Biomedical subjects

L Velísek

Publications and source records attributed to L Velísek.

At least 37 records · Page 2Linked to original sources

PubMed1997

West syndrome model: seek and you will find.

West syndrome is an age-specific epileptic syndrome with onset in infancy. It comprises infantile spasms (usually flexion convulsions), EEG pattern of hypsarrhythmia and mental retardation. Current therapy involves ACTH, corticosteroids, valproic acid, pyridoxine and vigabatrine. The treatment is difficult and more effective antiepileptic drugs are required. Unfortunately, there is no animal model of West syndrome that would accurately depict the situation found in humans. N-methyl-D-asparate (NMDA)-induced seizures in infant rats have certain features of the West syndrome model. These seizures are age-specific (they occur before 25 days of age), include hyperflection (emprosthotonus), their EEG is not specific and they somewhat respond to treatment with the benzodiazepine clonazepam. In 12 and 18 day old rats, we tested the effects of hydrocortisone, pyridoxine and sodium valproate against the seizures induced by 15 and 45 mg/kg of NMDA i.p., respectively. There were weak effects of sodium valproate against the NMDA-induced emprosthotonus. In contrast, high doses of pyridoxine were proconvulsant and hydrocortisone worsened the damage of nerve cells induced by NMDA. The data show that NMDA-induced seizures although similar to West syndrome are extremely resistant to therapy and may not be a good model of the West syndrome. However, the search for an adequate model that would allow for determination of possible mechanisms and testing of putative antiepileptic drugs will continue.

Animals↗

PubMed1996

Developmental regulation of regional functionality of substantial nigra GABAA receptors involved in seizures.

GABAergic (gamma-aminobutyric acid) transmission in the substantia nigra pars reticulata is critical for seizure control. We tested the hypothesis that there is a differential regional distribution and functionality of nigral GABAA receptor sites that is developmentally regulated. In adult rats, we determined the effects on flurothyl seizures of (Z)-3-[(aminoiminomethyl)thio]prop-2-enoic acid (ZAPA, a presumed agonist of the low-affinity GABAA receptor site), bicuculline (an antagonist of the low-affinity GABAA receptor site) and gamma-vinyl-GABA (a GABA-transaminase inhibitor), infused bilaterally in anterior or posterior substantia nigra pars reticulata. ZAPA infusions (8 micrograms) were anticonvulsant in anterior substantia nigra but proconvulsant in posterior substantia nigra. Bicuculline infusions (100 ng) were proconvulsant in anterior substantia nigra but ineffective in posterior substantia nigra. An anticonvulsant dose of gamma-vinyl-GABA, when infused in anterior substantia nigra, was proconvulsant when infused in posterior substantia nigra. In 15 day old rats, the effects of ZAPA, were biphasic: 2 micrograms was anticonvulsant while 8 micrograms was proconvulsant. There was no regional specificity. The data suggest that with maturation there is functional segregation of specific GABAA receptor subtypes involved in substantia nigra-mediated seizure control.

Acrylates↗

PubMed1996

Increased susceptibility of brain slices from carbonic anhydrase II-deficient mice to low [Mg2+]O-induced seizures.

Brain pH is thought to be an influential factor in determining susceptibility to seizures. We compared the susceptibility of brain slices from carbonic anhydrase II (CA II)-deficient mice to epileptiform activity induced by low extracellular [Mg2+], with slices from normal littermates, both bathed in artificial cerebrospinal fluid at pH 7.3. In both entorhinal cortex and hippocampal field CA1, epileptiform activity started earlier in CA II-deficient slices. Raising extracellular [CO2] (20%; extracellular pH, 6.7) reversibly blocked the epileptiform activity in normal, but not in CA II-deficient, slices. The data, combined with previous in vivo findings showing an increased resistance of mutants to seizures, suggest the presence of in vivo anticonvulsant acidosis with long-term compensatory changes that lead to in vitro 'proconvulsant' behavior in CA II-deficient slices clamped at pH 7.3.

Animals↗

PubMed1996

Age-specific effects of baclofen on pentylenetetrazol-induced seizures in developing rats.

