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Biomedical subjects

U Ebert

Publications and source records attributed to U Ebert.

At least 37 records · Page 2Linked to original sources
PubMed2000

Subdiffusive fluctuations of "pulled" fronts with multiplicative noise

We study the propagation of a "pulled" front with multiplicative noise that is created by a local perturbation of an unstable state. Unlike a front propagating into a metastable state, where a separation of time scales for sufficiently large t creates a diffusive wandering of the front position about its mean, we predict that for so-called pulled fronts, the fluctuations are subdiffusive with root mean square wandering Delta(t) approximately t(1/4), not t(1/2). The subdiffusive behavior is confirmed by numerical simulations: For t</=600, these yield an effective exponent slightly larger than 1/4.

Journal Article↗
PubMed2000

Anticonvulsant efficacy of topiramate in phenytoin-resistant kindled rats.

PURPOSE: We evaluated the anticonvulsant efficacy of topiramate (TPM), a structurally novel antiepileptic drug (AED), in amygdala kindled rats that had been preselected with respect to their response to phenytoin (PHT). METHODS: Anticonvulsant response was tested by determining the afterdischarge threshold (ADT; i.e., a sensitive measure for drug effects on focal seizure activity). By repeated testing with the PHT prodrug fosphenytoin (FOS) three groups of kindled rats were separated: rats in which consistent anticonvulsant effects were obtained (PHT responders), rats that showed no anticonvulsant response (PHT nonresponders), and rats with variable responses (variable PHT responders). The latter, largest group was used to evaluate at which doses and pretreatment times TPM exerted significant anticonvulsant effects on ADT. For this purpose, TPM was tested at four doses (20, 40, 80, 160 mg/kg i.p.) and two pretreatment times (1 and 4 h). The most effective treatment protocol was then used for TPM testing in PHT responders and nonresponders. RESULTS: TPM proved to be an effective AED in the kindling model. At 40 mg/kg, significant ADT increases were obtained after both 1 and 4 h after administration. In addition to the effect on focal seizure threshold, seizure severity and duration recorded at ADT were decreased by TPM, indicating that this drug acts on both seizure threshold and seizure spread. In PHT nonresponders, TPM significantly increased ADT, which is in line with its proven efficacy in patients with refractory partial epilepsy in whom phenytoin has failed. However, TPM was more efficacious in increasing ADT in PHT responders than in nonresponders, substantiating that the difference between these groups of kindled rats extends to other AEDs. Repeated testing of kindled rats with TPM indicated that, similar to PHT, there are individual kindled rats without anticonvulsant response to TPM (i.e., TPM nonresponders). CONCLUSIONS: The data of this study substantiate that PHT nonresponders are a unique model for the search of new AEDs with improved efficacy in refractory partial epilepsy.

Amygdala↗
PubMed2000

Influence of grapefruit juice on scopolamine pharmacokinetics and pharmacodynamics in healthy male and female subjects.

OBJECTIVES: To investigate the effects of grapefruit juice on absolute bioavailability of scopolamine in healthy subjects and to evaluate differences in pharmacokinetics and pharmacodynamics between genders. SUBJECTS, MATERIAL AND METHODS: 14 healthy subjects (7 men and 7 women) received scopolamine 0.5 mg as intravenous infusion, and as oral ingestion with and without grapefruit juice on separate occasions. Serum and urine samples were analyzed using gas chromatography-ion trap tandem mass spectrometry. Changes in subjective state were determined up to 24 hours after drug administration. RESULTS: After oral administration, pretreatment with grapefruit juice led to a 30% increase in systemic bioavailability of scopolamine (p = 0.005) and a significant increase in time to reach peak serum concentration (tmax) of scopolamine (p < 0.001). The Cmax value (6.61+/-0.63 ng/ml) of scopolamine after i.v. administration in male subjects was significant higher compared with the value in female subjects (3.93+/-0.04 ng/ml; geometric mean +/- SEM; p = 0.007). No differences were found in urinary excretion rate of scopolamine and scopolamine glucuronide across genders and between the three different routes of scopolamine administration. Scopolamine produced time-dependent decrements in subjective alertness while contentment and calmness were not influenced. CONCLUSIONS: Pretreatment with grapefruit juice delayed the absorption and increased the bioavailability of scopolamine, whereas elimination was not significantly affected. This study identified an influence of gender on Cmax of scopolamine after i.v. infusion.

