期刊
NATURE MEDICINE
卷 17, 期 10, 页码 1269-U299出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.2453
关键词
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资金
- National Center for Research Resources [S10 RR19231]
- US National Institutes of Health [U54 CA 100949, P50 AT00477, P30 DK079337, P30 AR50948, 2R01-NS052634, 5R01-NS036692, 5T32NS048039-03]
- Neuroscience Blueprint Core Grant [NS57098]
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.
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