Biomedical subjects

A M Coenen

Publications and source records attributed to A M Coenen.

At least 37 records · Page 2Linked to original sources

PubMed1996

Generalized absence epilepsy and catalepsy in rats.

Adult WAG/Rij rats are considered adequate genetic models for human generalized absence epilepsy. Rats of this strain of 8, 12, and 18 weeks old and age-matched control Wistar rats were exposed to sound stimulation. After offset of stimulation, all WAG/Rij rats showed cataleptic or even cataplexic reactions, which could persist for up to 20 min. Age effects could be demonstrated. None of the Wistar rats showed cataleptic reactions. Electroencephalographic studies in WAG/Rij rats of 21 weeks showed that spike-wave discharges were abundantly present in the background electroencephalogram prior to sound stimulation. Age-matched Wistar rats had almost no spike-wave discharges. Spike-wave discharges in WAG/Rij rats disappeared during sound stimulation and were then increased compared to the prestimulation and stimulation periods. The electroencephalogram during the cataleptic state was also characterized by the presence of large amplitude 2 Hz waves, interspersed with spike-wave discharges. The data suggest that the cataleptic state can be elicited in genetically epilepsy-prone rats. The youngest WAG/Rij rats showed no spike-wave discharges during the cataleptic state. In all, the data suggest that epilepsy-prone animals are sensitive for catalepsy at an age at which the EEG signs of generalized absence epilepsy are not yet manifest.

Animals↗

PubMed1995

Effects of remacemide and its metabolite FPL 12495 on spike-wave discharges, electroencephalogram and behaviour in rats with absence epilepsy.

The effects of the anti-convulsant drug remacemide and one of its active metabolites FPL 12495 were examined in a genetic model for generalized absence epilepsy, the WAG/Rij strain of rats. Number, mean and total duration of spike-wave discharges were measured following oral administration of remacemide and FPL 12495, together with parameters of background electroencephalographic activity (EEG) and spontaneous behaviour in the recording cage. A decrease in the number of the spike-wave discharges was found after remacemide administration. At the highest dose there was near total suppression of the spike-wave discharges. There were no important effects on behaviour and on spectral content of the background EEG, suggesting that remacemide has little side effects. A decrease in the number of spike-wave discharges was also found after FPL 12495 gavage and there was a prolongation of the mean duration. Behavioural changes were only noticed after the highest dose. These were accompanied by changes in the spectral content and particularly by an increase in the amplitude of the delta and the high beta frequencies, together with a decrease in the spindle frequency range. FPL 12495 appeared to be more potent that remacemide in all its effects. The effects of mainly FPL 12495 are uncommon in the sense that so far no other investigated drug shows a decrease in the number together with an increase in the mean duration of the discharges. It seems that in contrast to other anti-epileptic drugs, FPL 12495 exerts a differential action on the two commonly distinguished mechanisms controlling number and duration.

Acetamides↗

PubMed1995

Differential effects of midazolam and zolpidem on sleep-wake states and epileptic activity in WAG/Rij rats.

Hypnotic drugs are known to possess antiepileptic activity. Therefore, the effects of the benzodiazepine hypnotic midazolam (10 mg/kg) and the novel imidazopyridine hypnotic zolpidem (10 mg/kg) on sleep-wake states and on the number of spike-wave discharges were evaluated in WAG/Rij rats. Rats of this strain are considered to be a model for generalized absence epilepsy. Animals were implanted with chronic monopolar EEG electrodes and, after recovery from surgery, the EEG was recorded for 6 h during the dark period on 3 consecutive days. Sleep recordings were analyzed using Hjorth's parameters and number and duration of spike-wave discharges were visually determined. It was found that both drugs facilitated nonREM sleep at the cost of wakefulness. Both hypnotics also reduced the number and duration of spike-wave discharges. The initial decrease after midazolam, however, was followed by a rebound reflecting a poorer quality of vigilance expressed as an increase in spike-wave discharges. The strong antiabsence activity of zolpidem mimics that of midazolam and is well correlated with their equipotent hypnotic action and anticonvulsant effect in the isoniazid test.

