ABSTRACT
The effects of vigabatrin, which increases GABA concentrations by inhibiting GABA transaminase, on spike and wave discharges (SWDs) in the electroencephalogram of WAG/Rij rats were studied. Vigabatrin increased the incidence and duration of the SWDs, suggesting a quantitative GABA(A)ergic involvement in the mechanism(s) underlying the starting and stopping of an ongoing SWD. Also, vigabatrin decreased the SWD peak frequency, suggesting an important role of GABA(B) in the mechanism(s) underlying the peak frequency of the SWDs. Vigabatrin gradually changed the course of the hazard rates of the SWD durations, suggesting a qualitative GABAergic role in the mechanism(s) underlying the stopping of an ongoing SWD.
Subject(s)
Anticonvulsants/pharmacology , Electroencephalography/drug effects , Vigabatrin/pharmacology , Action Potentials/drug effects , Action Potentials/physiology , Action Potentials/radiation effects , Animals , Animals, Genetically Modified , Confidence Intervals , Male , Rats , Time FactorsABSTRACT
In this study, the effects of vigabatrin on spike-and-wave discharges (SWDs) were measured in WAG/Rij rats, an animal model of absence epilepsy. Vigabatrin was used with the aim of enhancing GABAergic neurotransmission, and in this way to investigate the role of this process in the properties of SWDs. The study was carried out both in the rat, in vivo, and also using a computational model, in order to test different mechanisms that may account for the changes in SWDs after vigabatrin. The model parameters, representing GABA levels, were changed according to the known, and assumed, mechanism of action of the drug. The results show that the computational model can most adequately simulate the data obtained in vivo on the assumption that the enhancement of GABAergic neurotransmission due to application of vigabatrin is most pronounced at the level of the thalamic relay nuclei (TC cells). Furthermore, vigabatrin was shown to affect both the SWD starting and stopping mechanisms, as reflected by hazard rates. Based on these results, we suggest that GABAergic neurotransmission in TC cells is actively involved in the SWD termination.
Subject(s)
Action Potentials/drug effects , Brain/drug effects , Epilepsy, Absence/drug therapy , Epilepsy, Absence/metabolism , Vigabatrin/pharmacology , gamma-Aminobutyric Acid/metabolism , Action Potentials/physiology , Animals , Animals, Genetically Modified , Anticonvulsants/pharmacology , Brain/metabolism , Brain/physiopathology , Computer Simulation , Disease Models, Animal , Epilepsy, Absence/physiopathology , Male , Neural Inhibition/drug effects , Neural Inhibition/physiology , Neural Pathways/drug effects , Neural Pathways/metabolism , Neurons/drug effects , Neurons/metabolism , Rats , Synaptic Transmission/drug effects , Synaptic Transmission/physiology , Thalamus/drug effects , Thalamus/metabolism , Thalamus/physiopathologyABSTRACT
In this paper, we investigate the dynamical scenarios of transitions between normal and paroxysmal state in epilepsy. We assume that some epileptic neural network are bistable i.e., they feature two operational states, ictal and interictal that co-exist. The transitions between these two states may occur according to a Poisson process, a random walk process or as a result of deterministic time-dependent mechanisms. We analyze data from animal models of absence epilepsy, human epilepsies and in vitro models. The distributions of durations of ictal and interictal epochs are fitted with a gamma distribution. On the basis of qualitative features of the fits, we identify the dynamical processes that may have generated the underlying data. The analysis showed that the following hold. 1) The dynamics of ictal epochs differ from those of interictal states. 2) Seizure initiation can be accounted for by a random walk process while seizure termination is often mediated by deterministic mechanisms. 3) In certain cases, the transitions between ictal and interictal states can be modeled by a Poisson process operating in a bistable network. These results imply that exact prediction of seizure occurrence is not possible but termination of an ictal state by appropriate counter stimulation might be feasible.
