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Biomedical subjects

U Ebert

Publications and source records attributed to U Ebert.

At least 73 records · Page 4Linked to original sources
PubMed1998

Characterization of phenytoin-resistant kindled rats, a new model of drug-resistant partial epilepsy: comparison of inbred strains.

PURPOSE: Previous work from our laboratory showed that amygdala-kindled Wistar outbred rats can be selected according to the increase of afterdischarge threshold (ADT) after phenytoin application. Animals that consistently do not respond to phenytoin (PHT) with an ADT increase (non-responders) are the first animal model of pharmacoresistant complex partial seizures. In this study, we determined the ability to respond to PHT in male kindled rats of different inbred strains. METHODS: The experiments were performed in fully kindled rats of five different inbred strains, Wistar-Kyoto, Lewis, Fischer 344, ACI, and Brown Norway. The response type of each rat was revealed by four consecutive PHT applications (75 mg/kg, i.p.) in fully kindled rats. RESULTS: PHT application resulted in plasma concentrations ranging from some 16 microg/ml in Lewis rats to 35 microg/ml in Fischer 344 rats, and in slight ataxia, most strongly in Fischer 344 rats. The rats of each strain did not show a homogeneous response to PHT. A significant increase of ADT was found after 86-97% of applications in Lewis, Wistar-Kyoto, and Fischer 344 rats. In contrast, Brown Norway rats responded in only 34% of experiments. This led to a considerable number of responders (i.e., consistent ADT increase by >20%) in Fischer 344, Wistar-Kyoto, and Lewis rats. The only strain revealing nonresponders (i.e., consistent lack of ADT increase by >20% with PHT treatment) was Brown Norway. CONCLUSIONS: Inbred strains, although genetically more homogenous than outbred strains, differ in their response to PHT. Brown Norway rats can offer advantages for further detailed investigation of the resistance to PHT in the kindling model of complex partial seizures.

Animals↗
PubMed1998

Selection of phenytoin responders and nonresponders in male and female amygdala-kindled Sprague-Dawley rats.

PURPOSE: We recently described that, by repeated testing of the anticonvulsant phenytoin (PHT), it is possible to select responders and nonresponders from large populations of amygdala-kindled Wistar rats. Whereas responders show marked and reproducible increases of focal seizure threshold (afterdischarge threshold: ADT) on repeated testing of PHT, 75 mg/kg i.p., nonresponders do not show any significant ADT increase after this dose, thus allowing use of these subgroups in the search for mechanisms of pharmacoresistance in temporal lobe epilepsy. In this study, we examined whether PHT responders and nonresponders can also be selected from large groups of kindled rats of the Sprague-Dawley strain. METHODS: Male and female Sprague-Dawley rats were amygdala kindled, followed by once weekly i.p. testing of PHT. RESULTS: In contrast to recent experiments in Wistar rats, 75 mg/kg PHT did not induce significant ADT increases in Sprague-Dawley rats, indicating strain differences in response to this drug after kindling. When the dose was lowered to 50 or 25 mg/kg, significant and reproducible ADT increases were obtained in Sprague-Dawley rats of both genders. Therefore these doses were used for selection of responders and nonresponders in a total of 42 rats. Almost 50% of the rats were PHT responders, whereas no rat was a nonresponder when tested in up to six subsequent drug trials. Many rats were variable responders (i.e., showed ADT increases in some but not all trials), which was not due to low or variable drug absorption after i.p. injection. CONCLUSIONS: The data indicate that, in contrast to Wistar rats, Sprague-Dawley rats are not suited for selection of PHT nonresponders, but rather are quite responsive to this drug. A further difference to the Wistar strain is the truncated dose-response with loss of anticonvulsant efficacy at 75 mg/kg in kindled Sprague-Dawley rats, which may, at least in part, explain the inconsistent results reported on the anticonvulsant efficacy of PHT in this strain in the literature. The lack of anticonvulsant activity after administration of 75 mg/kg may be a result of kindling, because administration of this dose before kindling causes a significant ADT increase in this strain. This kindling-induced alteration of the anticonvulsant activity of PHT is a phenomenon that contrasts Sprague-Dawley with Wistar rats and deserves further investigation.

Amygdala↗
PubMed1997

Anticonvulsant effects by combined treatment with a glycineB receptor antagonist and a polyamine site antagonist in amygdala-kindled rats.

