Glutamate Release by Primary Brain Tumors Induces Epileptic Activity

Epileptic seizures are a common and poorly understood co-morbidity for individuals with primary brain tumors. To investigate peritumoral seizure etiology, we implanted patient-derived glioma cells into scid mice. Within 14–18 days, glioma-bearing animals developed spontaneous, recurring abnormal EEG events consistent with epileptic activity that progressed over time. Acute brain slices from these animals showed significant glutamate release from the tumor mediated by the system x(c)(−) cystine/glutamate transporter. Biophysical and optical recordings showed glutamatergic epileptiform hyperexcitability that spread into adjacent brain. Glutamate release from the tumor and the ensuing hyperexcitability were inhibited by sulfasalazine (Azulfidine), an FDA approved drug that blocks system x(c)(−). Acute administration of sulfasalazine at concentrations equivalent to that used by those with Crohn’s disease reduced epileptic event frequency in tumor-bearing mice. Sulfasalazine should be considered as an adjuvant treatment to ameliorate peritumoral seizures associated with glioma.