Time filter

Source Type

Loscher W.,University of Veterinary Medicine Hannover | Loscher W.,Center for Systems Neuroscience | Kohling R.,University of Rostock
Epilepsy and Behavior

Little is known about how the brain limits seizure duration and terminates seizures. Depending on severity and duration, a single seizure is followed by various functional, metabolic, and synaptic changes that may form targets for novel therapeutic strategies. It is long known that most seizures are followed by a period of postictal refractoriness during which the threshold for induction of additional seizures is increased. The endogenous anticonvulsant mechanisms involved in this phenomenon may be relevant for both spontaneous seizure arrest and increase of seizure threshold after seizure arrest. Postictal refractoriness has been extensively studied in various seizure and epilepsy models, including electrically and chemically induced seizures, kindling, and genetic animal models of epilepsy. During kindling development, two antagonistic processes occur simultaneously, one responsible for kindling-like events and the other for terminating ictus and postictal refractoriness. Frequently occurring seizures may lead to an accumulation of postictal refractoriness that may last weeks. The mechanisms involved in seizure termination and postictal refractoriness include changes in ionic microenvironment, in pH, and in various endogenous neuromodulators such as adenosine and neuropeptides. In animal models, the anticonvulsant efficacy of several antiepileptic drugs (AEDs) is increased during postictal refractoriness, which is a logical consequence of the interaction between endogenous anticonvulsant processes and the mechanism of AEDs. As discussed in this review, enhanced understanding of these endogenous processes may lead to novel targets for AED development. © 2010 Elsevier Inc. Source

Loscher W.,University of Veterinary Medicine Hannover | Loscher W.,Center for Systems Neuroscience
Epilepsy and Behavior

Drug-refractory status epilepticus (RSE) is a major medical emergency with a mortality of up to 40% and the risk of severe long-term consequences. The mechanisms involved in RSE are incompletely understood. Animal models are important in developing treatment strategies for more effective termination of SE and prevention of its long-term outcomes. The pilocarpine and lithium-pilocarpine rat models are widely used in this respect. In these models, resistance to diazepam and other antiseizure drugs (ASDs) develops during SE so that an SE that is longer than 30 min is difficult to suppress. Furthermore, because all ASDs used in SE treatment are much more rapidly eliminated by rodents than by humans, SE recurs several hours after ASD treatment. Long-term consequences include hippocampal damage, behavioral alterations, and epilepsy with spontaneous recurrent seizures. In this review, different rational polytherapies for SE, which are more effective than monotherapies, are discussed, including a novel polytherapy recently developed by our group. Based on data from diverse seizure models, we hypothesized that cholinergic mechanisms are involved in the mechanisms underlying ASD resistance of SE. We, therefore, developed an intravenous drug cocktail, consisting of diazepam, phenobarbital, and the anticholinergic scopolamine. This drug combination irreversibly terminated SE when administered 60, 90, or 120 min after SE onset. The efficacy of this cocktail in terminating SE was comparable with the previously reported efficacy of polytherapies with the glutamate receptor antagonist ketamine. Furthermore, when injected 60 min after SE onset, the scopolamine-containing cocktail prevented development of epilepsy and hippocampal neurodegeneration, which was not observed with high doses of diazepam or a combination of phenobarbital and diazepam. Our data add to the existing preclinical evidence that rational polytherapy can be more effective than monotherapy in the treatment of SE and that combinatorial therapy may offer a clinically useful option for the treatment of RSE. © 2015 Elsevier Inc. Source

Loscher W.,University of Veterinary Medicine Hannover | Loscher W.,Center for Systems Neuroscience