PURPOSE: To determine whether seizures have age-specific features, we studied the role of gamma-aminobutyric acidB (GABAB) transmission in rats of various ages (9, 15, 30, and 60 postnatal days). METHODS: We used a GABAB receptor agonist baclofen (2 or 5 mg/kg intraperitoneally, i.p.) and a GABAB receptor antagonist CGP 35348 (100 or 600 mg/kg i.p.) in the pentylenetetrazol (PTZ)-induced model of clonic and tonic-clonic seizures (100 mg/kg subcutaneously, s.c.). RESULTS: Whereas baclofen was anticonvulsant and CGP 35348 proconvulsant in most animals, there were distinct age-related differences in the effectiveness of these drugs and the antagonist had some anticonvulsant activity in adults. Furthermore, the two drugs acting at GABAB receptors had a different profile of action in clonic seizures as compared with tonic-clonic seizures. CONCLUSIONS: The differences in the age-specific action of the GABAB agonist and antagonist suggest the different GABAB receptor subsets may mediate the drug effects. The results indicate that putative antiepileptic drugs (AEDs) must be tested during development because it may not be possible to extrapolate age-specific anticonvulsant effects from studies in adult animals.

Age Factors↗

PubMed1995

Resistance of hippocampal synaptic transmission to hypoxia in carbonic anhydrase II-deficient mice.

Mutant Car2n/Car2n mice deficient in carbonic anhydrase II (CA II; a major brain CA isozyme) suffer from systemic acidosis and are more resistant to experimental seizures than their normal littermates (+/+ or +/Car2n). The N-methyl-D-aspartate (NMDA) subtype of glutamate receptor has been shown to contribute to long-term potentiation (LTP) of synaptic transmission, hypoxic/ischemic neuronal injury and to be blocked by extracellular protons (acidosis). We compared the effects of hypoxia on synaptic transmission and LTP in field CA1 of hippocampal slices from CA II-deficient mice to their normal littermates. Slices were subjected to successive 5, 10 and 15 min-periods of hypoxia with 30 min-recovery periods in between. Hippocampal slices from mutant, CA II-deficient mice, were more resistant to all periods of hypoxia tested than slices from normal littermates. In a separate set of mutant and normal slices, there were no differences in LTP of population spike amplitude. The relative resistance of CA II-deficient mice to hypoxia-induced damage may be a consequence of severe interstitial acidosis. The sustained influence of increased extracellular proton concentrations may change the characteristics of NMDA receptors resulting in an increased resistance of synaptic transmission in CA II-deficient mice to hypoxia compared to controls.

Animals↗

PubMed1995

Kainate/AMPA receptor antagonists are anticonvulsant against the tonic hindlimb component of pentylenetetrazol-induced seizures in developing rats.

Non-NMDA receptor antagonists CNQX, DNQX, and NBQX (10-40 mg/kg IP) were tested against pentylenetetrazol-induced (100 mg/kg SC) seizures in 7 to 90-day-old rats. All three drugs significantly decreased the incidence of tonic hindlimb component of tonic-clonic pentylenetetrazol seizures, often in favor of increased incidence of forelimb tonus throughout development. In addition, in 7 to 25-day-old rats, DNQX and NBQX decreased the severity of seizures due to a decrease in total incidence of the tonic component of tonic-clonic seizures compared to age-matched controls. However, neither drug was able to consistently suppress the incidence or increase latency to onset of clonic and tonic-clonic pentylenetetrazol seizures. The data suggest that, during development, non-NMDA receptor transmission may play a role in the generation of the tonic component, but not in the generation of other components of pentylenetetrazol-induced seizures.

6-Cyano-7-nitroquinoxaline-2,3-dione↗

PubMed1995

Age-dependent anticonvulsant action of clonazepam in the N-methyl-D-aspartate model of seizures.