Antagonists of binding sites within the NMDA receptor complex, i.e., L-701,324 (7-chloro-4-hydroxy-3-(3-phenoxy)phenyl-2(H)quinolone), a brain penetrating glycineB receptor antagonist, and ifenprodil, a polyamine site antagonist, were tested for anticonvulsant properties in fully amygdala-kindled rats, a model of limbic epilepsy. Both drugs were not able to significantly change seizure parameters (focal afterdischarge threshold, seizure severity, and duration of seizure and afterdischarges), when administered intraperitoneally up to doses which produced severe motor impairment. However, the combination of 10 mg/kg ifenprodil and 5 mg/kg L-701,324 had a pronounced anticonvulsant effect on afterdischarge threshold and seizure severity without concomitant increase of adverse effects. These findings support the hypothesis that drugs acting only at one site of the NMDA receptor complex are ineffective, while combinations of such drugs may synergistically act to suppress limbic seizures, thus providing an adequate strategy for the treatment of this type of refractory epilepsy.

Amygdala↗
PubMed1997

Phenytoin's effect on the spread of seizure activity in the amygdala kindling model.

Phenytoin is a major antiepileptic drug for treatment of limbic seizures. The effect of phenytoin on the generation and spread of seizure activity was studied in a rat model of this type of seizures. Sprague-Dawley and Wistar rats were implanted with a stimulation and recording electrode in the basolateral amygdala. Naive Sprague-Dawley rats showed an increase in current intensity necessary for eliciting afterdischarges (afterdischarge threshold) of about 200% after administration of phenytoin (75 mg/kg i.p.), while seizure severity at threshold was increased compared to controls. Afterdischarge and seizure durations were significantly prolonged under phenytoin. This result suggests that phenytoin can exert a potent anticonvulsant effect on the generation of focal seizure activity, but it does not suppress or may even increase ongoing afterdischarge activity once it occurs. Following amygdala kindling in Wistar rats, administration of phenytoin again resulted in an increase in the afterdischarge threshold. However, all rats still showed generalized seizures, and epileptic afterdischarges could be recorded in various limbic brain regions at threshold current. This result suggests that phenytoin can increase the threshold for generation of epileptic discharges in kindled rats, but is not able to prevent the development of generalized seizure activity and the spread of afterdischarges within the limbic system when focal activity is initiated. We conclude that phenytoin is able to suppress focal seizure activity in the amygdala kindling model of the rat. However, it does not prevent the spread of seizure activity originating in the limbic system. Therefore, a decrease in focal seizure susceptibility seems to be the primary target for phenytoin's anticonvulsant action.

Animals↗
PubMed1997

Acoustic startle-evoked potentials in the rat amygdala: effect of kindling.

The electroencephalogram (EEG) of the basolateral nucleus of the amygdala (BLA) was recorded during presentation of acoustic stimuli (70-110 dB SPL) in rats. EEG recordings were performed by chronically implanted bipolar electrodes in the BLA. The auditory evoked response consisted of a broad negative wave followed by a slow positive wave. A characteristic pattern of 1 to 3 negative peaks with a latency of about 12 ms and an increased amplitude of the slow positive wave at about 30 ms was observed when an acoustic startle response (ASR) occurred. These findings suggest that the BLA is involved in the processing of adverse auditory stimuli. These ASR-correlated potentials in the BLA were used to characterize changes of the physiological state of the amygdala that occur after chronic epileptogenesis. To achieve this aim, the rats were subsequently partially or fully kindled by daily electrical stimulation via the recording electrode. The negative peak was depressed in the partially kindled rats, but not in fully kindled rats. These changes in the characteristic EEG pattern of the BLA during the ASR indicate alteration of the physiological response of the amygdala after limbic epileptogenesis.

Acoustic Stimulation↗
PubMed1997

Cytotoxic therapy and pregnancy.

The use of cytotoxic agents during pregnancy may be unavoidable in order to ensure maternal survival-despite the dangers to the developing fetus. We review 217 such cases published between 1983 and 1995, classifying them into 5 groups according to whether the cytotoxic drugs were used to treat leukaemias, malignant lymphomas, severe rheumatic diseases, gynaecological/breast neoplasms, or other grave conditions. Various factors, such as the drug type, dose, and timing to exposure to gestational age, are analysed with respect to the outcome of these pregnancies (teratogenicity, stillbirths, spontaneous abortions, prematurity, etc.). These results are then integrated in order to determine whether one can predict the individual risk of abnormality for the newborn when cytotoxic agents must be administered to pregnant women faced with a malignancy or other serious condition.

Abnormalities, Drug-Induced↗
PubMed1996

Amygdala kindling does not change emotional responding as measured by the acoustic startle response in the rat.

