Remy, S. & Beck, H. Molecular and cellular mechanisms of pharmacoresistance in epilepsy. Brain 129, 18-35

University of Bonn, Bonn, North Rhine-Westphalia, Germany
Brain (Impact Factor: 9.2). 02/2006; 129(Pt 1):18-35. DOI: 10.1093/brain/awh682
Source: PubMed


Epilepsy is a common and devastating neurological disorder. In many patients with epilepsy, seizures are well-controlled with currently available anti-epileptic drugs (AEDs), but a substantial (approximately 30%) proportion of patients continue to have seizures despite carefully optimized drug treatment. Two concepts have been put forward to explain the development of pharmacoresistance. The transporter hypothesis contends that the expression or function of multidrug transporters in the brain is augmented, leading to impaired access of AEDs to CNS targets. The target hypothesis holds that epilepsy-related changes in the properties of the drug targets themselves may result in reduced drug sensitivity. Recent studies have started to dissect the molecular underpinnings of both transporter- and target-mediated mechanisms of pharmacoresistance in human and experimental epilepsy. An emerging understanding of these underlying molecular and cellular mechanisms is likely to provide important impetus for the development of new pharmacological treatment strategies.

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    • "A list of structurally diverse anti-epileptic drugs (AEDs) is presently used for clinical therapeutic application for this disorder (Stafstrom, 2010). Despite the wide variety of available treatments, approximately 30% of people with epilepsy fail to respond satisfactorily to first line antiepileptic drugs (Remy and Beck, 2006). There is, therefore, an important unmet clinical need for new antiepileptic therapeutics with more specific mechanisms of action, fewer side effects and increased potency. "
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    ABSTRACT: Anti-epileptic drugs (AEDs) have high risk of teratogenic side effects, including neural tube defects while mother is on AEDs for her own prevention of convulsions during pregnancy. The present study investigated the interaction of major marketed AEDs and human placental (hp)-cadherin protein, insilico, to establish the role of hp-cadherin protein in teratogenicity and also to evaluate the importance of Ca2+ ion in functioning of the protein. A set of 21 major marketed AEDs were selected for the study and 3D-structure of hp-cadherin wa s constructed using homology modelling and energy minimized using MD simulations. Molecular docking studies were carried out using selected AEDs as ligand with hpcadherin (free and bound Ca 2+ ion) to study the behavioural changes in hp-cadherin due to presence of Ca2+ ion. The study refl ected that four AEDs (Gabapentin, Pregabalin, Remacimide and Vigabatrine) had very high affinity towards hp-cadherin and thus the later may have prominent role in the teratogenic effects of these AEDs. From docking simulation analysis it wa s observed that Ca2+ ion is required to make hp-cadherin energetically favourable and sterically functional.
    Full-text · Article · Nov 2016 · Computational Biology and Chemistry
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    • "Therapy resistance represents a major issue in the management of epilepsy. Diverse potential mechanistic causes have been proposed [1] [2] [3] [4], and new experimental approaches have been established in order to discover therapies providing better efficacy [5] [6]. Nevertheless, a clear medical need remains in order to achieve complete seizure control in a substantial population of patients with treatmentresistant epilepsy [7]. "
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    ABSTRACT: Treatment-resistant seizures affect about a third of patients suffering from epilepsy. To fulfill the need for new medications targeting treatment-resistant seizures, a number of rodent models offer the opportunity to assess a variety of potential treatment approaches. The use of such models, however, has proven to be time-consuming and labor-intensive. In this study, we performed pharmacological characterization of the allylglycine (AG) seizure model, a simple in vivo model for which we demonstrated a high level of treatment resistance. (d,l)-Allylglycine inhibits glutamic acid decarboxylase (GAD) - the key enzyme in γ-aminobutyric acid (GABA) biosynthesis - leading to GABA depletion, seizures, and neuronal damage. We performed a side-by-side comparison of mouse and zebrafish acute AG treatments including biochemical, electrographic, and behavioral assessments. Interestingly, seizure progression rate and GABA depletion kinetics were comparable in both species. Five mechanistically diverse antiepileptic drugs (AEDs) were used. Three out of the five AEDs (levetiracetam, phenytoin, and topiramate) showed only a limited protective effect (mainly mortality delay) at doses close to the TD50 (dose inducing motor impairment in 50% of animals) in mice. The two remaining AEDs (diazepam and sodium valproate) displayed protective activity against AG-induced seizures. Experiments performed in zebrafish larvae revealed behavioral AED activity profiles highly analogous to those obtained in mice. Having demonstrated cross-species similarities and limited efficacy of tested AEDs, we propose the use of AG in zebrafish as a convenient and high-throughput model of treatment-resistant seizures. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Apr 2015 · Epilepsy & Behavior
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    • "It is conceivable that ASD targets other than GABA or glutamate receptors are also affected by sustained seizure activity. For instance, molecular and functional changes in voltage-dependent sodium channels, which are targets of phenytoin and various other major ASDs, have been found after a pilocarpine-induced SE in rats [23] [24]. Furthermore, a decrease in surface expression of potassium channels has been described after prolonged SE [25]. "
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    ABSTRACT: 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 30min 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 120min 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 60min 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. This article is part of a Special Issue entitled "Status Epilepticus". Copyright © 2015 Elsevier Inc. All rights reserved.
    Preview · Article · Mar 2015 · Epilepsy & Behavior
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