Adult↗
PubMed2000

High susceptibility of the anterior and posterior piriform cortex to induction of convulsions by bicuculline.

Accumulating evidence suggests that the piriform cortex (PC) plays a critical role in the development of limbic motor seizures. In the anterior piriform cortex (aPC), a functionally defined, discrete epileptogenic site has been previously identified by unilateral microinjection of bicuculline in Sprague-Dawley (SD) rats and termed the 'area tempestas' (AT). Compared to this site in the aPC, more posterior PC sites, particularly a site in the transition zone between the posterior and aPC (central PC) exhibited a greater susceptibility to electrical stimulation. However, it is not known whether central and posterior sites in the PC differ from the aPC, including the AT, with regard to their sensitivity to bicuculline. In the present study, unilateral focal microinfusion of picomole quantities of bicuculline induced behavioural (focal and generalized) seizures in deep layers of all parts of the PC in two rat strains, Wistar and SD. The incidence of generalized seizures was higher in the AT of SD rats, but no such difference was seen in Wistar rats, arguing against the previous proposal that the rat AT is unique in its sensitivity to induction of seizures by bicuculline compared to other locations within or outside of the PC. Injection of biotin-dextran in PC seizure-sensitive sites in SD rats showed clear differences in anterograde and retrograde labelling between the different PC sites. Therefore, although it was possible to evoke generalized seizures from all parts of the PC, the anatomical connections of the bicuculline injection sites were qualitatively different. The results suggest that the deep layers of the entire PC are highly sensitive to seizure induction by bicuculline, thus substantiating the notion that the PC may be important in seizure generation and propagation.

Amygdala↗
PubMed1999

Altered seizure susceptibility after high-frequency transcranial magnetic stimulation in rats.

The long-term effect of repetitive transcranial magnetic stimulation (rTMS) on the susceptibility of amygdala kindling was studied. Two weeks after a single high-frequency rTMS train (120 A/micros, 20 Hz for 3 s), the rats had a 55% higher threshold for induction of epileptic afterdischarges compared with sham-treated or control rats. However, subsequent kindling revealed no difference between rTMS-treated and control rats. Our data suggest that a single rTMS train has long-term effects on the neuronal excitability. These effects may be anticonvulsant and therefore support the safety of rTMS in clinical use.

Amygdala↗
PubMed1999

Changes in 5-HT1A and NMDA binding sites by a single rapid transcranial magnetic stimulation procedure in rats.

The effects of a single rapid-rate transcranial magnetic stimulation (rTMS) exposure on neurotransmitter binding sites in the rat brain 24 h after the stimulation were examined. Quantification by in vitro-autoradiography showed no differences for 3H-paroxetine binding (5-HT uptake sites) between rTMS-treated, sham and control animals. In contrast, the number of 5-HT1A binding sites (labeled with 3H-8-OH-DPAT) were selectively increased in the rTMS-group with significantly higher BMAX values in the frontal cortex, the cingulate cortex, and the anterior olfactory nucleus. A non-specific increase in NMDA binding sites (labeled with 125I-MK-801) in rTMS and sham animals was observed in the hippocampal formation. A selective increase of these binding sites after rTMS was detected in the ventromedial hypothalamus, the basolateral amygdala and layers 5-6 of the parietal cortex. These findings imply that a single rTMS exposure can result in persistent effects on NMDA and 5-HT1A binding sites even 24 h after stimulation and therefore may be of relevance with respect to the therapeutic action of rTMS reported from clinical studies.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1999

Extracellular single-unit recordings of piriform cortex neurons in rats: influence of different types of anesthesia and characterization of neurons by pharmacological manipulation of serotonin receptors.