Seizures may result from an impaired balance between excitation and inhibition. We tested whether clonazepam [a benzodiazepine that enhances GABAA inhibitory transmission (0.2 or 1.0 mg/kg, intraperitoneally [i.p.])] suppresses an age-dependent pattern of N-methyl-D-aspartate (NMDA)-induced phenomena in 7-, 12-, 18-, 25-, and 60-day-old rats (10, 40, 100, 100, and 200 mg/kg of NMDA, i.p., respectively). There were no effects of clonazepam against the NMDA-induced automatisms and emprosthotonus. In 7-day-old rats, clonazepam was proconvulsant in clonic-tonic seizures (it decreased the latency to onset of seizures, whereas it was anticonvulsant in 25-day-old rats. There was no difference between anticonvulsant effects of clonazepam and its solvent in 12- and 60-day-old rats. Both cortical and hippocampal EEG seizures was extremely poor in this model. There was no improvement of EEG recording after clonazepam. The results demonstrate that impaired excitation cannot be simply balanced by an enhanced inhibition and that the drug effects in young animals cannot be predicted from the effects in adults.

Aging↗

PubMed1995

Excitatory amino acid antagonists and pentylenetetrazol-induced seizures during ontogenesis: III. The action of kynurenic acid and glutamic acid diethylester.

N-methyl-D-aspartate (NMDA) receptor antagonists are anticonvulsant drugs with specific activity against tonic-clonic pentylenetetrazol-induced seizures. However, they do not affect clonic seizures with preserved righting reflexes. In these experiments, we tested the anticonvulsant activity of strychnine-insensitive glycine receptor (at the NMDA site) antagonist kynurenic acid and nonspecific excitatory amino acid receptor antagonist glutamic acid diethylester (GDEE) in the pentylenetetrazol-induced seizure model in developing rats 7, 12, 18, 25, and 90 days old. Control rats were injected with pentylenetetrazol (100 mg/kg subcutaneously). Other rats were pretreated either with kynurenic acid (40, 80, or 240 mg/kg IP) or with GDEE (0.48-480 mg/kg IP), followed by pentylenetetrazol (100 mg/kg). In very young rats (7 and 12 days), both kynurenic acid and GDEE increased the incidence of clonic seizures, whereas the occurrence of tonic-clonic seizures was suppressed or delayed compared to controls. This effect is very similar to the anticonvulsant action of the competitive and noncompetitive NMDA receptor antagonists. In adult rats, the pretreatment with rather higher doses of kynurenic acid or GDEE suppressed or delayed clonic seizures as well as tonic-clonic seizures. Both drugs also induced behavioral side effects: repetitive orientation, wet dog shakes, and frequent jumping. Our data show that there are only weak and nonconsistent age-specific anticonvulsant effects resulting from the blockade of strychnine-insensitive glycine receptor often associated with serious side effects, thus decreasing chances to develop effective antiepileptic treatment in this drug class.

Age Factors↗

PubMed1995

Effects of MK-801 and phenytoin on flurothyl-induced seizures during development.

We determined the effects of the N-methyl-D-aspartate (NMDA) receptor blocker MK-801 (0.05, 0.1, and 0.5 mg/kg intraperitoneally, i.p.) and phenytoin (PHT, 5, 10, and 20 mg/kg i.p.) on flurothyl-induced clonic and tonic-clonic seizures in 9-, 15-, 30-, and 60-day-old male rats. Both agents had seizure-, age-, and dose-specific effects. The highest dose of MK-801 was anticonvulsant against clonic flurothyl-induced seizures only in 9- and 60-day-old rats, but suppressed tonic-clonic seizures in all ages. The lowest dose of MK-801 (0.05 mg/kg) produced significant anticonvulsant effects only in 15 day old rats. PHT did not have any effect on clonic seizures throughout development. Both doses of PHT (10 and 20 mg/kg) were anticonvulsant against tonic-clonic seizures in adult rats but not in any other age group. The results indicate that NMDA receptors play an important role in tonic-clonic flurothyl-induced seizures throughout development (especially in 15-day-old rats) and that the anticonvulsant effects of PHT may vary at different stages of brain development.

Age Factors↗

PubMed1995

Age-dependent effects of gamma-aminobutyric acid agents on flurothyl seizures.

