Currently available antiepileptic drugs (AEDs) are anticonvulsants that require continuous administration for suppression of seizures, and that do not prevent development of epilepsy. Furthermore, approximately 30% of patients develop drug refractory epilepsy. Therefore, discovery of drugs that can prevent or cure epilepsy, defined as antiepileptogenic or disease-modifying drugs, respectively, has been identified as a major epilepsy research goal. Development of these classes of drugs is complicated by the long time course of epileptogenesis and epilepsy progression. Variability in the duration of latent period and seizure intervals and frequency necessitate the use of continuous week-to-month long electrical recordings for sensitive, quantitative assessment of antiepileptogenic or disease-modifying effects. This proposal aims to increase the rate of drug development by significantly improving scalability of long-term electrical monitoring of epileptic activity in vitro. Hybrid microfluidic-multiple electrode array (Upsilon flow-MEA) chips will be developed for use with organotypic hippocampal culture model of epilepsy. Cultures will be placed in microwells, and maintained via perfusion of culture medium through inlet and outlet microchannels. This method will significantly reduce the area required for each culture. Each chip will be capable of monitoring 12-18 cultures simultaneously to quantitatively assess development and progression of epilepsy. Microchannel network will connect cultures into experimental groups to facilitate application of drugs, inhibitors, or other molecules. This platform will then be scaled up to conduct a pilot screen with a small molecule inhibitor library. The goal of the screen is to demonstrate an increase in scalability and experimental throughput achieved with Upsilon flow-MEA platform, and to discover new targets for antiepileptogenic or disease-modifying drugs.
Currently available antiepileptic drugs are anticonvulsants that require continuous administration and do not work in all patients. Therefore, discovery of drugs that can prevent or cure epilepsy is an important research goal. In this project, a new chip technology will be developed for use with in vitro model of epilepsy to increase the rate of drug target identification and facilitate drug discovery.