In epilepsy research, there is a 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. Neurophysiological studies on PC or amygdala-PC slice preparations 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 of PC neurons to evoked burst responses. These long-lasting electrophysiological changes in the PC during kindling appear to be due, at least in part, to impaired function of gamma-aminobutyric acid (GABA)ergic interneurons. The aim of the present study was to develop an anesthetic protocol allowing electrophysiological single-unit recordings from inhibitory, presumably GABAergic PC interneurons in vivo. In addition to recording of spontaneously active PC neurons, microiontophoretic application of glutamate was used to activate silent neurons. Anesthesia of rats with ketamine/xylazine was not suited for single-unit recordings in the PC because of marked cardiovascular depression. Anesthesia with chloral hydrate allowed recording of spontaneous or glutamate-driven single-unit activity in approximately 40% of all animals. A similar percentage was obtained when recordings were done with the narcotic opioid fentanyl (plus gallamine), after all surgical preparations were performed under anesthesia with repeated administration of the barbiturate methohexital. To avoid brain accumulation of methohexital by repeated applications, we modified the anesthetic protocol in that methohexital was only injected once for initiation of surgical anesthesia, followed by the short-acting anesthetic propofol which does not accumulate upon repeated application. Again, after surgical preparation, electrophysiological recordings were done under fentanyl (plus gallamine). By this procedure, spontaneous or glutamate-driven single-unit activity could be measured in all rats in either layer II or III of the PC. Based on shape and frequency of action potentials, two types of neurons were recorded. The predominant type was similar in its firing characteristics to GABAergic neurons in other brain regions, was mainly located in layer III, and could be suppressed by the serotonin2A receptor antagonist MDL 100,907, suggesting that this type of PC neuron represents inhibitory, putative GABAergic interneurons. This new in vivo preparation may be useful for evaluation of PC neurons in kindled rats.

Action Potentials↗
PubMed1999

Effects of captopril and enalapril on electroencephalogram and cognitive performance in healthy volunteers.

OBJECTIVE: Captopril and enalapril have been reported to influence cognitive functions and quality of life in hypertensive patients. METHODS: The effects of captopril (12.5 mg and 25 mg) and enalapril (5 mg and 10 mg) administered during 7-day periods on electroencephalogram (EEG), cognitive functions, and subjective assessments were investigated in healthy males. RESULTS: Neither captopril nor enalapril influenced EEG and cognitive functions compared with placebo. Captopril 12.5 mg decreased subjective activity compared with placebo. Enalapril did not alter subjective ratings. Both systolic and diastolic blood pressure were significantly lower after administration of captopril 25 mg, whereas blood pressure was unaffected by enalapril compared with placebo. CONCLUSION: Our results suggest that central effects of captopril and enalapril were minor and not constant in young healthy men.

Adult↗
PubMed1999

Anticonvulsant effects of eliprodil alone or combined with the glycineB receptor antagonist L-701,324 or the competitive NMDA antagonist CGP 40116 in the amygdala kindling model in rats.

The discovery that glutamate's activity at the N-methyl-D-aspartate (NMDA) receptor is positively modulated by glycine and polyamines has led to a new pharmacological strategy that NMDA receptor-mediated events could be antagonized indirectly at the strychnine-insensitive glycine co-agonist site (glycine(B) receptor) and the polyamine modulatory site. Recently we demonstrated that ifenprodil and L-701,324 (7-chloro-4-hydroxy-3(3-phenoxy)phenyl-2(H)quinoline), polyamine and glycine, receptor antagonists, respectively, at subeffective doses markedly increased after-discharge threshold (ADT) when applied together in amygdala-kindled rats. Because ifenprodil and its derivative, eliprodil, exhibit different affinities for NMDA receptors composed of different subunits, our current question was whether a combination of eliprodil and the glycine, receptor antagonist, L-701,324, would produce a super-additive anticonvulsant action. In addition, we examined the combined treatment of eliprodil with a competitive NMDA receptor antagonist CGP 40116 (D-(E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid) in the kindling model. Eliprodil alone (10-40 mg/kg) had no consistent ADT-increasing activity. When eliprodil was combined with an ineffective dose of L-701,324 (2.5 mg/kg), a significant rise in ADT was observed. Likewise, other measures of seizure activity such as severity and duration were modestly but significantly reduced. With respect to behavioral impairments, no signs of synergistic interaction were observed after the drug combinations. On the other hand, no anticonvulsant effects were found when CGP 40116 was administered alone at doses of 1.25-5 mg/kg or CGP 40116 1.25 mg/kg combined with eliprodil 10 mg/kg. These data suggest that combination therapy with antagonists at the polyamine and glycine sites might potentially treat therapy-resistant complex partial seizures.

