Early treatment suppresses the development of spike‐wave epilepsy in a rat model

Blumenfeld, Hal; Klein, Joshua P.; Schridde, Ulrich; Vestal, Matthew; Rice, Timothy; Khera, Davender S.; Bashyal, Chhitij; Giblin, Kathryn; Paul-Laughinghouse, Crystal; Wang, Frederick; Phadke, Anuradha; Mission, John; Agarwal, R. K.; Englot, Dario J.; Motelow, Joshua E.; Nersesyan, Hrachya; Waxman, Stephen G.; Levin, April R.

doi:10.1111/j.1528-1167.2007.01458.x

Cited by 187 publications

(205 citation statements)

References 53 publications

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“…In the WAG/Rij rat model of absence epilepsy, early prophylactic treatment with ethosuximide, levetiracetam, or zonisamide (but not carbamazepine) before the onset of spike-wave discharges in the EEG suppressed the development of such absence-like seizures [31][32][33], which was also subsequently observed in the GAERS model of absence epilepsy [34]. These findings suggest that models are available in which epileptogenesis can be controlled and that early treatment during development may provide a strategy for preventing genetic epilepsy in susceptible individuals.…”

Section: Studies With Aedsmentioning

confidence: 98%

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

White

Löscher²

2014

Neurotherapeutics

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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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Section: Studies With Aedsmentioning

confidence: 98%

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

White

Löscher²

2014

Neurotherapeutics

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“…Frontal lobe epilepsy usually responds to carbamazepine, but frontal lobe epilepsy with an S284L mutation in CHRNA4 responds to zonisamide but not carbamazepine; thus, the drug response is at least partly dependent on the kind of mutations (Zhu et al, 2008). Blumenfeld et al (2008) reported that early treatment (before onset of epilepsy) of Wistar albino Glaxo rats of Rijswijk (WAG/Rij), a genetic animal model of absence epilepsy, with ethosuximide (300 mg/kg/day), resulted in a favorable outcome. Conceivably, it is possible to prevent epilepsy to some extent, by initiating treatment before the onset of epilepsy.…”

Section: Resultsmentioning

confidence: 99%

Detection of SCN1A mutations in patients with severe myoclonic epilepsy in infancy by custom resequence array

Sugawara¹,

Yoshida²,

Onodera³

et al. 2013

Journal of Epileptology

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introduction. Very few epilepsy phenotypes have been associated with causative genes; nevertheless, it is becoming possible, for some epilepsy phenotypes, to predict the most efficacious anti-epileptic drugs for patients based on their genetic makeup. The development of individualized medicine based on genetic information and the genetic diagnosis of epilepsy are expected to greatly improve the diagnosis and treatment of epilepsy. Here, we developed a DNA array (resequencing array) for the genetic diagnosis of epilepsies in which 14 epilepsy -related genes (SCN1A,

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“…There is some evidence that valproate [13] and levetiracetam [14,15] may cause a delay in kindling acquisition that persists beyond the period of drug exposure, suggesting an antiepileptogenic action. In addition, long-term treatment with ethosuximide and levetiracetam has recently demonstrated a compelling ability to reduce the development of seizures in genetic animal models of absence epilepsy [16,17]. The reduction in seizures persists after the treatment is withdrawn, suggesting a true antiepileptogenic effect.…”

Section: Asds With Potential Antiepileptogenic Propertiesmentioning

confidence: 99%

The Potential of Antiseizure Drugs and Agents that Act on Novel Molecular Targets as Antiepileptogenic Treatments

2014

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A major goal of contemporary epilepsy research is the identification of therapies to prevent the development of recurrent seizures in individuals at risk, including those with brain injuries, infections, or neoplasms; status epilepticus; cortical dysplasias; or genetic epilepsy susceptibility. In this review we consider the evidence largely from preclinical models for the antiepileptogenic activity of a diverse range of potential therapies, including some marketed antiseizure drugs, as well as agents that act by immune and inflammatory mechanisms; reduction of oxidative stress; activation of the mammalian target of rapamycin or peroxisome proliferatoractivated receptors γ pathways; effects on factors related to thrombolysis, hematopoesis, and angiogenesis; inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reducatase; brainderived neurotrophic factor signaling; and blockade of α2 adrenergic and cannabinoid receptors. Antiepileptogenesis refers to a therapy of which the beneficial action is to reduce seizure frequency or severity outlasting the treatment period. To date, clinical trials have failed to demonstrate that antiseizure drugs have such disease-modifying activity. However, studies in animal models with levetiracetam and ethosuximide are encouraging, and clinical trials with these agents are warranted. Other promising strategies are inhibition of interleukin 1β signaling by drugs such as VX-765; modulation of sphingosine 1-phosphate signaling by drugs such as fingolimod; activation of the mammalian target of rapamycin by drugs such as rapamycin; the hormone erythropoietin; and, paradoxically, drugs such as the α2 adrenergic receptor antagonist atipamezole and the CB1 cannabinoid antagonist SR141716A (rimonabant) with proexcitatory activity. These approaches could lead to a new paradigm in epilepsy drug therapy where treatment for a limited period prevents the occurrence of spontaneous seizures, thus avoiding lifelong commitment to symptomatic treatment.

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Early treatment suppresses the development of spike‐wave epilepsy in a rat model

Cited by 187 publications

References 53 publications

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

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

Detection of SCN1A mutations in patients with severe myoclonic epilepsy in infancy by custom resequence array

The Potential of Antiseizure Drugs and Agents that Act on Novel Molecular Targets as Antiepileptogenic Treatments

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