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Biomedical subjects

Reinhard Dengler

Publications and source records attributed to Reinhard Dengler.

At least 37 records · Page 2Linked to original sources
PubMed2004

2,6 di-tert-butylphenol, a nonanesthetic propofol analog, modulates alpha1beta glycine receptor function in a manner distinct from propofol.

The anesthetic propofol (2,6 diisopropylphenol) mediates some of its effects by activating inhibitory chloride currents in the lower brainstem and spinal cord. The effects comprise direct activation of gamma-aminobutyric acid-A and glycine receptors in the absence of the natural agonist, as well as potentiation of the effect of submaximal agonist concentrations. Replacement of propofol's isopropyl groups by di-tert-butyl groups yields a compound without in vivo anesthetic effects. We have studied the effects of propofol and 2,6 di-tert-butylphenol on chloride inward currents via rat alpha1beta glycine receptors heterologously expressed in human embryonic kidney cells. Propofol, but not 2,6 di-tert-butylphenol, directly activated glycine receptors; half-maximal current activation was observed with propofol 114 +/- 27 microM. Both compounds potentiated the effect of a submaximal glycine concentration (10 microM) to a maximum value of 136% +/- 71% (propofol) and 279% +/- 109% (2,6 di-tert-butylphenol) of the response to glycine 10 microM. The 50% effective concentration for this effect was 12.5 +/- 6.4 microM and 9.4 +/- 10.2 microM for propofol and 2,6 di-tert-butylphenol, respectively. Propofol and its nonanesthetic structural analog do not differ in their ability to coactivate the glycine receptor but differ in their ability to directly activate the receptor in the absence of the natural agonist.

Algorithms↗
PubMed2003

An improved model for the binding of lidocaine and structurally related local anaesthetics to fast-inactivated voltage-operated sodium channels, showing evidence of cooperativity.

1. The interaction of lidocaine-like local anaesthetics with voltage-operated sodium channels is traditionally assumed to be characterized by tighter binding of the drugs to depolarized channels. As inactivated and drug-bound channels are both unavailable on depolarization, an indirect approach is required to yield estimates for the dissociation constants from channels in inactivated states. The established model, originally described by Bean et al., describes the difference in affinity between resting and inactivated states in terms of the concentration dependence of the voltage shift in the availability curve. We have tested the hypothesis that this model, which assumes a simple Langmuir relationship, could be improved by introducing a Hill-type exponent, which would take into account potential sources of cooperativity. 2. Steady-state block by lidocaine was studied in heterologously (HEK 293) expressed human skeletal muscle sodium channels and compared with experimental data previously obtained for 2,6-dimethylphenol, 3,5-dimethyl-4-chlorophenol, and 4-chlorophenol. Cells were clamped to membrane potentials from -150 to -5 mV, and a subsequent test pulse was used to assess the number of channels available to open. 3. All compounds shifted the voltage dependence of channel availability in the direction of negative prepulse potentials. Prediction of the concentration dependence of the voltage shift in the availability curve was improved by the modified model, as shown by a marked reduction in the residual sum of squares. 4. For all compounds, the Hill-type exponent was significantly greater than one. These results could be interpreted in the light of the contemporary hypothesis that lidocaine functions as an allosteric gating effector to enhance sodium channel inactivation by strengthening the latch mechanism of inactivation, which is considered to be a particle-binding process allosterically coupled to activation. Alternatively, they could be interpreted by postulating additional binding sites for lidocaine on fast-inactivated sodium channels.

Algorithms↗
PubMed2003

Mechanisms of cold sensitivity of paramyotonia congenita mutation R1448H and overlap syndrome mutation M1360V.

