Prevention or Modification of Epileptogenesis after Brain Insults: Experimental Approaches and Translational Research

Löscher, Wolfgang; Brandt, Claudia

doi:10.1124/pr.110.003046

Cited by 347 publications

(376 citation statements)

References 245 publications

(381 reference statements)

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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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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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“…By definition, acquired epilepsy results from a brain insult that is followed by a "latent period" that can be months or years in duration [4,6]. As discussed below, this latent period provides a "window of opportunity" wherein a potential antiepileptogenic or disease-modifying therapy could be administered in an effort to prevent, delay, or modify the epileptogenic process unleashed by the initial brain insult.…”

Section: Animal Models Of Acquired Epilepsymentioning

confidence: 99%

“…Of the myriad available rodent models of acquired epilepsy, the kindling, status epilepticus (SE), and traumatic brain injury (TBI) models represent the three models most often employed in the search for antiepileptogenic and diseasemodifying therapies [4,6]. With that said, a number of etiologically relevant models have emerged that display important properties of human acquired epilepsy (Fig.…”

Section: Animal Models Of Acquired Epilepsymentioning

confidence: 99%

“…In addition to the development of better therapies for the symptomatic treatment of epilepsy, the availability of a therapy that would prevent or delay the development of epilepsy, or the associated cognitive comorbidities would represent a substantial advance in the overall management of epilepsy [3][4][5][6]. As epilepsy is progressive and the seizures and comorbidities can worsen with continued duration, such a diseasemodifying or antiepileptogenic therapy, once available, could also have a disease-modifying effect when epilepsy is already established, for example by reducing or preventing the emergence of more severe seizures, pharmacoresistance, or comorbidities.…”

Section: Introductionmentioning

confidence: 99%

“…1, and that there is a clear path for the clinical development of a purported disease-modifying or antiepileptogenic therapy. Unfortunately, unlike the animal models that have successfully identified a number of new therapies for the symptomatic treatment of epilepsy, the animal models of epileptogenesis have not been validated clinically [4,6]. To this point, clinical validation will not be provided until that first truly "antiepileptic" or "disease-modifying" therapy, identified in a specific animal model, is proven effective in an appropriately designed clinical trial.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

White

Löscher²

2014

Neurotherapeutics

Self Cite

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A major unmet medical need is the lack of treatments to prevent (or modify) epilepsy in patients at risk, for example, after epileptogenic brain insults such as traumatic brain injury, stroke, or prolonged acute symptomatic seizures like complex febrile seizures or status epilepticus. Typically, following such brain insults there is a seizure-free interval ("latent period"), lasting months to years before the onset of spontaneous recurrent epileptic seizures. The latent period after a brain insult offers a window of opportunity in which an appropriate treatment may prevent or modify the epileptogenic process induced by a brain insult. A similar latent period occurs in patients with epileptogenic gene mutations. Studies using animal models of epilepsy have led to a greater understanding of the factors underlying epileptogenesis and have provided significant insight into potential targets by which the development of epilepsy may be prevented or modified. This review focuses largely on some of the most common animal models of epileptogenesis and their potential utility for evaluating proposed antiepileptogenic therapies and identifying useful biomarkers. The authors also describe some of the limitations of using animal models in the search for therapies that move beyond the symptomatic treatment of epilepsy. Promising results of previous studies designed to evaluate antiepileptogenesis and the role of monotherapy versus polytherapy approaches are also discussed. Recent data from both models of genetic and acquired epilepsies strongly indicate that it is possible to prevent or modify epileptogenesis, and, hopefully, such promising results can ultimately be translated into the clinic.

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Results of Phase 2 Safety and Feasibility Study of Treatment With Levetiracetam for Prevention of Posttraumatic Epilepsy

Klein¹,

Herr²,

Pearl³

et al. 2012

Arch Neurol

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Prevention or Modification of Epileptogenesis after Brain Insults: Experimental Approaches and Translational Research

Cited by 347 publications

References 245 publications

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

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

Searching for the Ideal Antiepileptogenic Agent in Experimental Models: Single Treatment Versus Combinatorial Treatment Strategies

Results of Phase 2 Safety and Feasibility Study of Treatment With Levetiracetam for Prevention of Posttraumatic Epilepsy

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