Models for Epilepsy and Epileptogenesis: Report from the NIH Workshop, Bethesda, Maryland

Stables, James P.; Bertram, Edward H.; White, H. Steve; Coulter, Douglas A.; Dichter, Marc A.; Jacobs, Margaret P.; Löscher, Wolfgang; Lowenstein, Daniel H.; Moshé, Solomon L.; Noebels, Jeffrey L.; Davis, Mirian

doi:10.1046/j.1528-1157.2002.06702.x

Cited by 123 publications

(87 citation statements)

References 7 publications

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“…CNS injury is the major cause of AE (Hauser & Hesdorffer, 1990). A thorough understanding of the signaling cascades associated with the development of epileptogenesis and maintenance of the chronic epileptic state are required for understanding the development of AE and for developing novel interventional protocols to prevent or even cure AE (Stables et al, 2002). This review will focus on the basic mechanisms underlying injury-induced AE and the evidence that Ca 2+ is a major second messenger that may play an important role in the development and maintenance of AE.…”

Section: Idiopathic and Acquired Epilepsymentioning

confidence: 99%

Cellular mechanisms underlying acquired epilepsy: The calcium hypothesis of the induction and maintainance of epilepsy

DeLorenzo

Sun

Deshpande

2005

Pharmacology & Therapeutics

258

286

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Epilepsy is one of the most common neurological disorders. Although epilepsy can be idiopathic, it is estimated that up to 50% of all epilepsy cases are initiated by neurological insults and are called acquired epilepsy (AE). AE develops in 3 phases: (1) the injury (central nervous system [CNS] insult), (2) epileptogenesis (latency), and (3) the chronic epileptic (spontaneous recurrent seizure) phases. Status epilepticus (SE), stroke, and traumatic brain injury (TBI) are 3 major examples of common brain injuries that can lead to the development of AE. It is especially important to understand the molecular mechanisms that cause AE because it may lead to innovative strategies to prevent or cure this common condition. Recent studies have offered new insights into the cause of AE and indicate that injury-induced alterations in intracellular calcium concentration levels [Ca 2+ ] i and calcium homeostatic mechanisms play a role in the development and maintenance of AE. The injuries that cause AE are different, but they share a common molecular mechanism for producing brain damage -an increase in extracellular glutamate concentration that causes increased intracellular neuronal calcium, leading to neuronal injury and/or death. Neurons that survive the injury induced by glutamate and are exposed to increased [Ca 2+ ] i are the cellular substrates to develop epilepsy because dead cells do not seize. The neurons that survive injury sustain permanent long-term plasticity changes in [Ca 2+ ] i and calcium homeostatic mechanisms that are permanent and are a prominent feature of the epileptic phenotype. In the last several years, evidence has accumulated indicating that the prolonged alteration in neuronal calcium dynamics plays an important role in the induction and maintenance of the prolonged neuroplasticity changes underlying the epileptic phenotype. Understanding the role of calcium as a second messenger in the induction and maintenance of epilepsy may provide novel insights into therapeutic advances that will prevent and even cure AE.

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Section: Idiopathic and Acquired Epilepsymentioning

confidence: 99%

Cellular mechanisms underlying acquired epilepsy: The calcium hypothesis of the induction and maintainance of epilepsy

DeLorenzo

Sun

Deshpande

2005

Pharmacology & Therapeutics

258

286

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“…There is now intense interest in such antiepileptogenic approaches and a paradigm shift is occurring in how we think about epilepsy therapeutic strategies, as exemplified by the work with RWJ-333369. There are major challenges in the preclinical identification of antiepileptogenic agents and even bigger challenges in validating them in the clinic (Pitkänen, 2002;Stables et al, 2002). However, the payoffs in terms of the unmet medical need provide a strong incentive to persevere.…”