Missense mutations of the human skeletal muscle voltage-gated Na+ channel (hSkM1) cause a variety of neuromuscular disorders. The mutation R1448H results in paramyotonia congenita and causes cold-induced myotonia with subsequent paralysis. The mutation M1360V causes an overlapping syndrome with both K+-induced muscle weakness and cold-induced myotonia. The molecular mechanisms of the temperature dependence of these disorders are not well understood. Therefore we investigated physiological parameters of these Na+ channel mutations at different temperatures. Channel proteins were recombinantly expressed in human embryonic kidney cells and studied electrophysiologically, using the whole-cell patch-clamp technique. We compared the wild-type (WT) channel with both mutants at different temperatures. Both mutations had slower inactivation and faster recovery from inactivation compared to WT channels. This effect was more pronounced at the R1448H mutation, leading to a larger depolarization of the cell membrane causing myotonia and paralysis. The voltage dependence of activation of R1448H was shifted to more negative membrane potentials at lower temperature but not at the M1360V mutation or in the WT. The window current by mutation R1448H was increased at lower temperatures. The results of this study may explain the stronger cold-induced clinical symptoms resulting from the R1448H mutation in contrast to the M1360V mutation.

Cell Line↗
PubMed2003

Kinetic properties of human AMPA-type glutamate receptors expressed in HEK293 cells.

AMPA-type glutamate receptors (AMPAR) display a high variability in functional properties, which determine the time course of excitatory postsynaptic potentials. They are assembled as tetramers of GluR subunits 1-4 of different splice variants and nuclear edited isoforms. Presently, the kinetics of activation, desensitization and recovery from desensitization of human AMPARs (GluR1, 3 and 4 flip and flop, and GluR2 flip and flop in R and G edited forms, respectively) transiently expressed in HEK293 cells were studied with patch-clamp techniques and ultra fast agonist application. Activation time constants were identical for all receptors (0.13 ms). The GluR2 flip G variant showed the slowest desensitization (10.8 ms), GluR4 flip the fastest (1.6 ms). Recovery from desensitization varied between 3.1 ms (GluR4 flip) and 178 ms (GluR1 flip). To determine functional interactions between subunits in heteromeric receptors the GluR1 flip and the GluR2 flip R were coexpressed. The time constant of desensitization increased linearly from 2.5 ms (GluR1 flip homomers) to 6.8 ms (GluR2 flip R homomers) with the amount of GluR2 flip R cDNA transfected. Recovery followed a monoexponential time course and had a time constant of 178 ms in GluR1 flip homomeric expression. In all GluR1 flip/GluR2 flip heteromers and in GluR2 flip R homomers desensitization recovered with a time constant of approximately 50 ms. Thus, subunit interaction seems likely during recovery but not desensitization. Both parameters might influence the ability of AMPA receptors to mediate glutamate induced chronic excitotoxicity in neurodegenerative diseases.

Cell Line↗
PubMed2003

Distribution of GABAA receptor mRNA in the motor cortex of ALS patients.

The pathomechanism of amyotrophic lateral sclerosis (ALS) remains unclear. There is some evidence that excitotoxic cell death is involved in the degeneration of the motor nervous system, and that ligand-gated receptor channels play a role in the pathogenesis of the disease. Several electrophysiological and anatomical studies support the pathophysiological concept of an impaired inhibitory, namely GABAergic, control of the motoneurons in the cerebral cortex of ALS patients. The aim of our study was to investigate the expression of GABAA-receptor subunit mRNAs and the GABA synthesizing enzyme glutamic acid decarboxylase (GAD) in the motor cortex of ALS patients compared to tissue of control persons. We performed in situ hybridization histochemistry (ISH) on human postmortem motor cortex sections of ALS patients (n = 5) and age matched controls with no history of neurological disease (n = 5). The most intriguing finding was a significantly reduced mRNA expression of the alpha1-subunit in ALS patients while the level of beta1-subunit mRNA was elevated in the patients group. This may indicate specific alterations of the GABAA receptor subunit composition and result in distinct physiological and pharmacological properties of these receptors in ALS patients.

Aged↗
PubMed2003

Intracortical inhibition and facilitation in paired-pulse transcranial magnetic stimulation: effect of conditioning stimulus intensity on sizes and latencies of motor evoked potentials.