Human patients with limbic epilepsy are often prone to anxiety and depression. The present study investigated the effect of seizures on emotional responding in the kindling model of complex-partial seizures. Male Wistar rats received electrodes into the right basolateral amygdala and were subsequently kindled until fully generalized seizures could be elicited. These rats did not show a change in the magnitude of the acoustic startle response (ASR) compared to the response amplitude before kindling, or compared to unimplanted controls and to only partially kindled rats. Since the ASR amplitude is a sensitive measure for anxiety or fear, these findings suggest that amygdala kindling does not induce a state of anxiety or fear. However, when analyzing the time course of the ASR within a session, the normally occurring habituation of the ASR was absent in electrode-implanted rats suggesting that the physiological changes induced by electrode implantation interfere with response habituation. Kindling even tended to sensitize the ASR in electrode-implanted rats. Finally, the effect of carbamazepine which is both anticonvulsant and antipsychotic was tested. Carbamazepine significantly reduced the ASR in control and partially kindled rats while this effect was less pronounced in fully kindled rats. It is concluded that amygdala kindling does not change emotional responding as measured by the ASR in rats.

Acoustic Stimulation↗
PubMed1996

Abnormal c-fos expression in the lateral habenula during dystonic attacks in a hamster model of idiopathic dystonia.

The genetically dystonic hamster (dtsz), an animal model of idiopathic dystonia, displays sustained twisting movements and postures either spontaneously or in response to mild stress. In the present study the expression of c-fos immunoreactive neurons (Fos-ir), used as an indicator of neuronal activity, was investigated within various brain regions in dtsz hamsters and non-dystonic control hamsters. Under baseline condition, i.e. in the absence of dystonia, the expression of Fos-ir did not reveal any differences between dtsz hamsters and controls. However, in response to mild stress several brain regions, particularly the lateral habenula (LHb), exhibited differences in c-fos induction in dtsz hamsters and controls. Whereas in the LHb the expression of Fos-ir was markedly enhanced in controls, it showed almost no increase in dystonic hamsters, indicating impaired neuronal activity. Since the lateral habenula receives major input from the basal ganglia via the entopeduncular nucleus, the present data might indicate that basal ganglia are involved in the dystonic syndrome in mutant hamsters.

Animals↗
PubMed1996

Determination of scopolamine in human serum by gas chromatography-ion trap tandem mass spectrometry.

The objective of this study was to develop a very sensitive and selective method for the determination of scopolamine in serum with a rapid and simple sample preparation. A capillary column gas chromatographic-ion trap tandem mass spectrometric technique has been applied. Scopolamine and the internal standard mexiletine were extracted from serum samples and cleaned up by using a single step liquid-liquid extraction. Derivatization was carried out using 2,2,2-trifluoro-N-methyl-N-trimethylsilylacetamide. The mass spectrometer was operated with positive ions in the selected reaction mode with chemical ionisation using methane. The sum of peak height of two daughter ions was used for quantification. The detection limit was 50 pg/ml in serum.

Cholinergic Antagonists↗
PubMed1996

Immunocytochemical localization of GABA immunoreactivity in dentate granule cells of normal and kindled rats.

In order to identify lasting alterations in gamma-aminobutyric acid (GABA) neurons in the kindling model of epilepsy, immunocytochemical techniques were used to quantify the number of GABA-immunoreactive (IR) neurons in different regions of the hippocampal formation (HCF) of amygdala-kindled rats, 40 days after the last fully kindled seizure. A new, highly specific monoclonal GABA antibody was used for these experiments. Unexpectedly, the antibody not only stained neurons in CA1, CA3, and hilus, but also intensively stained granule cells (GCs) in the dentate gyrus (DG) of both kindled rats and non-kindled controls, indicating that GCs may be capable of synthesizing GABA. Comparison with a polyclonal GABA and a glutamate decarboxylase antibody showed that staining of GCs with the monoclonal GABA antibody was much more intense. The number of GABA-IR cells that were counted in different regions of the HCF, including the DG, did not differ significantly between kindled rats and controls, which does not support the hypothesis of loss of hippocampal GABAergic neurons to explain the permanency of kindled epileptogenesis.

Anesthesia↗
PubMed1996

Kindling induces a lasting, regionally selective increase of kynurenic acid in the nucleus accumbens.

