Glutamate release by primary brain tumors induces epileptic activity
Open accessAbstract
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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The cellular and molecular changes underlying tumor-associated epilepsy collectively point to a decrease in GABAergic and increase in glutamatergic transmission as the major contributors.
“The cellular and molecular changes underlying tumor-associated epilepsy collectively point to a decrease in GABAergic and increase in glutamatergic transmission as the major contributors3–6.”
From Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy (2018) · cites this paper as [6]
Seizures originate from the PTC, and previous studies show altered excitation−inhibition balance in the PTC due to changes in glutamatergic and GABAergic activity.
“Seizures originate from the PTC, and previous studies3,5,6 show altered excitation−inhibition balance in the PTC due to changes in glutamatergic and GABAergic activity.”
From Perineuronal nets decrease membrane capacitance of peritumoral fast spiking interneurons in a model of epilepsy (2018) · cites this paper as [6]
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- Authors
- Buckingham, S. C., Campbell, S. L., Haas, B. R., Montana, V., Robel, S., Ogunrinu, T., & Sontheimer, H.
- Affiliations
- University of Alabama at Birmingham (US)
- Corresponding author
- Sontheimer, Harald
- Venue
- Nature Medicine
- Published
- 2011-09-11
- Volume
- 17
- Issue
- 10
- Pages
- 1269-1274
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC3192231
- OpenAlex
- W2104048484
- Cited by
- 578
- References
- 36
- Citations by year
- 2026: 67 · 2025: 58 · 2024: 50 · 2023: 56 · 2022: 38 · 2021: 30 · 2020: 37 · 2019: 41 · 2018: 26 · 2017: 28 · 2016: 24 · 2015: 29 · 2014: 41 · 2013: 25 · 2012: 24
- FWCI
- 20.57
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- University of Utah
- University of Alabama at Birmingham
- City of Hope
- National Institutes of Health
- National Cancer Institute (U54CA100949, P50CA097247)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK079337)
- National Institute of Neurological Disorders and Stroke (R01NS052634, 2R01-NS052634, 5R01-NS036692, P30NS057098, R01NS036692, T32NS048039, NS57098)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30 AR 50948, P30AR050948)
- National Center for Research Resources (S10 RR 19231, S10RR019231)
- National Center for Complementary and Integrative Health (P50 AT-00477, P50AT000477)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD038985)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Keywords
- glioma, glutamate release, system xc-, SLC7A11, sulfasalazine, excitotoxicity, brain tumors, adjuvant therapy
- MeSH terms
- Analysis of Variance, Animals, Brain Neoplasms, Electroencephalography, Electrophysiology, Epilepsy, Glioma, Humans, Sulfasalazine, Mice, SCID, Cell Transplantation, Glutamic Acid, Amino Acid Transport System y+, Mice
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