The influence of the intensity of the conditioning stimulus on intracortical inhibition (ICI) and intracortical facilitation (ICF) was assessed in a study using paired-pulse transcranial magnetic stimulation. Interstimulus intervals (ISIs) between conditioning and test stimuli were 3 msec and 13 msec. Latencies and areas of motor evoked potentials in response to the test stimulus were measured in the right extensor carpi radialis muscle. Motor evoked potential areas with ISIs of 3 msec and 13 msec showed a different dependence on the intensity of the conditioning stimulus. In contrast, the changes of motor evoked potential latencies were fairly similar with both ISIs. The findings point to a parallel action of ICI and ICF. Furthermore, the latencies seem to be a more sensitive indicator for ICF action than the size parameters of motor evoked potentials.

Action Potentials↗
PubMed2003

Tourette syndrome and obsessive-compulsive disorder: event-related brain potentials show similar mechanisms [correction of mechansims] of frontal inhibition but dissimilar target evaluation processes.

OBJECTIVES: Tourette Syndrome (TS) and Obsessive-Compulsive Disorders (OCD) share many clinical similarities and show a strong comorbidity. Current theories view a frontal-striatal dysfunction as the underlying cause of many clinical aspects of both disorders. This study sought to investigate mechanisms of conceptual integration and attention in both disorders. We hypothesized that the processing of stimuli with interfering aspects would be altered in a similar way while attentional mechanisms could differ. METHODS: Event-related brain potentials (ERPs) were recorded in a modified STROOP-paradigm in groups of TS and OCD patients and in a control group. The paradigm involved the presentation of color words in a range of different colors. The subjects had to respond to words of matching word content and color and to ignore mismatching stimuli. RESULTS: Incongruent stimuli elicited a frontal negative component ("N450") which was enhanced in amplitude and prolonged in latency in both patient groups. Matching stimuli evoked enhanced N2 and P3b components representing target evaluation mechanisms. The OCD group alone displayed a larger P3b amplitude in comparison to both other groups. CONCLUSIONS: The data are interpreted to indicate that frontal inhibitory mechanisms are altered alike in TS and OCD. In contrast, only the OCD group showed evidence for aberrant target evaluation.

Adolescent↗
PubMed2003

Disturbed monitoring and response inhibition in patients with Gilles de la Tourette syndrome and co-morbid obsessive compulsive disorder.

OBJECTIVE: Fronto-striatal dysfunction has been discussed as underlying symptoms of Tourette syndrome (TS) with co-morbid Obsessive Compulsive Disorder (OCD). This suggests possible impairments of executive functions in this disorder, which were therefore targeted in the present study. METHODS: A comprehensive series of neuropsychological tests examining attention, memory and executive functions was performed in a group of 14 TS/OCD in co-occurrence with OCD patients and a matched control group. RESULTS: While attentional and memory mechanisms were not altered, TS/OCS patients showed deficits in executive functions predominantly in the areas of response inhibition and action monitoring. CONCLUSIONS: These findings provide further evidence for a substantial impairment of the frontal-striatal-thalamic-frontal circuit. We propose that the deficits in monitoring, error detection and response inhibition constitute the major impairment of TS/OCD patients in the cognitive domain.

Adult↗
PubMed2003

Gender differences in coping with tension-type headaches.

OBJECTIVE: To study gender differences of coping with illness strategies in tension-type headaches. METHOD: We enrolled 89 subjects (50 women, 39 men) suffering from episodic (n = 37) and chronic (n = 52) tension-type headaches (TTH). Patients were required to answer a Freiburg Questionnaire of Coping with Illness (FQCI), a Von Zerssen Depression Scale (D-S), quality-of-life questionnaires, and a headache home diary (over 4 weeks). In addition, pressure pain thresholds (temporal muscles) and Total Tenderness Scores were obtained. RESULTS: While pain intensity, frequency and quality-of-life parameters were basically the same for female and male EPISODIC TTH sufferers, women scored significantly higher on the F3 subscale (distracting and encouraging) of the FQCI and tended to score higher on the F1 subscale (depressive). Among CHRONIC TTH patients, women reported the pain to be more intense (VAS), were more depressed (D-S), and scored lower on several quality-of-life scores. Female chronic TTH sufferers scored significantly lower on the F2 subscale (active coping) and tended to score higher on F5 (denying). CONCLUSIONS: We conclude that pessimistic coping with illness strategies are more frequent in female episodic and chronic TTH sufferers. We would like to recommend special psychologic intervention in particular to female chronic TTH sufferers which would offer counseling in developing active coping skills.