Section: Resultsmentioning

confidence: 99%

Diverse mechanisms of antiepileptic drugs in the development pipeline

2006

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There is a remarkable array of new chemical entities in the current antiepileptic drug (AED) development pipeline. In some cases, the compounds were synthesized in an attempt improve upon the activity of marketed AEDs. In other cases, the discovery of antiepileptic potential was largely serendipitous. Entry into the pipeline begins with the demonstration of activity in one or more animal screening models. Results from testing in a panel of such models provide a basis to differentiate agents and may offer clues as to the mechanism. Target activity may then be defined through cellbased studies, often years after the initial identification of activity. Some pipeline compounds are believed to act through conventional targets, whereas others are structurally novel and may act by novel mechanisms. Follow-on agents include the levetiracetam analogs brivaracetam and seletracetam that act as SV2A-ligands; the valproate-like agents valrocemide, valnoctamide, propylisopropyl acetamide, and isovaleramide; the felbamate analog flurofelbamate, a dicarbamate, and the unrelated carbamate RWJ-333369; the oxcarbazepine analog licarbazepine, which probably acts as a use-dependent sodium channel blockers, and its prodrug acetate BIA 2-093; and various selective partial benzodiazepine receptor agonists, including ELB139, which is a positive allosteric modulator of α3-containing GABA A receptors. A variety of AEDs that may act through novel targets are also in clinical development: lacosamide, a functionalized amino acid; talampanel, a 2,3-benzodiazepine selective noncompetitive AMPA receptor antagonist; NS1209, a competitive AMPA receptor antagonist; ganaxolone, a neuroactive steroid that acts as a positive modulator of GABA A receptors; retigabine, a KCNQ potassium channel opener with activity as a GABA A receptor positive modulator; the benzanilide KCNQ potassium channel opener ICA-27243 that is more selective than retigabine; and rufinamide, a triazole of unknown mechanism.

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“…The most widely used models of epileptogenesis include electrical kindling, poststatus epilepticus (SE; chemical kindling with, e.g., kainate or pilocarpine) models of temporal lobe epilepsy (TLE), and models of traumatic brain injury‐induced epilepsy (Kharatishvili & Pitkanen, 2010; Loscher & Brandt, 2010; Stables et al., 2002). Post‐SE chemical kindling models, in which the acute triggering process of SE is frequently followed by a latency period with subsequent development of spontaneous motor seizures, closely mimic the clinical manifestations of human TLE and electrical kindling.…”

Section: Discussionmentioning

confidence: 99%

Linking kindling to increased glutamate release in the dentate gyrus of the hippocampus through the STXBP5/tomosyn‐1 gene

et al. 2017

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IntroductionIn kindling, repeated electrical stimulation of certain brain areas causes progressive and permanent intensification of epileptiform activity resulting in generalized seizures. We focused on the role(s) of glutamate and a negative regulator of glutamate release, STXBP5/tomosyn‐1, in kindling.MethodsStimulating electrodes were implanted in the amygdala and progression to two successive Racine stage 5 seizures was measured in wild‐type and STXBP5/tomosyn‐1−/− (Tom−/−) animals. Glutamate release measurements were performed in distinct brain regions using a glutamate‐selective microelectrode array (MEA).ResultsNaïve Tom−/− mice had significant increases in KCl‐evoked glutamate release compared to naïve wild type as measured by MEA of presynaptic release in the hippocampal dentate gyrus (DG). Kindling progression was considerably accelerated in Tom−/− mice, requiring fewer stimuli to reach a fully kindled state. Following full kindling, MEA measurements of both kindled Tom+/+ and Tom−/− mice showed significant increases in KCl‐evoked and spontaneous glutamate release in the DG, indicating a correlation with the fully kindled state independent of genotype. Resting glutamate levels in all hippocampal subregions were significantly lower in the kindled Tom−/− mice, suggesting possible changes in basal control of glutamate circuitry in the kindled Tom−/− mice.ConclusionsOur studies demonstrate that increased glutamate release in the hippocampal DG correlates with acceleration of the kindling process. Although STXBP5/tomosyn‐1 loss increased evoked glutamate release in naïve animals contributing to their prokindling phenotype, the kindling process can override any attenuating effect of STXBP5/tomosyn‐1. Loss of this “braking” effect of STXBP5/tomosyn‐1 on kindling progression may set in motion an alternative but ultimately equally ineffective compensatory response, detected here as reduced basal glutamate release.

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Models for Epilepsy and Epileptogenesis: Report from the NIH Workshop, Bethesda, Maryland

Abstract: Understanding the epidemiology of therapy resistance and providing support for new approaches to therapy development were identified as key issues for introduction of new and more effective treatments.

Cited by 123 publications

References 7 publications

Cellular mechanisms underlying acquired epilepsy: The calcium hypothesis of the induction and maintainance of epilepsy

Cellular mechanisms underlying acquired epilepsy: The calcium hypothesis of the induction and maintainance of epilepsy

Diverse mechanisms of antiepileptic drugs in the development pipeline

Linking kindling to increased glutamate release in the dentate gyrus of the hippocampus through the STXBP5/tomosyn‐1 gene

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