Animals↗

PubMed1995

Neuronal activities underlying the electroencephalogram and evoked potentials of sleeping and waking: implications for information processing.

The low amplitude, high frequency waves of the electroencephalogram (EEG) indicative of wakefulness, are produced by a summation of potentials of thalamocortical neurons, which fire in a "tonic mode" of depolarization. In this mode, the transfer of information from the peripheral sense organs to the sensory cortex is facilitated, due to a tonic lowering of the discharge threshold of thalamocortical neurons. The transfer decreases during drowsiness when thalamocortical units are more hyperpolarized and have higher thresholds. In this state, neurons fire synchronously in a "burst mode," which is expressed in EEG spindling. During slow wave sleep sensory blocking reaches a maximum, when thalamocortical cells are yet more deeply hyperpolarized, although that what still passes to the cortex allows a shallow, subconscious, evaluation. The collective burst firing is more irregular, which results in large and slow EEG waves. In contrast, during rapid eye movement (REM) sleep the depolarized tonic mode of firing commonly associated with waking, is again reached. Similar to EEG-patterns, the architecture of evoked potentials is dependent on the state of alertness. During waking, components in event related potentials (ERP) are moderate in amplitude, while during slow wave sleep larger waves are visible. This is caused by more synchronized unit responses with sharper phases of excitations and inhibitions, which results from increased hyperpolarizations. In contrast, visual ERPs belonging to REM sleep closely resemble those of wakefulness. In analyzing unit responses of thalamocortical neurons, it appeared that neuronal excitations are expressed in negative components of the ERP, while inhibitory neuronal activities are associated with positivity. Transient phenomena in the EEG, such as ERP waves, spindles and spike-wave discharges, are the expression of synaptic potentials in superficial cortical layers, where numerous synapses of afferent thalamocortical fibers are localized on the apical dendrites of deeper lying pyramidal neurons. It is suggested that the morphology of these EEG components is primarily due to the discharge characteristics of thalamocortical relay cells, whereby excitations underly negative waves and inhibitions positive waves. The notion of a general correspondence between thalamocortical neuronal activities and the polarity of transients in the cortical surface EEG, allows prudent speculations regarding components of ERPs. Two examples are given: the contingent negative variation (CNV) and the P300 of an ERP which can be elicited by an infrequent stimulus.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1995

Effects of the GABA-uptake inhibitor tiagabine on electroencephalogram, spike-wave discharges and behaviour of rats.

Effects of the anticonvulsant tiagabine in doses of 1, 3 and 10 mg/kg were investigated on electroencephalogram (EEG), spike-wave discharges and behaviour of WAG/Rij rats. These rats are considered as an animal model of generalized, non-convulsive, absence epilepsy. WAG/Rij rats spontaneously show a considerable number of spike-wave discharges in their EEG. These discharges can be facilitated by GABA agonists. The facilitatory effects of these agonists are completely opposite to their effects on convulsive seizures, which are reduced by these drugs. Tiagabine enhances the effects on the GABA system, since it acts as a GABA re-uptake inhibitor. According to expectations, tiagabine enhanced in a dose-related way both the number and mean duration of spike-wave discharges. The low dose of 1 mg/kg had almost no effects, but doses of 3 and 10 mg/kg were effective. Furthermore, tiagabine in the latter two doses increased the power in the higher beta band of the background EEG, whereas no significant changes in behavioural parameters were found. An unexpected finding was the occurrence of a second type of spike-wave discharges. These were again seen with the two higher doses of tiagabine, while 1 mg/kg had no effect. An assumption is that this second type of discharges are forerunners of genuine spike-wave discharges. In general, this experiment supports that non-convulsive epilepsy is associated with a GABA hyperfunction. It also underlines the biochemical differences of convulsive and non-convulsive animal models of epilepsy. Tiagabine, with its GABA-mimetic properties, belongs to the category of drugs effective in convulsive animal models and not in non-convulsive models of epilepsy.

Action Potentials↗

PubMed1995

Sleep deprivation and spike-wave discharges in epileptic rats.

