Abstracts

Rationale: Epilepsy affects around 2.2 million Americans and current therapeutics offer no benefit to 1-in-3 patients. Prior studies identified increased expression of system xc (xCT), a cystine/glutamate antiporter, on glioma cells as a major contributor to elevated glutamate levels in tumor-implanted mice. Inhibition of xCT via sulfasalazine (SAS), an FDA-approved drug, decreased glutamate release and seizures. The current study evaluates the efficacy of SAS to decrease seizure burden in the beta-1 integrin knockout (B1KO) model of epilepsy, which is characterized by chronic astrogliosis leading to the development of spontaneous, recurrent behavioral seizures in vivo. We hypothesize that gliosis may cause an increase in xCT activity and that treatment with SAS can decrease seizure occurence. Methods: 2 weeks of continuous, 24/7 video-EEG recordings were used to identify a baseline seizure burden in B1KO mice, followed by a 1 week treatment period in which mice received either SAS treatment or a control saline treatment. The effect of SAS on seizure frequency and duration was then determined. Cortical and hippocampal tissue lysates were also analyzed using western blot to characterize the effect of SAS treatment on glutamate receptors, GABA receptors, and xCT protein levels. Results: B1KO mice receiving a control, saline treatment experienced a significant increase in seizure frequency from week 1 to week 3 (n=7, p=0.01), while seizure frequency in B1KO mice receiving SAS treatment did not significantly increase during the 3 week video-EEG monitoring period (n=6, p=0.86). Additionally, the number of seizure-free days was significantly higher in the mice receiving SAS compared to saline (n=13, p=0.01). Analysis of cortical and hippocampal tissue lysates did not reveal any significant changes in glutamate or GABA receptors, however, significantly increased cortical xCT protein was observed in B1KO mice compared to age-matched controls (n=6, p=0.02). Conclusions: This study provides evidence that seizure burden appears to increase with age and that SAS treatment can prevent the significant increase in seizure frequency seen in B1KO mice. We propose that SAS treatment inhibits the activity of xCT, resulting in a decrease in ambient glutamate and a decrease in extra-synaptic NMDAR-mediated tonic currents. Our results suggest that xCT may play a role in the pathology of epilepsy and that further studies on xCT and the effects of SAS are warranted.  Funding: No funding