Adaptation, Psychological↗
PubMed2003

Blockade of voltage-operated neuronal and skeletal muscle sodium channels by S(+)- and R(-)-ketamine.

UNLABELLED: Besides its general anesthetic effect, ketamine has local anesthetic-like actions. We studied the voltage- and use-dependent interaction of S(+)- and R(-)-ketamine with two different isoforms of voltage-operated sodium channels, with a special emphasis on the difference in affinity between resting and inactivated channel states. Rat brain IIa and human skeletal muscle sodium channels were heterologously expressed in human embryonic kidney 293 cells. S(+)- and R(-)-ketamine reversibly suppressed whole-cell sodium inward currents; the 50% inhibitory concentration values at -70 mV holding potential were 240 +/- 60 microM and 333 +/- 93 microM for the neuronal isoform and 59 +/- 10 microM and 181 +/- 49 microM for the skeletal muscle isoform. S(+)-ketamine was significantly more potent than R(-)-ketamine in the skeletal muscle isoform only. Ketamine had a higher affinity to inactivated than to resting channels. However, the estimated difference in affinity between inactivated and resting channels was only 8- to 10-fold, and the time course of drug equilibration between inactivated and resting channels was too fast to cause use-dependent block at 10 Hz up to a concentration of 300 microM. These results suggest that ketamine is less effective than lidocaine-like local anesthetics in stabilizing the inactivated channel state. IMPLICATIONS: Blockade of sodium channels by ketamine shows voltage dependency, an important feature of local anesthetic action. However, ketamine is less effective than lidocaine-like local anesthetics in stabilizing the inactivated state. Because it does not elicit phasic blockade at small concentrations, its ability to reduce the firing frequency of action potentials may be small.

Animals↗
PubMed2002

Increased intracortical inhibition in middle-aged humans; a study using paired-pulse transcranial magnetic stimulation.

Using single and paired-pulse transcranial magnetic stimulation we compared the cortical excitability in two different age groups of healthy subjects (mean+/-SD age: 28.5+/-5.2 vs. 56.1+/-4.9 years). Motor evoked potentials were recorded from right extensor and flexor carpi radialis muscles. The effect of paired-pulse stimulation was assessed by the ratio conditioned/unconditioned response area with interstimulus intervals of 3 and 13 ms to test for intracortical inhibition and facilitation, respectively. To test the influence of sensory input the experiments were conducted without and with vibration of the extensor carpi radialis muscle. The intracortical inhibition was significantly greater in older subjects; however, during muscle vibration this difference between the two groups vanished. The different effect of vibration favors compensatory mechanisms to be responsible for a different paired-pulse excitability in middle-aged subjects.

Adult↗
PubMed2002

[N-methyl 11C]meta-Hydroxyephedrine positron emission tomography in Parkinson's disease and multiple system atrophy.

