Understanding mechanisms that underlie the evolution of chronic epilepsy (i.e. epileptogenesis) is instrumental for developing effective preventive therapies of the epileptic process. In turn, the development and validation of clinically relevant animal models are needed that could be used for both basic and preclinical studies. The majority of currently available models of epileptogenesis employ a precipitating insult (e.g. status epilepticus, SE), which leads to progressive neurodegenerative and neuronal plastic changes, and culminates in the occurrence of spontaneous recurrent seizures. While being indispensable for basic epilepsy research, the inherent features of these models (e.g. slow progression;high inter-animal and temporal variability of seizure frequency and severity;unpredictability of individual seizure occurrence) represent significant challenges for preclinical antiepileptic drug (AED) evaluation due to time, labor and costs involved. The objective of the proposed project is to validate a high-throughput screening assay for rapid identification and evaluation of antiepileptogenic and/or disease-modifying drugs. We propose that the rapid kindling model of epileptogenesis can be used for AED drug discovery. The validation will consist of analysis of the effects of fifteen compounds with established pharmacological profiles (bumetanide, diazepam, ethosuximide felbamate, gabapentin, ganaxolone, lamotrigine, levetiracetam, MK-801;phenytoin, retigabine, topiramate, valproate sodium, vigabatrin, zonisamide) on rapid kindling epileptogenesis in experimental animals of five different ages (neonatal;post-neonatal;pre-adolescent;adolescent;adult). Rapid kindling will be induced by 60 electrical stimulations delivered to the hippocampus every 5 minutes at a suprathreshold current (total procedure duration is 5 hours). The animals will receive a single injection of an AED prior to kindling;the progression and the pattern of electrographic and behavioral seizures will be monitored and analyzed. AEDs are chosen so that, based on the mechanisms of their action and known mechanisms of epileptogenesis, they are expected to modify seizure progression in different ways, including complete prevention of seizures (antiepileptogenic effect), mitigation of epileptic process (disease modification), and failure to affect seizures at all. As a result of the study, we will generate an expanded pharmacological profile of the rapid kindling model of epileptogenesis. The compiled database can then be used for mapping of emerging antiepileptogenic drugs against known AEDs in terms of their efficiency. The progressive nature of epilepsy (epileptogenesis) dictates the necessity for developing therapies that can block the epileptic process during its early stages. In turn, the introduction and validation of experimental models that would (a) closely resemble human condition, and (b) allow large scale screening of prospective antiepileptogenic drugs are required. The current project is designed to introduce and validate an animal model of epileptogenesis that would allow for the quick and effective screening of emerging antiepileptogenic drugs on a large scale.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS059505-02
Application #
7563307
Study Section
Special Emphasis Panel (ZNS1-SRB-B (06))
Program Officer
Stewart, Randall R
Project Start
2008-02-15
Project End
2011-01-31
Budget Start
2009-02-01
Budget End
2011-01-31
Support Year
2
Fiscal Year
2009
Total Cost
$168,438
Indirect Cost
Name
University of California Los Angeles
Department
Pediatrics
Type
Schools of Medicine
DUNS #
092530369
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
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Wu, J Y; Salamon, N; Kirsch, H E et al. (2010) Noninvasive testing, early surgery, and seizure freedom in tuberous sclerosis complex. Neurology 74:392-8
Auvin, Stéphane; Mazarati, Andrey; Shin, Don et al. (2010) Inflammation enhances epileptogenesis in the developing rat brain. Neurobiol Dis 40:303-10
Sankar, Raman; Auvin, Stephane; Kwon, Young Se et al. (2010) Evaluation of development-specific targets for antiepileptogenic therapy using rapid kindling. Epilepsia 51 Suppl 3:39-42
Mazarati, Andrey M; Shin, Don; Kwon, Young Se et al. (2009) Elevated plasma corticosterone level and depressive behavior in experimental temporal lobe epilepsy. Neurobiol Dis 34:457-61
Mazarati, Andréy; Shin, Don; Sankar, Raman (2009) Bumetanide inhibits rapid kindling in neonatal rats. Epilepsia 50:2117-22
Mazarati, Andrey; Wu, Jim; Shin, Don et al. (2008) Antiepileptogenic and antiictogenic effects of retigabine under conditions of rapid kindling: an ontogenic study. Epilepsia 49:1777-86
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