Subject(s)
Artificial Intelligence , Diagnosis, Computer-Assisted/methods , Electroencephalography/methods , Epilepsy/diagnosis , Adolescent , Adult , Animals , Child , Child, Preschool , Data Interpretation, Statistical , Female , Humans , Male , Mice , Mice, Inbred C57BL , Models, Neurological , Models, Statistical , Rats , Rats, Wistar , Reproducibility of Results , Sensitivity and SpecificityABSTRACT
We show that the hazard function provides useful information about the starting and the stopping mechanisms of absence epileptic seizures. The hazard function quantifies changes in the probability that an event (respectively, the starting and the stopping of a seizure) occurs in some small time interval given that it has not occurred yet. It informs us about changes in the concentration of endogenous substances that modulate the neuronal signalling properties of (parts of) the brain. In a pharmacological experiment, we used the hazard function to study the effect of a GABA-transaminase inhibitor (vigabatrin) on the starting and the stopping mechanisms of absence epileptic seizures in a genetic rat model of absence epilepsy (the WAG/Rij rat). This experiment showed that a high GABA level changed the stopping mechanism of the absence epileptic seizures, creating much better conditions for very long seizures to develop. With respect to the starting mechanism, it was found that both with a high and a low GABA level, there was evidence for a recovery mechanism that decreases the probability that a new seizure starts. Initially, this probability is larger with a high GABA level, but gradually it converges to the same constant baseline probability as in the condition with a low GABA level.
Subject(s)
Epilepsy, Absence/physiopathology , Algorithms , Animals , Anticonvulsants/therapeutic use , Data Interpretation, Statistical , Electroencephalography/statistics & numerical data , Models, Neurological , Models, Statistical , Neural Networks, Computer , Proportional Hazards Models , Rats , Vigabatrin/therapeutic use , gamma-Aminobutyric Acid/metabolism , gamma-Aminobutyric Acid/physiologyABSTRACT
Effects of the novel anti-epileptic drug levetiracetam (50 and 100 mg/kg) on spike and wave discharges (SWDs) of WAG/Rij rats were studied. Levetiracetam decreased the incidence, average duration, total duration and peak frequency of the SWDs. There was no difference between the two doses. These results agree with results obtained in Genetic Absence Epilepsy Rat from Strasbourg (GAERS). Furthermore, the decrease of the SWD peak frequency might support the suggestions that levetiracetam might have a GABAergic mechanism of action.
Subject(s)
Anticonvulsants/pharmacology , Anticonvulsants/therapeutic use , Electroencephalography/drug effects , Epilepsy, Absence/drug therapy , Piracetam/analogs & derivatives , Piracetam/pharmacology , Piracetam/therapeutic use , Animals , Levetiracetam , Male , RatsABSTRACT
To test whether polytherapy with two gamma-aminobutyric acid (GABA) -ergic drugs might be clinically relevant for epilepsy treatment, effects on spike and wave discharges, the fraction of time spent being behaviourally active, and the background electroencephalogram (EEG) during behavioural activity of vigabatrin (15-500 mg/kg i.p.) and diazepam (1.25-10 mg/kg i.p.) were compared with their combination (dose ratio 1:25) in rats. Isobolic analyses were performed to describe the interactions. Unfortunately, no conclusions can be drawn concerning the interaction of both drugs on the spike and wave discharge activity because the effect of diazepam was shown to be dominant. Only vigabatrin decreased the behavioural activity, whereas there was a trend towards a decrease after diazepam. All treatments dose dependently increased the power in the beta frequency band. Unfortunately, the dose ratio was not optimal to describe the interaction. The theta peak frequency was dose dependently decreased after all treatments. There was a synergistic interaction between the two drugs on this variable. These data support both the idea that an increase in power in the beta frequency band can serve as a biomarker for GABAergic inhibition and the suggestion that clinically effective anxiolytics decrease the theta peak frequency. Furthermore, we show that on different variables, there might be different optimal dosage combinations, which might complicate the clinical application of polytherapy.
Subject(s)
Behavior, Animal/drug effects , Diazepam/pharmacology , Electroencephalography/drug effects , GABA Modulators/pharmacology , Vigabatrin/pharmacology , Animals , Dose-Response Relationship, Drug , Drug Interactions , Male , Rats , Rats, Inbred Strains , Theta Rhythm/drug effectsABSTRACT
The antiepileptic drug vigabatrin increases GABA concentrations by inhibiting GABA transaminase. The effects of vigabatrin on type II spike wave discharges (SWDs) in the electroencephalogram of ACI rats were studied in order to learn more about the effects of altering GABA concentration on SWDs. The incidence of type II SWDs increased after vigabatrin (60/h) as compared to saline treatment (3.7/h). This effect appeared with a halftime of 100 min. The duration of type II SWDs increased after vigabatrin (1.52 s) as compared to saline treatment (1.04 s), but the peak-frequency of the type II SWDs decreased after vigabatrin (5.6 Hz) as compared to saline treatment (7.5 Hz). Thus, vigabatrin alters the type II SWD morphology. These results are in agreement with predictions of Destexhe's theoretical model, modulating both GABA(A) and GABA(B) conductances.
