Oscar Alcoreza's Dissertation Defense (5/3/2021): Modulating System xc- Activity As A Treatment For Epilepsy

About this Dissertation

Epilepsy, characterized by unpredictable seizures, affects approximately 2.2 million Americans, with 150,000 new cases being diagnosed each year. Seizures typically occur when there is an imbalance between the excitatory and inhibitory processes in the brain. Because neurons are the primary cell in the brain that carry out these processes, clinically used anti-epileptic drugs (AEDs) work by either decreasing neuronal excitation or increasing neuronal inhibition. Despite success with managing seizures, up to 1-in-3 patients with epilepsy do not find any relief with existing AEDs. A statistic that has not changed in over 50 years of drug development. With this in mind, the overarching goal of Alcoreza's project is to broaden the search for new AED targets by further characterizing a unique mouse model of epilepsy and exploring the efficacy of targeting non-neuronal processes to treat epilepsy. One such target studied in Alcoreza's research in the Sontheimer Lab is system xc- (SXC), a glutamate/cystine antiporter present on astrocytes, a non-neuronal cell that provides maintenance, support and protection for neurons. Investigations in tumor-associated epilepsy from the Sontheimer lab revealed that hyperactivity of SXC in tumor cells was directly related to the development of tumor-associated epilepsy. These studies also revealed that SXC inhibition using sulfasalazine (SAS), an FDA approved drug, can decrease seizure burden in a tumor mouse model. Therefore, the principal objective of this study is to further investigate the role of astrocytic SXC activity in the development of epilepsy and seizure generation. Alcoreza's research shows that SXC inhibition, using SAS, is able to decrease neuronal hyperactivity and decreases seizure burden in an astrogliosis-mediated epilepsy model.

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