The effects of sleep deprivation were studied on the occurrence of spike-wave discharges in the electroencephalogram of rats of the epileptic WAG/Rij strain, a model for absence epilepsy. This was done before, during and after a period of 12 hours of near total sleep deprivation. A substantial increase in the number of spike-wave discharges was found during the first 4 hours of the deprivation period, whereas in the following deprivation hours epileptic activity returned to baseline values. Immediately after termination of deprivation, a decrease in the number of spike-wave discharges parallelled a rebound of rapid eye movement (REM) sleep and deep non-REM sleep. An initial increase in epileptic activity has also been reported during sleep deprivation of humans. This initial increase as well as the epileptogenic effects during the course of the sleep deprivation and during the recovery period after sleep deprivation can be interpreted in terms of changes in sleep-wake states. Although the epilepsy-provoking mechanisms are not yet understood, an explanation is suggested based on changes of transitions between sleep-wake states and shifts in level of synchronization.

Animals↗

PubMed1995

Role of L-type calcium channel modulation in nonconvulsive epilepsy in rats.

Old male Wistar rats spontaneously showing hundreds of spike-wave discharges daily were used to investigate the role of calcium ions in nonconvulsive epilepsy. The effects of the L-type calcium channel blocker nimodipine and the L-type channel opener BAY K 8644 on number and duration of these spike-wave discharges were investigated. In rats aged 84-94 weeks standard EEG electrodes were chronically implanted; animals were allowed to recover for 10 days. After a baseline registration, nimodipine 2.2, 8.8, and 35.2 mg/kg or BAY K 8644 in dosages of 0.12, 0.47, and 1.88 mg/kg was administered. A control group received the solvent. EEG recordings were made to evaluate drug effects. The highest dose of nimodipine increased the number of spike-wave discharges, whereas BAY K 8644 reduced the number of spike-wave discharges dose dependently. The highest dose of BAY K 8644 also induced fatal convulsions in 3 animals. Our results demonstrate that the L-type calcium antagonist nimodipine facilitates spike-wave discharges and that the L-type calcium agonist BAY K 8644 protects against these discharges, in contrast to previous results suggesting that calcium channel blockers act as antiepileptic drugs (AEDs) and that calcium channel openers act as convulsants. Our results are a further example of the different pharmacologic profile of convulsive and nonconvulsive epilepsy and are also in contrast to what has been described for T-type calcium channel modulation. We therefore propose that modulation of L-type and T-type calcium channels have opposite effects in nonconvulsive epilepsy.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1995

Carbon dioxide euthanasia in rats: oxygen supplementation minimizes signs of agitation and asphyxia.

This paper records the effects of carbon dioxide when used for euthanasia, on behaviour, electrical brain activity and heart rate in rats. Four different methods were used. Animals were placed in a box (a) that was completely filled with carbon dioxide; (b) into which carbon dioxide was streamed at a high flow rate; (c) into which carbon dioxide was streamed at a low flow rate and (d) into which a mixture of carbon dioxide and oxygen was streamed at a fast rate. It was found that the cessation of behaviour was associated with an aberrant pattern of electrical brain activity together with an abnormally low heart rate. The time to reach this point was shortest in those animals placed in the box filled with pure carbon dioxide, longer when carbon dioxide was introduced at a high rate into the box, longer still when oxygen was added to the carbon dioxide gas, and longest when carbon dioxide was streamed slowly into the box. In the condition with pure carbon dioxide, signs of behavioural agitation and asphyxia were seen. This was also true for the two conditions in which carbon dioxide streamed into the box, but to a lesser degree. These signs occurred when some degree of consciousness may still have been present in the animals. Signs of agitation and asphyxia were almost completely absent in the condition where oxygen was added to the carbon dioxide. These results not only demonstrate the usefulness of behavioural criteria next to electrophysiological indices, but also demonstrate that the negative effects of carbon dioxide euthanasia can be prevented by an additional supply of oxygen.

Animal Welfare↗

PubMed1994

Effects of the neuroleptanalgesic fentanyl-fluanisone (Hypnorm) on spike-wave discharges in epileptic rats.

