Levetiracetam therapeutically targets GABAergic synapses in diffuse midline glioma

Antiseizure medications, such as levetiracetam, are commonly used in glioma patients. Retrospective analyses evaluating effects of antiseizure medications on glioma patient survival have yielded inconsistent results, probably due to confounding factors of glioma subtype and drug class. Here we present retrospective real-world clinical data that demonstrate longer overall survival for children with diffuse midline glioma (DMG) who were taking levetiracetam, which was not evident in pediatric patients with hemispheric high-grade glioma. In preclinical models, levetiracetam reduces glioma proliferation and tumor burden, extending survival of mice bearing DMG orthotopic xenografts. These beneficial effects were not found in hemispheric high-grade glioma patient-derived orthotopic xenograft models. The subtype-specificity of this antiproliferative effect of levetiracetam is congruent with recent findings that GABAergic neuron-to-glioma synapses promote glioma growth in DMG but not hemispheric high-grade glioma. We demonstrate here that levetiracetam attenuates low-frequency GABAergic synaptic transmission in a glioma-specific manner, reducing GABAergic synaptic currents in DMG but not in healthy neurons. This effect is independent of action on SV2A, the chief mechanism by which levetiracetam functions to prevent and treat seizures. Taken together, these findings indicate a promising approach to target GABAergic synapses in DMG and suggest that use of levetiracetam in DMG should be further studied in future prospective clinical studies.

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Publication Details

Journal
Nature Medicine
Published
2026-09-17
DOI
https://doi.org/10.1038/s41591-026-04646-6
Primary Topic
Glioma Diagnosis and Treatment
Type
article
Field-Weighted Citation Impact
0.00

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article

Levetiracetam therapeutically targets GABAergic synapses in diffuse midline glioma

Tara Barron, Paul G. Fisher, Lijun Ni, Vilina Mehta et al.
Nature Medicine
Glioma Diagnosis and Treatment
article

Levetiracetam therapeutically targets GABAergic synapses in diffuse midline glioma

Tara Barron, Paul G. Fisher, Lijun Ni, Vilina Mehta, Samantha Lyons, Kathryn R. Taylor, Linh Thuy Vo, Cynthia Campen, Aaron Mochizuki, Michelle Monje, Neeraj Soni, Pamelyn J. Woo, Dana Tlais, Kai Kaila, Hannes Vogel, Kiarash Shamardani, Andrea Franson, Sonia Partap, Michael A. Quezada, Ulrich Schüller, Evan Cantor, Franz Ricklefs, Richard Drexler, Samuel H. Wu, Truman Knowles, Michael B. Keough, Sabine Mueller, Shannon Raber, Kim Kilian, Enrique Herrera Castañeda, Carl Koschmann, Samin Malaki Jahan
article en

Abstract

Antiseizure medications, such as levetiracetam, are commonly used in glioma patients. Retrospective analyses evaluating effects of antiseizure medications on glioma patient survival have yielded inconsistent results, probably due to confounding factors of glioma subtype and drug class. Here we present retrospective real-world clinical data that demonstrate longer overall survival for children with diffuse midline glioma (DMG) who were taking levetiracetam, which was not evident in pediatric patients with hemispheric high-grade glioma. In preclinical models, levetiracetam reduces glioma proliferation and tumor burden, extending survival of mice bearing DMG orthotopic xenografts. These beneficial effects were not found in hemispheric high-grade glioma patient-derived orthotopic xenograft models. The subtype-specificity of this antiproliferative effect of levetiracetam is congruent with recent findings that GABAergic neuron-to-glioma synapses promote glioma growth in DMG but not hemispheric high-grade glioma. We demonstrate here that levetiracetam attenuates low-frequency GABAergic synaptic transmission in a glioma-specific manner, reducing GABAergic synaptic currents in DMG but not in healthy neurons. This effect is independent of action on SV2A, the chief mechanism by which levetiracetam functions to prevent and treat seizures. Taken together, these findings indicate a promising approach to target GABAergic synapses in DMG and suggest that use of levetiracetam in DMG should be further studied in future prospective clinical studies.

Nature Medicine
University of Helsinki (FI), Howard Hughes Medical Institute (US), Universität Hamburg (DE), University of California, San Francisco (US), University of Michigan (US), University Medical Center Hamburg-Eppendorf (DE), Kinderkrebs-Zentrum Hamburg (DE), Stanford Medicine (US), Southwestern Medical Center (US), Harold C. Simmons Comprehensive Cancer Center, The University of Texas Southwestern Medical Center (US), Stanford University (US)
Pediatric Cancer Research Foundation, Alex's Lemonade Stand Foundation for Childhood Cancer, Cancer Prevention and Research Institute of Texas, Virginia and D.K. Ludwig Fund for Cancer Research, ChadTough Foundation, Robert J. Kleberg, Jr. and Helen C. Kleberg Foundation, Cancer Research UK, National Institutes of Health, National Cancer Institute
Good health and well-being
Openalex Percentile: Top 11%
Glioma Diagnosis and Treatment
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