Animal models for seizures and epilepsy have played a fundamental role in advancing our understanding of basic mechanisms underlying ictogenesis and epileptogenesis and have been instrumental in the discovery and preclinical development of novel antiepileptic drugs (AEDs). However, there is growing concern that the efficacy of drug treatment of epilepsy has not substantially improved with the introduction of new AEDs, which, at least in part, may be due to the fact that the same simple screening models, i.e., the maximal electroshock seizure (MES) and s.c. pentylenetetrazole (PTZ) seizure tests, have been used as gatekeepers in AED discovery for >6 decades. It has been argued that these old models may identify only drugs that share characteristics with existing drugs, and are unlikely to have an effect on refractory epilepsies. Indeed, accumulating evidence with several novel AEDs, including levetiracetan, has shown that the MES and PTZ models do not identify all potential AEDs but instead may fail to discover compounds that have great potential efficacy but work through mechanisms not tested by these models. Awareness of the limitations of acute seizure models comes at a critical crossroad. Clearly, preclinical strategies of AED discovery and development need a conceptual shift that is moving away from using models that identify therapies for the symptomatic treatment of epilepsy to those that may be useful for identifying therapies that are more effective in the refractory population and that may ultimately lead to an effective cure in susceptible individuals by interfering with the processes underlying epilepsy. To realize this goal, the molecular mechanisms of the next generation of therapies must necessarily evolve to include targets that contribute to epileptogenesis and pharmacoresistance in relevant epilepsy models. © 2011 British Epilepsy Association. Source

Broer S.,University of Veterinary Medicine Hannover | Loscher W.,Center for Systems Neuroscience
Epilepsy and Behavior

The discovery and validation of biomarkers in neurological and neurodegenerative diseases is an important challenge for early diagnosis of disease and for the development of therapeutics. Epilepsy is often a consequence of brain insults such as traumatic brain injury or stroke, but as yet no biomarker exists to predict the development of epilepsy in patients at risk. Given the complexity of epilepsy, it is unlikely that a single biomarker is sufficient for this purpose, but a combinatorial approach may be needed to overcome the challenge of individual variability and disease heterogeneity. The goal of the present prospective study in the lithium-pilocarpine model of epilepsy in rats was to determine the discriminative utility of combinations of phenotypic biomarkers by examining their ability to predict epilepsy. For this purpose, we used a recent model refinement that allows comparing rats that will or will not develop spontaneous recurrent seizures (SRS) after pilocarpine-induced status epilepticus (SE). Potential biomarkers included in our study were seizure threshold and seizure severity in response to timed i.v. infusion of pentylenetetrazole (PTZ) and behavioral alterations determined by a battery of tests during the three weeks following SE. Three months after SE, video/EEG monitoring was used to determine which rats had developed SRS. To determine whether a biomarker or combination of biomarkers performed better than chance at predicting epilepsy after SE, derived data underwent receiver operating characteristic (ROC) curve analyses. When comparing rats with and without SRS and sham controls, the best intergroup discrimination was obtained by combining all measurements, resulting in a ROC area under curve (AUC) of 0.9592 (P. <. 0.01), indicating an almost perfect discrimination or accuracy to predict development of SRS. These data indicate that a combinatorial biomarker approach may overcome the challenge of individual variability in the prediction of epilepsy. © 2015 Elsevier Inc. Source

Loscher W.,University of Veterinary Medicine Hannover | Brandt C.,Center for Systems Neuroscience

Purpose: Progress in the management of patients with medically intractable epilepsy is impeded because we do not fully understand why pharmacoresistance happens and how it can be predicted. The presence of multiple seizures prior to medical treatment has been suggested as a potential predictor of poor outcome. In the present study, we used an animal model of temporal lobe epilepsy to investigate whether pharmacoresistant rats differ in seizure frequency from pharmacoresponsive animals. Methods: Epilepsy with spontaneous recurrent seizures (SRS) was induced by status epilepticus. Frequency of SRS was determined by video/EEG (electroencephalography) monitoring in a total of 33 epileptic rats before onset of treatment with phenobarbital (PB). Results: Thirteen (39%) rats did not respond to treatment with PB. Before treatment with PB, average seizure frequency in PB nonresponders was significantly higher than seizure frequency in responders, which, however, was due to six nonresponders that exhibited > 3 seizures per day. Such high seizure frequency was not observed in responders, demonstrating that high seizure frequency predicts pharmacoresistance in this model, but does not occur in all nonresponders. Discussion: The data from this study are in line with clinical experience that the frequency of seizures in the early phase of epilepsy is a dominant risk factor that predicts refractoriness. However, resistance to treatment also occurred in rats that did not differ in seizure frequency from responders, indicating that disease severity alone is not sufficient to explain antiepileptic drug (AED) resistance. These data provide further evidence that epilepsy models are useful in the search for predictors and mechanisms of pharmacoresistance. © 2009 International League Against Epilepsy. Source

Discover hidden collaborations