Orthostatic hypotension (OH) can be present in idiopathic Parkinson's disease (IPD) as well as in atypical parkinsonian syndromes such as multiple system atrophy (MSA). According to clinical tests of sympathetic nerve function and histopathological data, OH is caused by primarily postganglionic sympathetic dysfunction in IPD and by predominantly central and preganglionic degeneration in MSA. It has been proposed that this concept of a different underlying pathogenesis for OH should be applied in the differential diagnosis of parkinsonian disorders, in the form of measurements of sympathetic myocardial innervation. In this pilot study, myocardial imaging with [ N-methyl (11)C]meta-hydroxyephedrine ((11)C-HED) and positron emission tomography (PET) was used as a quantitative tool to evaluate the feasibility of such an approach. Seven patients were included in the study. Two had MSA and OH, three had probable IPD and OH (duration of disease, >3 years), one had probable IPD without OH (disease duration, 3 years) and one had possible IPD without OH (disease duration, 2 years). Ratios of maximal (11)C-HED uptake in the myocardium to that in the liver at 5 and 40 min post injection (p.i.) and - based on kinetic modelling - tracer influx rates K(1) were calculated. Compared with MSA patients ( n=2), IPD patients with OH ( n=3) showed definitely lower uptake ratios at both 5 min p.i. (0.39-0.57 vs 0.78-0.79) and 40 min p.i. (0.21-0.60 vs 0.89-1.06), as well as lower K(1) values (0.198-0.359 vs 0.384-0.450 min(-1)). The patient with probable IPD without OH showed intermediate values (uptake ratio at 5 min: 0.65; uptake ratio at 40 min: 0.87; K(1)=0.363). In the patient with possible IPD, values (uptake ratio at 5 min: 0.96; uptake ratio at 40 min: 1.04; K(1)=0.400) did not differ from those observed in MSA. These results support the hypothesis that measurement of myocardial innervation may contribute to the differential diagnosis of parkinsonian disorders and suggest a need for quantitative pathophysiological imaging, particularly at early stages of disease.

Carbon Radioisotopes↗
PubMed2002

Human GABA A receptors on dopaminergic neurons in the pars compacta of the substantia nigra.

The gamma-aminobutyric acid A (GABA(A)) receptor subunit expression of the dopaminergic cells of the substantia nigra (SN) was investigated in the present study. Especially the dopaminergic cells, located in the pars compacta of SN (SNc), are of great neurologic interest, because the functional deficit and depletion of these cells are the correlate of Parkinson's disease. We used a combination of in situ hybridization histochemistry (ISH) and immunohistochemistry (IHC) on sections of human postmortem mesencephalon to investigate the expression of GABA(A) receptor subunit messenger RNAs (mRNAs) and of the receptor protein in dopaminergic SN cells. Immunohistochemical detection of tyrosine hydroxylase (TH), the pivotal enzyme of dopamine synthesis, was used to define the boundaries of SN pars reticulata (SNr) and pars compacta subregions. In SNr, all neurons were labeled by subunit-specific oligonucleotide probes and the amount of GABA(A) receptor mRNA expression was quantified as alpha(1) = beta(2) > gamma(2) > alpha(3). In contrast, in SNc, only around 25% of neurons expressed mRNA transcripts of GABA(A) receptor subunits, quantified as alpha(1) = beta(2) > gamma(2) > alpha(3) > alpha(4) = beta(3). In approximately the same percentage of neurons, which were labeled by alpha(1)-subunit-specific probe, the alpha(1)-subunit also was detected at the protein level by a specific monoclonal antibody. We, therefore, could demonstrate that a subset of dopaminergic neurons in human SNc receive inhibitory synaptic input by means of GABA(A) receptors mainly of the alpha(1)beta(2)gamma(2) subtype. This might represent a negative feedback loop between the striatum and the SNc and be a target of pharmacologic interventions in neurodegenerative diseases such as Parkinson's disease.

Antibodies, Monoclonal↗
PubMed2002

Kinetic analysis of the agonistic and blocking properties of pentobarbital on recombinant rat alpha(1)beta(2)gamma(2S) GABA(A) receptor channels.

Barbiturates have three different effects on the GABA(A) receptor channels: coactivation, direct activation, and blockage. We investigated the activation and blockage of the GABA(A) receptor channels by pentobarbital using the alpha(1)beta(2)gamma(2S) GABA(A) receptor channels transiently expressed in HEK293 cells in combination with the ultrafast application of agonists. The peak current amplitude of the pentobarbital activated ionic current proportionally increased to the first power of the pentobarbital concentration (Hill coefficient approximately 0.7), indicating that one binding step of pentobarbital at alpha(1)beta(2)gamma(2S) GABA(A) receptor channels can describe the experimental dose-response relation. The maximum peak current amplitude occurred at 1 mM pentobarbital and decreased at higher concentrations due to an open channel block. After the end of the pentobarbital pulses, rebound currents due to transition from the open-blocked to the open state of the receptor were observed. A kinetic scheme was constructed allowing the quantitative analysis of the pentobarbital activated ionic currents through GABA(A) receptor channels.