Behavioral characteristics of seizures have age-dependent features, which suggests that effective treatment of seizures may be age-specific as well. In experiments that used the flurothyl seizure model, we examined the effects of several drugs that affect GABAergic neurotransmission in rats of various ages. Systemic administration of phenobarbital (PB, a drug that enhances GABAA receptor-mediated inhibition) was anticonvulsant in most age groups. In contrast, gamma-vinyl GABA (VGB, a drug that increases endogenous GABA levels and enhances both GABAA and GABAB receptor transmission) did not have anticonvulsant effects. Baclofen (a GABAB receptor agonist) was proconvulsant in 9-day-old rat pups, and anticonvulsant in 15-30-day-old rats and lost its anticonvulsant activity in 60-day-old rats. CGP 35348 (a GABAB receptor antagonist) was proconvulsant in developing rats but not in 60-day-old rats. A novel GABAB receptor antagonist, CGP 36742, was proconvulsant in 9- and 15-day-old rats but had no effects in 30- and 60-day-old rats. These results indicate that the effects of presumed GABAergic agents are not uniform across the age span. The differences may reflect age-dependent maturational changes of GABA receptor subtypes, differential action of the drugs on pre- and postsynaptic sites and possible non-GABAergic effects.

Age Factors↗

PubMed1994

Developmental changes of ketamine action against epileptic afterdischarges induced by hippocampal stimulation in rats.

Action of ketamine (5-40 mg/kg) was tested against electrically induced hippocampal afterdischarges (four stimulations in one session; 8 Hz, 15 s) in rats 7, 12, 18, 25 and 90 days old. In control sessions, there was either stable afterdischarge (AD) duration and wet dog shakes (WDS) number or there was an increase in ADs' duration with repeated stimulations. Ketamine had dose-dependent and age-dependent effects. In 7-18-day-old rats, ketamine suppressed better WDS number than AD duration, with nearly absent action on AD duration in 18-day-old animals. Ketamine was equipotent for both phenomena in 25-day-old rats and, in contrast, it decreased more AD duration than WDS number in 90-day-old rats. The data suggest a differentiation induced by ketamine in the expression of motor and electrographic phenomena of the experimental seizures.

Age Factors↗

PubMed1994

Lowering of extracellular pH suppresses low-Mg(2+)-induces seizures in combined entorhinal cortex-hippocampal slices.

Lowering [Mg2+]o induces epileptiform bursting in hippocampus and entorhinal cortex (EC), presumably by activation of N-methyl-D-aspartate (NMDA) receptors. Since increasing [H+]o has been shown to reduce NMDA receptor activation, we hypothesized that this could contribute to anticonvulsant actions of acidic pH. To test this, we studied the effects of raising extracellular PCO2 (20.6%, pH = 6.7) or lowering extracellular pH (6.7 or 6.2) on low-Mg(2+)-induced epileptiform discharges. Lowering the pH to 6.7 by either means increased the interval between seizure-like events (SLEs), decreased the maximal amplitude of SLEs, and if the site of seizure generation was at a distance from the recording site, acidification slowed the rate of seizure propagation. In contrast, the duration of SLEs was unaffected by acidic pH or high PCO2. Raising PCO2 or lowering pH to 6.7 also blocked early (8-10 min) but not late (> 20 min) phases of status-like discharges. All effects of the extracellular pH changes were fully reversible. Further lowering of extracellular pH to 6.2 completely and reversibly blocked both SLEs and status-like discharges. Our data show that the effects of high PCO2 and low pH on seizures in the EC in vitro may be dose-dependent and consistent with induction by proton blockade of NMDA receptors. Thus, blockade of NMDA currents by protons may be an important component of the anticonvulsant action of extracellular acidosis. The results also suggest that acidosis may be a desirable property for new antiepileptic treatments.

Acidosis↗

PubMed1994

Clonidine, but not ritanserin, suppresses kainic acid-induced automatisms in developing rats.