We determined endogenous kynurenic acid in nine brain regions and plasma of amygdala-kindled rats at different intervals (24 h or 50 days) after the last fully kindled seizure. Data obtained were compared with age-matched electrode-implanted and non-implanted control groups. Kindling induced a lasting increase in kynurenate in nucleus accumbens, whereas no significant alterations were seen in hippocampus, cerebral cortex, olfactory bulb, striatum, thalamus, tectum, cerebellum, pons/medulla, or plasma. The regionally selective alteration in the nucleus accumbens is in line with previous studies indicating that this brain region functions as a modulatory interface between the limbic and motor systems and may be critically involved in seizure propagation in the kindling model of temporal lobe epilepsy. The increased levels of the endogenous glutamate antagonist kynurenate in nucleus accumbens may be interpreted as a compensatory change to reduce enhanced excitation in this brain region.

Amygdala↗
PubMed1996

Behavioral and neurochemical dysfunction in the circling (ci) rat: a novel genetic animal model of a movement disorder.

One of the crucial breakthroughs in research on parkinsonism was the observation of circling behaviour in rodents after unilateral intranigral injection of 6-hydroxydopamine. This Ungerstedt model remains one of the basic animal models of Parkinson's disease. We report here the first mutant rat strain with abnormal circling behaviour and several other features reminiscent of the Ungerstedt Parkinson model. The neurological disorder in the novel mutant rat strain is determined monogenetically by a recessive autosomal gene termed circling (ci). Mutant rats of both genders exhibit an intense asymmetric circling in an open-field or rotometer, which is enhanced by treatment with amphetamine. Neurochemical determinations show that mutants of both genders have significantly lower concentrations of dopamine and dopamine metabolites in the striatum ipsilateral to the preferred direction of rotation. Furthermore, in a forelimb-reaching test for assessing the skilled motor capacities of rats, ci rats show a marked deficit on the side contralateral to the preferred direction of turning, which is analogous to motor deficits previously described for rats subjected to unilateral 6-hydroxydopamine lesions. The new mutant rat strain thus exhibits remarkable similarities to the Ungerstedt model and could be used to study the endogenous processes, particularly the genetic components, that might eventually lead to progressive motor dysfunctions.

Amphetamine↗
PubMed1996

The role of the piriform cortex in kindling.

In epilepsy research, there is growing interest in the role of the piriform cortex (PC) in the development and maintenance of limbic kindling and other types of limbic epileptogenesis leading to complex partial seizures, i.e. the most common type of seizures in human epilepsy. The PC ("primary olfactory cortex") is the largest area of the mammalian olfactory cortex and receives direct projections from the olfactory bulb via the lateral olfactory tract (LOT). Beside the obvious involvement in olfactory perception and discrimination, the PC, because of its unique intrinsic associative fiber system and its various connections to and from other limbic nuclei, has been implicated in the study of memory processing, spread of excitatory waves, and in the study of brain disorders such as epilepsy with particular emphasis on the kindling model of temporal lobe epilepsy with complex partial seizures. The interest in the kindling model is based primarily on the following observations. (1) The PC contains the most susceptible neural circuits of all forebrain regions for electrical (or chemical) induction of limbic seizures. (2) During electrical stimulation of other limbic brain regions, broad and large afterdischarges can be observed in the ipsilateral PC, indicating that the PC is activated early during the kindling process. (3) The interictal discharge, which many consider to be the hallmark of epilepsy, originates in the PC, independent of which structure serves as the kindled focus. (4) Autoradiographic studies of cerebral metabolism in rat amygdala kindling show that, during focal seizures, the area which exhibits the most consistent increase in glucose utilization is the ipsilateral paleocortex, particularly the PC. (5) During the commonly short initial afterdischarges induced by stimulation of the amygdala at the early stages of kindling, the PC is the first region that exhibits induction of immediate-early genes, such as c-fos. (6) The PC is the most sensitive brain structure to brain damage by continuous or frequent stimulation of the amygdala or hippocampus. (7) Amygdala kindling leads to a circumscribed loss of GABAergic neurons in the ipsilateral PC, which is likely to explain the increase in excitability of PC pyramidal neurons during kindling. (8) Kindling of the amygdala or hippocampus induces astrogliosis in the PC, indicating neuronal death in this brain region. Furthermore, activation of microglia is seen in the PC after amygdala kindling. (9) Complete bilateral lesions of the PC block the generalization of seizures upon kindling from the hippocampus or olfactory bulb. Incomplete or unilateral lesions are less effective in this regard, but large unilateral lesions of the PC and adjacent endopiriform nucleus markedly increase the threshold for induction of focal seizures from stimulation of the basolateral amygdala (BLA) prior to and after kindling, indicating that the PC critically contributes to regulation of excitability in the amygdala. (10) Potentiation of GABAergic neurotransmission in the PC markedly increases the threshold for induction of kindled seizures via stimulation of the BLA, again indicating a critical role of the PC in regulation of seizure susceptibility of the amygdala. Microinjections of NMDA antagonists or sodium channel blockers into the PC block seizure generalization during kindling development. (11) Neurophysiological studies on the amygdala-PC slice preparation from kindled rats showed that kindling of the amygdala induces long-lasting changes in synaptic efficacy in the ipsilateral PC, including spontaneous discharges and enhanced susceptibility to evoked burst responses. The epileptiform potentials in PC slice preparations from kindled rats seem to originate in neuron at the deep boundary of PC. Spontaneous firing and enhanced excitability of PC neurons in response to kindling from other sites is also seen in vivo, substantiating the fact that kindling induces long-lasting changes in the PC c