2-Amino-5-phosphonovalerate↗
PubMed1999

Immunohistochemical and neurochemical studies on nigral and striatal functions in the circling (ci) rat, a genetic animal model with spontaneous rotational behavior.

Asymmetrical spontaneous turning behavior or circling phenomena are often related to components of the dopaminergic system, particularly to an imbalance of nigrostriatal function. When a rotational preference is observed, it is typically in a direction away from the brain hemisphere with higher striatal dopaminergic transmission. We have recently described a rat mutant (ci) with spontaneous circling behavior and other signs of functional brain asymmetry. Neurochemical determinations showed that mutants of both genders have significantly lower concentrations of dopamine and dopamine metabolites in the striatum ipsilateral to the preferred direction of rotation. In the present study, we used immunohistochemical, neurochemical, and autoradiographic techniques to characterize the dopaminergic abnormalities of the ci rat mutant in more detail. Age-matched non-affected controls of the same strain were used for comparison. Immunohistochemical labeling of dopaminergic neurons and fibers in substantia nigra pars compacta, ventral tegmental area, and striatum did not indicate any significant neurodegeneration or asymmetry that could explain the lateralization in dopamine levels in striatum of ci rats. Neurochemical determinations substantiated that ci rats of both genders have a significant imbalance in striatal dopamine metabolism, but a similar significant lateralization was also seen in non-affected female controls. Comparison of dopamine, serotonin, noradrenaline and several monoamine metabolite levels in substantia nigra, striatum, nucleus accumbens and frontal cortex of ci rats and controls did not disclose any marked difference between affected and non-affected animals which was consistently found in both genders. Quantitative autoradiographic determination of binding densities of dopamine transporter and D1 and D2 receptors in several parts of the striatum and substantia nigra indicated that ci rats have a significantly higher binding density of dopamine transporter and receptors than controls. Taken together, ci mutant rats of both genders exhibit an asymmetry in striatal dopamine and metabolite levels and an enhanced dopamine transporter and receptor binding, but the link of these differences in dopaminergic parameters with the rotational behavior of the animals is not clear yet. The lack of any significant dopaminergic cell loss in the substantia nigra and the locomotor hyperactivity observed in the mutants clearly suggest that the ci rat is not suited as a model of Parkinsonism but rather constitutes a model of a hyperkinetic motor syndrome.

Animals↗
PubMed1999

5'-Nucleotidase activity of mossy fibers in the dentate gyrus of normal and epileptic rats.

Sprouting of mossy fibers in the hippocampus of rats that underwent limbic epileptogenesis by amygdala kindling or kainate injection was studied at the light microscopic and ultrastructural levels by cytochemical demonstration of the enzyme 5'-nucleotidase. This adenosine-producing ectoenzyme has previously been shown to characterize malleable terminals during brain development and lesion-induced synaptogenesis, but to be otherwise associated with glial membranes. At the light microscopic level, kainate-treated but not control or kindled rats showed 5'-nucleotidase activity in the CA3 region and in the inner molecular layer of the dentate gyrus. At the ultrastructural level, in control animals, the synapses of the molecular and granular layers were enzyme negative. Only some mossy fiber boutons of the dentate hilus exhibited 5'-nucleotidase activity. In epileptic rats, synaptic labeling within the hilus appeared more intense. Moreover, 5'-nucleotidase-containing terminals within the inner molecular layer, presumably ectopic mossy fiber boutons, were found in both kindled and kainate-treated rats. It is concluded that, in both the normal and epileptic hippocampus, 5'-nucleotidase is associated with axons capable of a plastic sprouting response. The synaptic enzyme may attenuate the glutamatergic transmission of mossy fibers, in particular of the aberrant mossy fibers in epileptic rats, by producing the inhibitory neuromodulator adenosine. Alternatively, 5'-nucleotidase may influence synapse formation by its putative non-enzymatic, adhesive functions.