Effects of fentanyl-fluanisone (Hypnorm), a combination often used as a neuroleptanalgesic and anaesthetic, were investigated on spike-wave discharges of epileptic WAG/Rij rats. Fentanyl-fluanisone has stimulating effects on the amount of spike-wave discharges, but not in a dose-dependent manner. A low dose of 0.01 mg/kg fentanyl with 0.5 mg/kg fluanisone causes a large increase in epileptic activity. This effect is larger than with a middle dose of 0.1 mg/kg fentanyl and 5 mg/kg fluanisone and much larger than with a high dose of 0.2 mg/kg fentanyl with 10 mg/kg fluanisone. The last two doses cause a prolonged anaesthetic state in rats. The frequency of the spikes in the spike-wave discharges was decreased by the mixture of fentanyl-fluanisone; this decrease was dose-dependent. Administration of fentanyl alone in the same doses as in the combination abolishes spike-wave activity during the anaesthetic phase but causes a moderate increase after this phase. It also causes a lowering in spike frequency, which is of the same order as with fentanyl-fluanisone. The mechanisms of action of fentanyl are not completely clear, but the opposite effects of mu- and kappa-opioid receptors on spike-wave discharges may play a role in this biphasic effect. Fluanisone alone in the same doses as in the mixture induces a large dose-dependent increase in spike-wave activity, with only a small effect on spike frequency. This might be caused by the antagonistic action of this drug at dopamine receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

The WAG/Rij rat model for nonconvulsive absence epilepsy: involvement of nonNMDA receptors.

The involvement of AMPA and kainate receptors in nonconvulsive epilepsy was studied by intracerebroventricular injections of AMPA, GDEE, kainic acid and kynurenic acid in WAG/Rij rats. The WAG/Rij rat strain is recognized as an animal model for human absence epilepsy. EEG registrations showed that AMPA (0.1 pmol/5 microliters; 1 pmol/5 microliters; 10 pmol/5 microliters) dose-dependently increased the nonconvulsive absence epilepsy while GDEE (0.2 mumol/5 microliters; 1 mumol/5 microliters; 5 umol/5 microliters) caused a dose-dependent decrease. All effects of GDEE could be blocked by an inactive AMPA dosage. Kainic acid (0.01 nmol/5 microliters; 0.1 nmol/5 microliters; 0.15 nmol/5 microliters) had no effects on the nonconvulsive epilepsy but induced convulsions in the two highest dosages. Kynurenic acid (50 nmol/5 microliters; 100 nmol/5 microliters; 500 nmol/5 microliters) decreased dose-dependently the incidence of nonconvulsive epilepsy. The effect of kynurenic acid could be blocked by a nonconvulsive dosage of kainic acid. These results show that the AMPA and kainate receptor appear to be involved in nonconvulsive epilepsy. Furthermore, blockage of these two receptor subtypes led to an antiepileptic effect without inducing behavioural alterations. Therefore, selective AMPA and kainate receptor antagonists might be potent anti-epileptics.

Animals↗

PubMed1994

Interactions between NMDA and nonNMDA receptors in nonconvulsive epilepsy in the WAG/Rij inbred strain.

The interaction between NMDA and nonNMDA receptors was studied in nonconvulsive epilepsy in WAG/Rij rats. Compounds acting on NMDA (NMDA, APH) and nonNMDA (AMPA, GDEE, kainic acid, kynurenic acid) receptors were coinjected intracerebroventricularly. The WAG/Rij rat strain may be an animal model for human nonconvulsive absence epilepsy. The effects on the epilepsy, EEG and behaviour were measured. It appeared that the epilepsy increase, induced by the nonNMDA receptor agonist AMPA, and in a less obvious way, kainic acid, was blocked by the NMDA receptor antagonist APH. The effects of NMDA were completely blocked by the nonNMDA receptor antagonists GDEE and kynurenic acid. These results suggest that there is an interaction between NMDA and nonNMDA receptors. It might be that nonNMDAergic compounds act via activation or inactivation of NMDA receptors and that this latter receptor subtype is the trigger for an epileptic seizure.