Animals↗
PubMed1996

Noradrenalin enhances the activity of cochlear nucleus neurons in the rat.

The cochlear nucleus of rats is heavily innervated by noradrenergic fibres from the locus coeruleus. The physiological meaning of this innervation is poorly understood. Therefore, iontophoretically applied noradrenalin was tested on single neurons of the cochlear nucleus in urethane-anaesthetized rats. Iontophoresis of noradrenalin had a dual effect. During application noradrenalin led to moderate inhibition of tone-evoked activity in 37% of the tested neurons. In contrast, approximately 20-30 s after the onset of iontophoresis a long-lasting increase in discharge activity was found in most neurons. Data from iontophoresis of the alpha1-receptor agonist phenylephrine and the alpha2-receptor agonist clonidine suggest that the fast moderate inhibition is mediated by alpha2-receptors while the pronounced long-lasting elevated neuronal firing is mediated by alpha1-receptors. However, these data do not exclude the possibility that part of the response to noradrenalin is also mediated by beta-receptors. Electrical stimulation of the locus coeruleus resulted in an increase in discharge activity comparable with iontophoresis of noradrenalin or phenylephrine. Thus, activation of the locus coeruleus predominantly increases spontaneous and tone-evoked neuronal firing in the cochlear nucleus of the rat. This alpha-receptor-mediated enhanced discharge activity may serve to increase the sensitivity of acoustic processing mechanisms or to lower the threshold for short-latency acoustic reflexes.

Acoustic Stimulation↗
PubMed1996

Long-term studies on anticonvulsant tolerance and withdrawal characteristics of benzodiazepine receptor ligands in different seizure models in mice. I. Comparison of diazepam, clonazepam, clobazam and abecarnil.

We have reported recently that the seizure model and experimental protocol may markedly influence anticonvulsant tolerance and withdrawal characteristics of benzodiazepine (BDZ) receptor ligands so that predictions on tolerance and dependence liability of novel drugs should be based on a battery of chronic experiments. In the present study, we compared BDZ receptor ligands with different intrinsic efficacy and/or gamma-aminobutyric acidA/BDZ receptor subtype selectivity in two seizure models, by using different experimental approaches to assess the tolerance and dependence liability. In one approach, mice were chronically treated with either diazepam, clonazepam, clobazam or the novel anxiolytic and anticonvulsant beta-carboline derivative abecarnil for 4 weeks, at doses which were about equipotent to increase the threshold for myoclonic seizures induced by pentylenetetrazole. Anticonvulsant activity was determined several times during the period of chronic treatment as well as up to 2 weeks after termination of treatment in the same group of animals per drug. The threshold for electroshock-induced tonic seizures was used as a second seizure model in separate groups of mice. In another approach, drug treatment protocols were the same but the seizures were induced only twice during the 4-week period of treatment to reduce the number of trials which could lead to "learned" tolerance. In additional groups of mice, the seizure thresholds were only determined before and after the period of treatment to assess whether repeated seizure induction during the chronic treatment affects the development of dependence. All four drugs lost anticonvulsant activity during the chronic treatment in the different models and experimental approaches, without indication for a significant involvement of learned tolerance. However, marked protocol-related differences were seen with respect to withdrawal symptoms, i.e., measures of physical dependence-inducing properties of the different drugs. For instance, the pentylenetetrazole model was more sensitive than the electroshock-induced tonic seizures model to detect significant decreases in the seizure threshold in the withdrawal period. Both in terms of tolerance- and dependence-inducing properties and adverse effects seen during the chronic treatment in mice, abecarnil did not seem to offer clear advantages compared to the more traditional BDZ receptor ligands. The data substantiate the importance of study design for obtaining predictable informations on the tolerance and withdrawal characteristics of BDZ receptor ligands.

Animals↗