title: Glutamate release by primary brain tumors induces epileptic activity.
abstract: Epileptic seizures are a common and poorly understood comorbidity for individuals with primary brain tumors. To investigate peritumoral seizure etiology, we implanted human-derived glioma cells into severe combined immunodeficient mice. Within 14-18 d, glioma-bearing mice developed spontaneous and recurring abnormal electroencephalogram events consistent with progressive epileptic activity. Acute brain slices from these mice showed marked glutamate release from the tumor mediated by the system x(c)(-) cystine-glutamate transporter (encoded by Slc7a11). Biophysical and optical recordings showed glutamatergic epileptiform hyperexcitability that spread into adjacent brain tissue. We inhibited glutamate release from the tumor and the ensuing hyperexcitability by sulfasalazine (SAS), a US Food and Drug Administration-approved drug that blocks system x(c)(-). We found that acute administration of SAS at concentrations equivalent to those used to treat Crohn's disease in humans reduced epileptic event frequency in tumor-bearing mice compared with untreated controls. SAS should be considered as an adjuvant treatment to ameliorate peritumoral seizures associated with glioma in humans.
authors: Department of Neurobiology, Center for Glial Biology in Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors: Susan C
authors: SC
authors: Buckingham
authors: Susan L
authors: SL
authors: Campbell
authors: Brian R
authors: BR
authors: Haas
authors: Vedrana
authors: V
authors: Montana
authors: Stefanie
authors: S
authors: Robel
authors: Toyin
authors: T
authors: Ogunrinu
authors: Harald
authors: H
authors: Sontheimer
mesh_terms: D027182:Amino Acid Transport System y+ / Q000037:antagonists & inhibitors / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D001932:Brain Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000378:metabolism*; D017690:Cell Transplantation; D004569:Electroencephalography; D004594:Electrophysiology; D004827:Epilepsy / Q000209:etiology* / Q000473:pathology; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D012460:Sulfasalazine / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D027182:Amino Acid Transport System y+; C492255:Slc7a11 protein, mouse; D018698:Glutamic Acid; D012460:Sulfasalazine