Animals↗

PubMed1994

Hypoxic-ischemic encephalopathy sustained in early postnatal life may result in permanent epileptic activity and an altered cortical convulsive threshold in rat.

The aim of this study was to investigate whether the rat cerebral cortex, damaged by hypoxia-ischemia in early postnatal life, would show an increased seizure susceptibility and/or spontaneous epileptic discharges in adulthood. To that end 12-13-day-old Wistar rat pups were unilaterally exposed to hypoxic-ischemic conditions. After a recovery period of about 2.5 months, recording and stimulation electrodes were permanently implanted over the left and right fronto-parietal neocortex. Long-term recording of baseline electrocortical activity showed that only those animals that had incurred severe brain damage, as was reflected by the presence of a cortical infarction, ran a high risk of developing permanent epileptic activity. With the aid of the stimulation electrodes the initial threshold for localized seizure activity was found to be the same for the experimental and non-treated groups. However, when the kindling-like decline of this threshold was assessed by repeated testing over a 2-week period, the infarcted animals tended to a more rapid decline but a higher stabilization level than the non-infarcted and control animals.

Animals↗

PubMed1993

Thalamic multiple-unit activity underlying spike-wave discharges in anesthetized rats.

In epilept WAG/Rij rats, multiple unit activity coinciding with the occurrence of spike-wave discharges was recorded under neurolept anesthesia. Recordings were made in the frontal cortex and in various nuclei of the thalamus, in specific nuclei such as the ventroposterolateral, the ventroposteromedial and the ventrolateral nuclei, as well as in non-specific nuclei such as the mediodorsal nucleus, the reticular thalamic nucleus, the interanteromedial nucleus and the intralaminar nuclei (the central medial nucleus, the centrolateral nucleus and the paracentral nucleus). Rhythmic unit firing concurrent with the spike component of the cortical spike-wave discharge was observed in deep layers of the cortex and in the following thalamic nuclei: in specific nuclei, the mediodorsal and the reticular thalamic nucleus. The activity in the specific nuclei and the mediodorsal nucleus shortly preceded the peak of the spike component. The burst in the reticular thalamic nucleus occurred later than in the specific nuclei. A wave-concurrent firing pattern was observed in the centrolateral nucleus and the paracentral nucleus. Cells in the central medial nucleus and interanteromedial nucleus did not fire in a phase-locked manner. Neurons in the latter nucleus, however, were generally tonically activated during the occurrence of spike-wave discharges. It is suggested that those thalamic nucleic thought to be involved in the production of cortical spindles, and that also fire concurrently with the spike component of the spike-wave discharges, are mediated in the genesis of the latter activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Anesthesia↗

PubMed1993

Aberrant transients in the EEG of epileptic rats: a spectral analytical approach.

Aberrant transients in the cortical electroencephalogram of rats of the epileptic WAG/Rij strain were studied by means of spectral analysis. The EEG of rats of this strain contains, besides normal sleep spindles, high-voltage spiky phenomena, epileptic spike-wave discharges, and deviant intermediate stage. Spectral analysis of these transient phenomena shows that some features, like their peak frequency, are alike, but that they differ in other spectral characteristics, as in the first harmonic of the peak frequency and in the domain of the high frequencies. The results provide arguments for the view that spike-wave discharges might be considered as unique aberrant phenomena, presumably related but dissimilar to the high-voltage spiky phenomena and intermediate stage. Next to this, spectral analysis was used to study the intraphenomenal dynamics of spike-wave discharges. The peak frequency was found to decrease monotonously from about 10 Hz at the beginning of the spike-wave discharge to about 8 Hz at the end. Other spike-wave discharge frequency bands showed an intraphenomenal increase followed by a decrease. These time-variant EEG dynamics in spike-wave discharges might correlate with the cognitive disturbances during absence seizures in man.

Animals↗

PubMed1992

Genetics of spike-wave discharges in the electroencephalogram (EEG) of the WAG/Rij inbred rat strain: a classical mendelian crossbreeding study.