In young rats, systemic or local administration of kainic acid (KA) elicits scratching as the prevailing automatism whereas in adult rats, wet dog shakes (WDS) are usually recorded. We tested the effects of the alpha 2-adrenergic agonist clonidine (0.25 mg/kg, IP; also acting, however, on imidazoline receptors), which has been reported to block KA-induced WDS in adult rats and the 5-HT2 antagonist ritanserin (20 mg/kg, IP) in rats aged 7, 12, 18, 25, and 90 days treated IP with doses of KA that induce maximum number of automatisms with minimal early lethal effects (i.e., 4, 6, 8, 10, and 14 mg/kg, respectively). Both WDS and scratching were frequently recorded together in one animal. Neither ritanserin nor its solvent had significant effects on the total number of automatisms or on their distribution between WDS and scratching. In contrast, clonidine suppressed automatisms throughout the development studied. In 90-day-old (adult) rats clonidine decreased the incidence of both WDS and scratching, whereas it usually attenuated scratching at younger ages. Kainic acid-induced seizures were also recorded because of reported incompatibility between tonic-clonic seizures and WDS in adult rats. In 18-90-day-old rats, tonic-clonic seizures and WDS were found incompatible. In 7-18-day-old pups, scratching and KA-induced tonic-clonic seizures occurred together. Moreover, in 7-day-old rats, clonidine was anticonvulsant. We have demonstrated that KA-induced automatisms develop from scratching in pups to prevailing WDS in adult rats, whereas the incidence of scratching rather decreases during development.(ABSTRACT TRUNCATED AT 250 WORDS)

Age Factors↗

PubMed1994

The development of epilepsy in the paediatric brain.

The immature central nervous system (CNS) is more susceptible to the development of seizures than its adult counterpart. Developmental studies of experimental seizures have suggested that young animals have unique behavioural seizure patterns, including the presence of bilateral, though asymmetric, convulsions. There are differences in the mechanisms responsible for the generation of seizures, propagation patterns and seizure arrest and recurrences. These differences are due to local factors as well as factors that affect neural systems consisting of long neuronal circuits. The substantia nigra, a site involved in the control of seizures, will be used as an example to demonstrate how evolving neurobiological processes modulates the suppression or exacerbation of seizures with age. Evidence will also be presented indicating that early in life, seizures may not produce hippocampal damage. An understanding of the age-related differences is important for the development of rational approaches to treating seizures and their consequences.

Age Factors↗

PubMed1994

Anticonvulsant action of carbonic anhydrase inhibition.

In this paper we review our data from in vivo and in vitro experiments with mutant, carbonic anhydrase II (CA II) deficient mice (Car2n/Car2n mutants) compared to their nonmutant littermates (Car2n/+ or +/+). In vivo, mutant mice were more resistant to flurothyl-, pentylenetetrazol, and loud sound-induced seizures than normal littermates. The increased resistance to flurothyl seizures was age dependent for clonic seizures, occurring after 19 days of age and disappearing after 90 postnatal days. In in vitro experiments, synaptic transmission in hippocampal slices from mutant mice were more resistant to hypoxia than synaptic transmission in slices from normal littermates. There was almost no difference in hippocampal CA1 long-term potentiation of synaptic transmission between mutants and nonmutants. However, studying in vitro epileptogenesis, we found hippocampal slices from mutants to be more prone to seizures in the low Mg2+ environment than slices from normal littermates. This striking difference between in vivo and in vitro seizures susceptibility in CA II-deficient mutants suggests and existence of an anticonvulsant factor present in conditions in vivo, but not in vitro. We suggest that extracellular proton concentrations (extracellular pH) acting as N-methyl-D-aspartate (NMDA) receptor antagonist may be such a factor. Mutant mice suffer from severe systemic acidosis that can decrease NMDA receptor function and thus be anticonvulsant in vivo. However in vitro, the steady pH of perfusing solution is relatively alkalinic for mutant mouse slices enhancing the thus NMDA receptor conductance and leading to proconvulsant effects. Thus, the anticonvulsant action of CA inhibition in vivo may be mediated by acidotic extracellular pH rather than an accumulation of CO2 as suggested previously.

Animals↗

PubMed1993

Age dependence of homosynaptic non-NMDA mediated long-term depression in field CA1 of rat hippocampal slices.

