benzodiazepine receptor.

Animals↗

PubMed1985

Muscle relaxant action of excitatory amino acid antagonists.

Antagonists of neuronal excitation induced by dicarboxylic amino acids were tested in genetically spastic rats of the Han-Wistar strain. These animals exhibit an increased muscle tone which can be measured as a spontaneous tonic activity in the electromyogram of the gastrocnemius-soleus muscle. Compounds that block excitation due to N-methyl-D-aspartic acid reduced the spontaneous activity measured in the electromyogram in a dose-related manner. The most potent compounds, 2-amino-7-phosphonoheptanoic and kynurenic acids were effective muscle relaxants when given either intraperitoneally or intracerebroventricularly. 2-Amino-5-phosphonopentanoic acid possessed much weaker muscle relaxant activity, while L-glutamic acid diethylester was inactive by either route. The results suggest that blockade of N-methyl-D-aspartic acid receptors results in a myorelaxant effect. Specific antagonists of excitation at N-methyl-D-aspartic acid receptors may provide a new class of muscle relaxants.

2-Amino-5-phosphonovalerate↗

PubMed1985

Rigidity and catalepsy after injections of muscimol into the ventromedial thalamic nucleus: an electromyographic study in the rat.

The cataleptic state induced by injection of the GABAmimetic drug muscimol into the rat's ventromedial thalamic nucleus (VM) was examined using an electromyographic (EMG) approach. Muscimol in doses up to 50 ng/0.5 microliter injected into the VM induced a tonic EMG activity in the gastrocnemius muscle which is considered to be a measure of limb rigidity. This tonic EMG activity was found to be dose-dependent, GABA specific and locus specific. By recording EMG signals from chronically implanted electrodes in awake, unrestrained rats it was shown that muscular reactions serving to maintain the animal's static equilibrium were intact in the state of VM induced catalepsy. However, animals were unable to initiate movements or locomotion even when they were forced by strong external stimuli. It was found that the animals' immobility was due to an inability to induce a phasic activation of their muscles whereas tonic activation still occurred. It is concluded that the rat's VM is part of a neuronal chain conducting information relevant for the expression of limb rigidity, the VM is involved in the central mechanisms responsible for the phasic activation of a set of muscles.

Animals↗

PubMed1985

Evaluation of the muscle relaxant properties of a novel beta-carboline, ZK 93423 in rats and cats.

The muscle relaxant action of ZK 93423 (6-benzyloxy-4-methoxymethyl-beta-carboline-3-carboxylate ethyl ester), a novel beta-carboline with agonistic properties at the benzodiazepine receptor, was examined by assessing its effect on the tonic electromyogram (EMG) activity of the gastrocnemiussoleus (GS) muscle of genetically spastic rats and on ventral root reflexes, presynaptic inhibition and fusimotor activity in the spinal cord of decerebrate cats. ZK 93423 (0.1-10.0 mg kg-1) depressed the tonic EMG activity in mutant rats in a dose-dependent manner. This effect was reversed by the benzodiazepine antagonist Ro 15-1788 (5.0 mg kg-1). Both ZK 93423 (0.5 mg kg-1) and diazepam (0.3 mg kg-1) enhanced the presynaptic inhibition of the GS muscle and associated dorsal root potentials in decerebrate cats in an almost identical manner. The actions of both drugs were reversed by Ro 15-1788 (5.0 mg kg-1). ZK 93423 (0.5 mg kg-1) and diazepam (0.3 mg kg-1) depressed the activity of both static and dynamic fusimotor neurones, as deduced from changes in the afferent responses of muscle spindle primary endings to low frequency (1 s-1) sinusoidal stretching. The depressant action of diazepam (0.3 mg kg-1) was weaker than that of ZK 93423 (0.5 mg kg-1). The actions of both drugs were reversed by Ro 15-1788 (5.0 mg kg-1). ZK 93423 (0.5 mg kg-1) failed to alter the magnitude of monosynaptic ventral root reflexes evoked by electrical stimulation of a flexor and an extensor nerve, whereas diazepam (0.3 mg kg-1) had a depressant effect on both types of monosynaptic reflexes, which was antagonized by Ro 15-1788 (5.0 mg kg-1). Neither ZK 93423 (0.5 mg kg-1) nor diazepam (0.3 mg kg-1) depressed polysynaptic ventral root reflexes evoked by electrical stimulation of a flexor and a cutaneous nerve. The present results demonstrate that ZK 93423 exerts a potent muscle relaxant action due to a specific interaction with benzodiazepine receptors. However, its profile of actions on spinal motor mechanisms is not identical to that of diazepam.

