AbstractObjectivePreviously, we reported that inhibition of the astrocytic cystine/glutamate antiporter system xc‐ (SXC), using sulfasalazine (SAS), decreased evoked excitatory signaling in three distinct hyperexcitability models ex vivo. The current study expands on this work by evaluating the in vivo efficacy of SAS in decreasing astrogliosis‐mediated seizure burden seen in the beta‐1 integrin knockout (B1KO) model.MethodsVideo‐EEG (electroencephalography) monitoring (24/7) was obtained using Biopac EEG acquisition hardware and software. EEG spectral analysis was performed using MATLAB. SAS was used at an equivalence of doses taken by Crohn’s disease patients. Whole‐cell patch‐clamp recordings were made from cortical layer 2/3 pyramidal neurons.ResultsWe report that 100% of B1KO mice that underwent 24/7 video‐EEG monitoring developed spontaneous recurrent seizures and that intraperitoneal administration of SAS significantly reduced seizure frequency in B1KOs compared to B1KOs receiving sham saline. Spectral analysis found an acute reduction in EEG power following SAS treatment in B1KOs; however, this effect was not observed in nonepileptic control mice receiving SAS. Finally, whole‐cell recordings from SXC knockout mice had hyperpolarized neurons and SXC‐B1 double knockouts fired significantly less action potentials in response to current injection compared to B1KOs with SXC.SignificanceTo devise effective strategies in finding relief for one‐in‐three patients with epilepsy who experience drug‐resistant epilepsy we must continue to explore the mechanisms regulating glutamate homeostasis. This study explored the efficacy of targeting an astrocytic glutamate antiporter, SXC, as a novel antiepileptic drug (AED) target and further characterized a unique mouse model in which chronic astrogliosis is sufficient to induce spontaneous seizures and epilepsy. These findings may serve as a foundation to further assess the potential for SAS or inform the development of more potent and specific compounds that target SXC as a novel treatment for epilepsy.