Epilepsy is a neurological disorder that presents a significant public health burden, with an estimated five million people being newly diagnosed each year. However, current therapeutics designed to modify neuronal processes, provide no relief to 1-in-3 epileptic patients. Additionally, no disease modifying therapies currently exist to treat the underlying pathological processes involved in epileptogenesis. The overarching goal of this project is to further characterize the role astrocytes play in epileptogenesis, in hopes of revealing novel therapeutic targets to benefit patients who otherwise have no effective treatment options. System xc- (SXC), a cystine/glutamate antiporter expressed in astrocytes, is one such target that has been shown to play a critical role in establishing ambient extracellular glutamate levels in both health and disease. SXC has been shown to play a major role in setting ambient glutamatergic tone in the central nervous system (CNS) as pharmacological inhibition of SXC, using (S)-4-carboxyphenylglycine (S-4-CPG) or antisense xCT, resulted in a 60% reduction in extrasynaptic glutamate in the nucleus accumbens. Additionally, investigations in tumor-associated epilepsy revealed that overexpression of SXC seen in glioblastomas lead to higher levels of peritumoral glutamate, neuronal excitotoxicity, and ultimately seizures. These studies also found that SXC inhibition with sulfasalazine (SAS), an FDA approved drug and potent inhibitor of SXC, can ameliorate seizure burden in a glioblastoma mouse model. Therefore, the principal objective of this study is to further investigate the role of astrocytic SXC activity in epileptogenesis and seizure generation. In doing so, we also evaluated the efficacy of SAS in reducing seizure burden in vivo using an astrogliosis-mediated epilepsy mouse model. In this dissertation we show that (1) SXC inhibition, using SAS, is able to decrease induced epileptiform activity in multiple models of chemically induced hyperexcitability (2) this is due to a preferential decrease of NMDAR-mediated currents and (3) SXC inhibition, via SAS, decreases seizure burden in vivo in an astrogliosis-mediated epilepsy model. / Doctor of Philosophy / 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 this dissertation is to explore the efficacy of targeting non-neuronal processes to treat epilepsy and broaden the search for new AED targets by further characterizing a unique mouse model of epilepsy. One such target studied in our 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 our 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. In this dissertation we show that SXC inhibition, using SAS, is able to decrease neuronal hyperactivity and decreases seizure burden in an astrogliosis-mediated epilepsy model.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/103628 |
| Date | 28 May 2021 |
| Creators | Alcoreza, Oscar Jr. |
| Contributors | Graduate School, Sontheimer, Harald, Olsen, Michelle L., Shah, Aashit, Campbell, Susan |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
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