Development of Novel Antiepileptic Drugs

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DESCRIPTION (provided by applicant): Epilepsy, a neurological disorder, is a major public health issue affecting over 2 million Americans. Each year over 100,000 new cases of epilepsy are diagnosed. Current treatment for patients suffering from epileptic seizures involves the suppression of these seizures with antiepileptic drugs (AEDs). Since sodium channels control cellular excitability, they have become important targets for the suppression of seizures. In fact, many of the clinically used AEDs target sodium channels as a major mechanism of their action. However, the continued introduction of new AEDs has not helped the estimated 750,000 Americans that are resistant to current drugs. In addition, many achieve seizure control but only at the cost of significant toxic side effects. One potential reason for this unacceptable statistic is the use of screens that are not representative of the pathological conditions that exist in a diseased "epileptic" neuron. For example, studies have shown that in both animal and human limbic epilepsy, alterations in sodium channel isoform expression as well as their activity/gating occurs. These changes have been associated with the hyper-excitability of neurons involved in limbic epilepsy and also the altered pharmacology that has been well documented in temporal lobe epilepsy, reducing the efficacy of the sodium channel blockers in suppressing epileptic seizures. These observations emphasize the important need to develop screening assays that represent the "epileptic" condition and not the control "non-epileptic" condition. A direct consequence of developing such a screen would be the identification of candidate therapeutics effective in therapy resistant patients. In this exploratory/developmental translational proposal we plan to develop an "epileptic" screening profile using neurons isolated from animals with chronic limbic epilepsy (CLE). We will develop an electrophysiology screening profile using clinically used AEDs, known to target sodium channels as a mechanism of action, and a series of selective sodium channel blockers that have a different efficacy profile against sodium channel isoforms. We will validate our screening assay by assessing anticonvulsant activity in CLE rats, a model of pharmacoresistant epilepsy with spontaneous seizures. This proposal will allow us to ascertain two important features 1) it will allow us to develop and validate an electrophysiology screening assay that will permit the preliminary screening of candidate therapeutics 2) it will provide preliminary data on the efficacy of candidate therapeutics leading to the identification of candidate therapeutics that can be evaluated through further preclinical testing. Specifically we plan to: 1) Develop an electrophysiology screening profile for candidate therapeutics using "epileptic" brain slices - identification of candidate therapeutics. 2) Pre-clinical testing of candidate therapeutics for anticonvulsant activity in an animal model of chronic limbic epilepsy - validation of the electrophysiology screen. Public Health Relevance: Epilepsy, a neurological disorder, is a major public health issue affecting over 2 million Americans. Approximately 750,000 Americans experience seizures that cannot be suppressed by currently available drugs. The patients continue to experience un-controlled, life threatening, epileptic seizures. In this exploratory/developmental proposal, we will develop a drug testing screen that will identify drugs that are effective in epileptic neurons. These drugs could be effective in patients that are "pharmaco-resistant" to currently available drugs.