5'-Nucleotidase↗
PubMed1999

Characterization of phenytoin-resistant kindled rats, a new model of drug-resistant partial epilepsy: influence of experimental and environmental factors.

It has been recently shown that the variable anticonvulsant effect of phenytoin in the kindling model is not a characteristic of all kindled rats. In a population of amygdala-kindled Wistar rats, subgroups can be selected which consistently respond to phenytoin with an increase in afterdischarge threshold (responders) or which never show such an increase (non-responders). This study examined retrospectively the influence of technical and environmental factors on the results of several prospectively performed phenytoin selections during the last few years. Male and female Wistar rats were implanted with bipolar electrodes aimed at the basolateral amygdala and subsequently kindled. The fully kindled rats were tested for their ability to consistently respond to phenytoin (75 mg/kg i.p.) with an increase of afterdischarge threshold in three consecutive trials. Analysis of 158 Wistar rats of both genders revealed no significant influence of either plasma concentration of phenytoin, kindling parameters, precise electrode location, or differences in focal histology on the result of phenytoin selection. Furthermore, the ability to respond to phenytoin was not associated with the season or the ambient atmospheric pressure during the selection procedure. The data suggest that the difference between phenytoin responders and non-responders is not due to experimental factors, but may rather be genetically determined.

Animals↗
PubMed1999

Characterization of phenytoin-resistant kindled rats, a new model of drug-resistant partial epilepsy: influence of genetic factors.

It has been recently shown that a subpopulation of amygdala-kindled Wistar rats can be selected which do not respond to phenytoin with an increase in afterdischarge threshold (ADT). Such non-responders could be a perfect model for studying the mechanisms of pharmacoresistance of complex partial seizures. Further studies on these rats suggested that the lack of anticonvulsant response was not due to the influence of experimental factors, but is an inherent property of each rat. In this study the influence of genetic factors on the pharmacoresistance to phenytoin by breeding Wistar rats which have been selected for their ability to consistently respond or not respond to phenytoin is examined. Male and female Wistar rats were implanted with bipolar electrodes in the basolateral amygdala and kindled. The fully kindled rats were repeatedly tested for their ability to respond to phenytoin (75 mg/kg i.p.) with an ADT increase. Responders and non-responders were mated and the offspring underwent the same kindling and repeated phenytoin testing procedure. Altogether, four generations of kindled rats were studied. The incidence of responses to phenytoin, i.e. ADT increased by more than 20% of control, was significantly higher in the F2 generation of the responder line compared to the non-responder line, but the number of responders and non-responders in the offspring generations F1-F3 did not significantly increase. The data suggest that the ability to respond or not to respond to phenytoin is genetically determined, although it does not follow a simple scheme of inheritance. The low reproductive success of the kindled and phenytoin-treated rats made it impossible to achieve a strain of phenytoin non-responders.

Animals↗
PubMed1999

Regional drug information service.

BACKGROUND: Drug information centers (DICs) were established in Europe more than two decades ago. The majority of German DICs were created in the 90s. The regional University hospital-based DIC, which offers services to physicans, is now in operation for three and a half years . OBJECTIVE: To evaluate the types of enquiries received and the profile of the users of a drug information service. METHODS: The working procedure at a regional center in Dresden, Germany, is described. The topics for consultation (adverse reactions, pharmacokinetics, etc.) are presented, and the types of drugs involved are classified according to the Anatomical Therapeutic Chemical (ATC) classification. Users are grouped by medical specialty. Future plans for the DIC are discussed. RESULTS: A total of 516 enquiries were received. Questions concerning therapeutic use (34%), adverse drug reactions (28%), pregnancy/lactation (16%), and pharmacokinetics/dosage (15%) were asked most frequently. Cardiovascular drugs (20%), systemic antiinfectives (19%) as well as drugs targeting the central nervous system (15%) and alimentation/metabolism (9%) were the predominant foci of enquiries. The major users of the DIC were internists (19%), general practitioners (19%), pediatricians (18%), and gynecologists (11%). CONCLUSIONS: The types of questions and users of this service were generally similar to those recorded at many other European DICs. The service has begun producing educational bulletins on drug-related topics of clinical relevance.