It has been hypothesized that high levels of presynaptic activity that fail to activate postsynaptic N-methyl-D-aspartate (NMDA) receptors may lead to long-term depression (LTD). Therefore, we tested the ability of high-frequency (50 Hz) synaptic stimulation in the presence of a blocker of NMDA receptors to elicit homosynaptic LTD at Schaffer collateral-CA1 synapses in hippocampal slices from 15-, 30- and 60-day-old rats. In control slices, there were no developmental differences in the incidence of long-term potentiation (LTP) of either EPSP slope or population spike amplitude. However, while NMDA receptor blockade with the specific antagonist D-2-amino-5-phosphonopentanoic acid (AP5; 25 microM) completely eliminated LTP in 30 and 60-day-olds, a significant number of slices from 15-day-old rats displayed some non-NMDA LTP of synaptic transmission. Moreover, under NMDA receptor blockade, the same high-frequency stimulation now induced homosynaptic LTD of population spike amplitude in a significant number of slices from 15- and 60-day-old rats (47% and 42%, respectively) but not in 30-day-olds (7%). LTD of population spike amplitude was most pronounced in 15-day-old slices (27 +/- 6% of baseline), whereas, in 60-day-old slices, LTD was 81 +/- 3% of baseline. LTD of EPSP slopes occurred in 44% of 15-day-olds, 13% of 30-day-olds, and 33% of slices from 60-day-old rats; the magnitude of EPSP was similar in 15 and 60-day-old slices (70 +/- 9% versus 81 +/- 1% of baseline).(ABSTRACT TRUNCATED AT 250 WORDS)

2-Amino-5-phosphonovalerate↗

PubMed1993

Ethosuximide suppresses seizures and lethality induced by picrotoxin in developing rats.

The action of ethosuximide (125 or 250 mg/kg, IP) against picrotoxin-induced seizures (3-6 mg/kg, IP) was assessed in rats 12, 18, 25, and 90 days old. In 18-day-old and older controls, picrotoxin regularly elicited clonic seizures; tonic-clonic seizures were induced in all age categories with high consequent mortality. Only the higher dose of ethosuximide (250 mg/kg) increased the latency of clonic seizures in 18- and 25-day-old pups. Tonic-clonic seizures were delayed by ethosuximide in 12-, 18-, and 90-day-old rats. Picrotoxin-induced lethality was suppressed only in 18- and 90-day-old rats by the 250-mg/kg dose of ethosuximide. In contrast, ethosuximide pretreatment increased the incidence of clonic seizures in 12-day-old rats. The results suggest that only high doses of ethosuximide can suppress clonic seizures, and this action is not consistent. Tonic-clonic seizures probably have model-specific sensitivity to ethosuximide because in previous studies ethosuximide completely suppressed pentylenetetrazol-induced tonic-clonic seizures but had no effect on kainic acid-induced tonic-clonic seizures. The suppression of mortality rates is probably due to nonspecific effects of high doses of ethosuximide.

Animals↗

PubMed1993

Models of simple partial and absence seizures in freely moving rats: action of ketamine.

The action of ketamine was studied in two models of seizures: a) bilateral neocortical discharges produced by topical application of pentylenetetrazol (model of simple partial seizures); and b) rhythmic spike-and-wave activity induced by systemic administration of pentylenetetrazol (model of absence seizures). Ketamine exerted biphasic effects. In the first model, the dose of 20 mg/kg ketamine significantly suppressed the ictal neocortical discharges (i.e., continuous spiking or ictal activity) accompanied by clonic motor seizures. However, at the dose of 40 mg/kg ketamine significantly accentuated the onset and increased the number of individual discharges (interictal spikes) in bilateral neocortical foci. In the model of rhythmic spike-and-wave activity, the lower dose of ketamine (20 mg/kg) decreased the number of rhythmic spike-and-wave episodes when compared to the higher dose (40 mg/kg) of ketamine, which increased the number of episodes. However, neither result differed significantly from control values. The present results suggest a dose-dependent action of ketamine: Lower doses (10 and 20 mg/kg in the rat) are able to suppress seizure activity, whereas a higher dose (40 mg/kg) potentiates the seizures. Moreover, the action of ketamine may be dependent upon the seizure model used. The study presents a new model of acute epileptic focus in freely moving rats.

Animals↗