The WAG inbred strain might be an animal model for human absence epilepsy. To study the inheritance pattern of absence epilepsy, WAG rats were crossbred, in a classical Mendelian way, with inbred ACI rats which show no signs of epilepsy. In the parental strains, reciprocal F1 hybrids, F2, B1, and B2 generations, the number and duration of spike-wave discharges were determined. One hundred percent of the F1 animals showed spike-wave discharges, while the percentages for the F2, B1, and B2 generations were 79, 95, and 37%, respectively. These results suggest that the occurrence of spike-wave discharges is determined by one gene with a dominant mode of inheritance. Cavalli's least-squares fitting procedure suggested different genetic models for the two parameters (number and duration) during the two periods (dark and light). These results confirm our previous findings (Peeters et al., Behav. Genet. 20, 453-460, 1990) that a number of genes are involved in absence epilepsy. One dominant gene appears to determine the occurrence, however, while others manipulate the number and duration of epileptic phenomena during the two periods dark and light.

Animals↗

PubMed1992

Effects of the beta-carboline abecarnil on epileptic activity, EEG, sleep and behavior of rats.

The profile of the anxiolytic beta-carboline isopropyl 6-benzyloxy-4-methoxymethyl beta-carboline-3-carboxylate (abecarnil; ZK 112 119), a partial agonist at benzodiazepine receptors, was determined in two experiments. In the first, abecarnil was given to WAG/Rij rats; these rats generate spontaneously occurring spike-wave discharges and are regarded as a model for absence epilepsy. Effects were measured on epileptic activity, together with those on the spectral content of the background electroencephalograph (EEG), as well as on ongoing behavior. In a second experiment, effects on sleep and behavior were investigated in Wistar rats. It was found that, similarly to classical benzodiazepines, abecarnil possessed a strong antiepileptic character and also changed the background EEG to more high-frequency waves and less spindle activity. It also produced more immobile behavior. Abecarnil induced only small, marginally significant increases in slow-wave sleep while reducing REM sleep as a proportion of total sleep. It also reduced the number of REM periods. These observations are consistent with the proposed partial agonist activity of abecarnil, a drug with interesting therapeutic implications.

Animals↗

PubMed1992

Endogenous opioid peptides in brain and pituitary of rats with absence epilepsy.

The level of opioid peptides in several brain areas and in the pituitary was estimated in WAG/Rij rats, which are considered to be a genetic animal model for human absence epilepsy. In comparison with three groups of non-epileptic controls, these epileptic rats had an elevated level of the proenkephalin-derived peptide Met-enkephalin-Arg6-Gly7-Leu8 in the mesencephalon and striatum, while the level of the prodynorphin-derived peptide alpha-neoendorphin was increased in the striatum and hippocampus. In addition various age- and/or strain-related changes in these peptide levels were found in the hippocampus, thalamus, striatum, frontal cortex and neurointermediate lobe of the pituitary. No difference in the hypothalamic beta-endorphin level were found between epileptic and non-epileptic rats, though strain- and/or age-related changes in the peptide content were detected in both lobes of the pituitary. The increased level of proenkephalin and prodynorphin opioid peptides in brain structures, essential for the appearance of spike-wave discharges, suggests that these opioid systems, but not proopiomelanocortin one, may play a role in absence epilepsy.

Animals↗

PubMed1992

Effects of loreclezole on epileptic activity and on EEG and behaviour in rats with absence seizures.

The antiepileptic profile of loreclezole, a new putative antiepileptic compound, has been determined in rats of the WAG/Rij strain, a genetic model of generalized absence epilepsy. In addition, the effects of 0, 5, 10 and 20 mg/kg loreclezole on the spectral content of the background EEG and on spontaneous behaviour of rats were investigated. Both the number of spike-wave discharges and their total duration dose-dependently decreased following administration of loreclezole. Furthermore, the behaviour of the animals was not markedly influenced and significant changes in the background EEG were not noticed after administration. These data suggest that the broad-spectrum antiepileptic loreclezole can be a valuable new drug in the treatment of absence epilepsy.

Animals↗