Drug Information Services↗
PubMed1998

Anticonvulsant effects of melatonin in amygdala-kindled rats.

Different doses of melatonin (50-100 mg/kg i.p.) were tested for their ability to suppress complex partial seizures in the amygdala kindling model of the rat. Thirty minutes after injection of 75 or 100 mg/kg melatonin, the current threshold necessary to elicit epileptic afterdischarges (ADT) was significantly increased by about 200 or 250%, respectively. These doses were also sufficient to suppress generalised seizures at threshold current. All doses of melatonin decreased body temperature by more than 0.5 degrees C, but caused no pronounced ataxia. Seizure susceptibility in terms of ADT changed with the time of the day but seems not to depend on the circadian variation of endogenous melatonin, since the highest ADT was found in the morning when endogenous melatonin levels are low.

Amygdala↗
PubMed1998

Deficient sensorimotor gating following seizures in amygdala-kindled rats.

BACKGROUND: Human patients with limbic epilepsy may develop a psychosis. We combined animal models for epileptogenesis and schizophrenia to investigate possible mechanisms underlying the occurrence of psychoses in epileptics. Since the dysfunction of sensorimotor gating is the basis of some psychotic symptoms, we tested if epileptogenesis or acute seizures influence sensorimotor gating in rats, measured as prepulse inhibition (PPI) of the acoustic startle response (ASR). PPI is the reduction of the ASR that is observed when a startling pulse is preceded by a nonstartling prepulse. Reduced PPI was found in schizophrenics and in rats under certain conditions. METHODS: We investigated the effects on PPI of different models of limbic epileptogenesis (repeated stimulation of the basolateral amygdala, treatment with pentylenetetrazole, injection of kainate). RESULTS: PPI was normal in chronic epileptic rats 1 week after the last generalized seizure. Impaired PPI was found in amygdala-kindled rats 10 min after seizures. The ASR amplitude in the absence of prepulses was increased in kainate-treated rats, but not in the other groups. CONCLUSIONS: Chemical epileptogenesis or repeated stimulation of the amygdala per se did not disrupt sensorimotor gating, but the recent occurrence of seizures in amygdala-kindled rats compromised sensorimotor gating in a way compatible with psychotic states in humans.

Acoustic Stimulation↗
PubMed1998

Differences in the distribution of GABA- and GAD-immunoreactive neurons in the anterior and posterior piriform cortex of rats.

There is accumulating evidence of anterior-posterior differences in the susceptibility of the piriform cortex to seizure induction and to functional alterations in response to seizures elicited from other limbic brain regions, but the reasons for such differences along the anterior-posterior axis of the piriform cortex are not clear. In the present study, GABAergic neurons have been identified in the piriform cortex of the rat at light microscopic level by immunocytochemical localization of GABA and the GABA-synthesizing enzyme glutamic acid decarboxylase. A monoclonal antibody to GABA and, for comparison, polyclonal antibodies to GABA and glutamic acid decarboxylase were used for this purpose. In both anterior and posterior piriform cortex, the highest number and density of GABA-immunoreactive cells was found in layer II. Lower density of GABAergic cells was found in layers I and III and the subjacent endopiriform cortex. When cells were quantified in 19 corresponding sections of the piriform cortex, covering most of anterior-posterior extension of this region, there appeared to be an increased density of GABAergic neurons in sections near to or within the transition zone between anterior and posterior piriform cortex. A more detailed analysis at 4 section levels in the anterior and posterior piriform cortex and the transition zone between the 2 parts substantiated a significantly higher density of GABAergic neurons in the transition zone, which was predominantly due to increased numbers of cells in layers II and III. We propose that the transition zone between anterior and posterior piriform cortex is a location where numerous GABAergic interneurons regulate the activity of neighbouring deep pyramidal cells which receive dense excitatory input from both the olfactory bulb and distant pyramidal cells in the more anterior and posterior parts of the piriform cortex at the same time, thus increasing the risk of paroxysmal activation within this restricted area. This proposal is in line with recent observations of increased susceptibility to epileptiform activation and to kindling-induced neurochemical alterations within the transition zone between anterior and posterior piriform cortex.

Animals↗