Animals↗

PubMedDate not supplied

Patterns of age-related shrinkage in cerebellum and brainstem observed in vivo using three-dimensional MRI volumetry.

This study investigates the time course and regional differences in age-related volume loss in cerebellum and brainstem. Three-dimensional (3D) magnetic resonance imaging (MRI) volumetry was used to measure the volumes of 11 regions in the cerebellum and three regions in the brainstem in 48 healthy volunteers (age 19.8-73.1 years). Landmark-adjusted lattices were used to divide the cerebellum into three radial (lobules I-V = lingula/lobulus/culmen, lobules VI-VII = declive/folium/tuber, lobules VIII-X = pyramis/uvula/nodulus) and three transverse subdivisions (vermis, medial, lateral hemisphere). The radial sectors extended laterally throughout the vermis and the medial hemisphere. The brainstem was divided into midbrain, metencephalon (pons and tegmentum pontis) and medulla. Total cerebellar volume marginally declined with age using a linear regression model. An exponential model better described the age dependency of total cerebellar volume. The curve predicted that the volume remained stable until age 50 years and declined thereafter. Volume loss in the cerebellar vermis was striking. Shrinkage in the medial hemisphere was markedly less and only the inferior sector showed a trendwise negative association with age. The lateral hemisphere was not affected by age. No age effects were found for total brainstem volume, metencephalon and medulla. Only the mid-brain showed a trend for age-related shrinkage. The mediolateral gradient of decreasing age effects is similar to the histological pattern of alcoholic cerebellar atrophy (although our subjects were non-alcoholics according to DSM-IIIR criteria and laboratory data) suggesting that a common factor is involved in both processes. In search for a cause of the regional vulnerability, vascular, functional, structural and molecular/genetic factors may be considered.

Adult↗

PubMedDate not supplied

Tremorlytic activity of budipine in Parkinson's disease.

To objectively quantify the tremorlytic activity of budipine in Parkinson's disease (PD), we performed long-term tremor recordings in addition to the Columbia University Rating Scale (CURS) in a subset of patients (n = 14) who enrolled in a multicenter, double-blind, placebo-controlled study. Tremor occurrence improved in the budipine group (n = 7) from 24.7 +/- 15.5% to 14.8 +/- 14.5% (p < 0.05). Tremor intensity decreased from 9.1 +/- 2.5 (signal-to-noise ratio) to 7.2 +/- 1.6. The CURS sum score improved from 5.7 to 3.0 in the budipine group, whereas there was only a small improvement in the placebo group (from 7.1 to 5.5). These data suggest that budipine is an effective tremorlytic agent in PD and that it may be used as an alternative to anticholinergics.

Aged↗

PubMedDate not supplied

Neuronal intranuclear inclusions, dysregulation of cytokine expression and cell death in spinocerebellar ataxia type 3.

OBJECTIVE: We analyzed the expression of the inflammatory mediators IL-1beta, IL-1ra, IL-6 and the transcription factors IRF-1 and C/EBPdelta (previously identified in a transgenic model of spinocerebellar ataxia type 3 (SCA3) by gene expression profiling) in the central nervous system of SCA3 patients in relation to neuronal cell loss and ataxin-3-positive neuronal intranuclear inclusions (NI), to identify a putative upregulation of cytokines or microglia in SCA3 brains and to investigate whether enhanced cytokine expression was a generalized event mediating neuronal dysfunction in SCA3. MATERIALS AND METHODS: Light- and electronmicroscopic immunohistochemistry was performed on SCA3 tissues derived from five patients from unrelated families with genetically confirmed diagnosis, and six individuals without a history of neurological or inflammatory disease. RESULTS: NI were found almost exclusively in brain regions that also showed neuronal cell loss, i.e. in pons and dentate nucleus neurons, rarely in putamen and thalamus, but not in cerebral or cerebellar cortex. NI displayed an irregular surface and were mostly attached to the nucleoli. Quantitative analysis of NI in the pons revealed an inverse relation of NI and cell loss, i.e. patients with more severe neuronal cell loss had a smaller proportion of neurons with NI. Thus, formation of NI is not necessarily an indicator of cell death but could exert a protective effect. We found increased expression of IL-1beta, IL-1ra, IL-6 and C/EBPdelta only in pons and dentate nucleus neurons and both in neurons with and without NI, suggesting that NI are not a prerequisite for transcriptional changes. CONCLUSIONS: Our data suggest that the selectively affected neuronal populations in SCA3 undergo a complex alteration of gene expression independent from the formation of NI.

Aged↗