Animals↗
PubMed2002

Block of recombinant nicotinic receptor channels by IgG from myasthenic patients.

In myasthenia gravis (MG), specific antibodies directed against nicotinic acetylcholine receptor (nAChR) channels are produced. Recently, a distinct blockade of native embryonic-type nAChR channels by purified IgG from MG patients has been demonstrated. In the present study, we investigated the interaction of myasthenic IgG with recombinant embryonic- or adult-type nAChR channels expressed on human embryonic kidney (HEK) 293 cells. For the experiments, the patch clamp technique was applied in combination with an ultra-fast application system for agonists. Repetitive 20-ms pulses of 1 mM acetylcholine (ACh) were applied with or without purified IgG added to the perfusion system. The purified IgG from MG patients blocked currents through both, embryonic- and adult-type nAChR channels to a similar extent. A block by myasthenic IgG of adult-type nAChR channels, which are present exclusively at the postsynaptic membrane of the neuromuscular synapse, was shown to occur. The reversible pharmacological blockade of adult-type nAChR channels by myasthenic IgG may be one factor responsible for rapid fluctuations of weakness or rapid recovery of muscle strength after plasmapheresis in MG.

Acetylcholine↗
PubMed2002

Interaction of high concentrations of riluzole with recombinant skeletal muscle sodium channels and adult-type nicotinic receptor channels.

Riluzole is a neuroprotective drug that modulates glutamergic transmission but also blocks the inactivated state of voltage-gated neuronal sodium channels at very low concentrations (about 0.1 microM). After nausea, the most common adverse effect of riluzole is asthenia, which could be due to a block of muscle sodium channels or acetylcholine receptor channels. Using the patch-clamp technique, we applied riluzole on recombinant voltage-gated skeletal muscle sodium and adult nicotinic acetylcholine receptor channels expressed in a mammalian cell line (HEK 293). Riluzole blocked the inactivated state of voltage-gated skeletal muscle sodium channels, shifting the midpoint of the steady-state inactivation curve to more negative potentials, but only in comparatively high concentrations (> or = 0.1 mM). At these concentrations, riluzole also caused an open-channel block at acetylcholine receptor channels. We conclude that riluzole has only a mild blocking effect on the inactivated state of voltage-gated skeletal muscle sodium channels and nicotinic acetylcholine receptor channels. As the plasma concentration of riluzole in amyotrophic lateral sclerosis (ALS) patients approximates 2 microM, it seems unlikely that asthenia is caused by a block of skeletal muscle sodium channels or acetylcholine receptor channels by riluzole.

Dose-Response Relationship, Drug↗
PubMed2002

Excessive action monitoring in Tourette syndrome.

Tourette Syndrome (TS) has been related to hyperactive basal-ganglia thalamocortical pathways. This suggests that action monitoring might also be hyperactive. The present study used the event-related brain potential (ERP) technique to investigate this hypothesis. A simple "oddball" reaction time experiment was administered to a group of TS patients and a matched control group. In order to investigate variations in attentional allocation separate experimental runs were undertaken with target frequencies of 50% and 80%. The P3b component to targets was taken as an indicator of the target evaluation process and the response locked error-related negativity (ERN) served as an indicator of action monitoring. We hypothesized that the amplitudes of ERN and P3b would vary with respect to target frequency. The TS group would show an overall enhanced ERN but an unchanged P3b.ERN and P3b amplitudes were lower in the 80% target condition than in the 50% condition. In comparison with control subjects TS patients displayed an ERN of overall higher amplitude but with similar variations between target conditions. P3b amplitudes did not differ between groups. The data are interpreted to support the assumption of an abnormal action monitoring system in TS. A number of similarities to Obsessive-Compulsive Disorder are outlined and it is argued that the findings could be related to a hyperactive frontal-striatal-thalamic-frontal circuit.

Adolescent↗