Modulating System xc- Activity As A Treatment For Epilepsy

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.