Targeting LDH enzymes with a stiripentol analog to treat epilepsy
Abstract
Targeting metabolism to tackle seizures: About 1% of us suffer from epilepsy. Unfortunately, presently available drugs do not work for a third of epileptic patients. Sada et al. wanted to develop compounds to treat drug-resistant epilepsy (see the Perspective by Scharfman). They focused on a metabolic pathway in the brain, the astrocyte-neuron lactate shuttle. They found that lactate dehydrogenase, a key molecule in nerve cell metabolism, controls brain excitability. Searching for a substance that selectively targets this molecule, they found a potential anti-epileptic drug that strongly suppressed drug-resistant epilepsy in an animal model. Science , this issue p. 1362 ; see also p. 1312
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Lactate dehydrogenase inhibition with sodium oxamate suppresses seizures and hippocampal CA1 neuronal activity by enhancing pyruvate levels.
“LDH inhibition with sodium oxamate (OXO) suppresses seizures and hippocampal CA1 neuronal activity by enhancing pyruvate levels (Sada et al., 2015; Skwarzynska et al., 2023).”
From APOE4 reduces hippocampal expression of phosphoglycerate kinase 1 and sodium potassium pump to enhance seizure susceptibility in mice (2026) · cites this paper as Sada et al., 2015
Cites
Early Identification of Refractory Epilepsy
Kwan, P., & Brodie, M. J. (2000) · New England Journal of Medicine · doi:10.1056/nejm200002033420503 · Cited by 5,204 · see citing works
Brain energy metabolism: focus on Astrocyte-neuron metabolic cooperation
Bélanger, M., Allaman, I., & Magistretti, P. J. (2011) · Cell Metabolism · doi:10.1016/j.cmet.2011.08.016 · Cited by 2,313 · see citing works
Astrocyte-Neuron Lactate Transport Is Required for Long-Term Memory Formation
Suzuki, A., Stern, S. A., Bozdagi, O., Huntley, G. W., Walker, R. H., Magistretti, P. J., & Alberini, C. M. (2011) · Cell · doi:10.1016/j.cell.2011.02.018 · Cited by 1,711 · see citing works
Regulation of Blood Glucose by Hypothalamic Pyruvate Metabolism
Lam, T. K. T., Gutierrez-Juarez, R., Pocai, A., & Rossetti, L. (2005) · Science · doi:10.1126/science.1112085 · Cited by 341 · see citing works
Chuquet, J., Quilichini, P., Nimchinsky, E. A., & Buzsáki, G. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.0762-10.2010 · Cited by 217 · see citing works
Inoue, T., & Imoto, K. (2006) · Journal of Neurophysiology · doi:10.1152/jn.00301.2006 · Cited by 67 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Cancer metabolism: a therapeutic perspective
Martinez-Outschoorn, U. E., Peiris-Pagés, M., Pestell, R. G., Sotgia, F., & Lisanti, M. P. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.60 · Cited by 1,505 · see citing works
Lactate in the brain: from metabolic end-product to signalling molecule
Magistretti, P. J., & Allaman, I. (2018) · Nature Reviews Neuroscience · doi:10.1038/nrn.2018.19 · Cited by 1,298 · see citing works
A Cellular Perspective on Brain Energy Metabolism and Functional Imaging
Magistretti, P. J., & Allaman, I. (2015) · Neuron · doi:10.1016/j.neuron.2015.03.035 · Cited by 1,285 · see citing works
In vivo evidence for a lactate gradient from astrocytes to neurons
Mächler, P., Wyss, M. T., Elsayed, M., Stobart, J., Gutierrez, R., von Faber-Castell, A., Kaelin, V., Zuend, M., San Martín, A., Romero-Gómez, I., et al. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.10.010 · Cited by 571 · see citing works
Protein lactylation induced by neural excitation
Hagihara, H., Shoji, H., Otabi, H., Toyoda, A., Katoh, K., Namihira, M., & Miyakawa, T. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109820 · Cited by 349 · see citing works
Astrocytes in the initiation and progression of epilepsy
Vezzani, A., Ravizza, T., Bedner, P., Aronica, E., Steinhäuser, C., & Boison, D. (2022) · Nature Reviews Neurology · doi:10.1038/s41582-022-00727-5 · Cited by 272 · see citing works
Bioenergetics and redox adaptations of astrocytes to neuronal activity
Bolaños, J. P. (2016) · Journal of Neurochemistry · doi:10.1111/jnc.13486 · Cited by 262 · see citing works
Clasadonte, J., Scemes, E., Wang, Z., Boison, D., & Haydon, P. G. (2017) · Neuron · doi:10.1016/j.neuron.2017.08.022 · Cited by 200 · see citing works
Stress gates an astrocytic energy reservoir to impair synaptic plasticity
Murphy-Royal, C., Johnston, A. D., Boyce, A. K. J., Diaz-Castro, B., Institoris, A., Peringod, G., Zhang, O., Stout, R. F., Spray, D. C., Thompson, R. J., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-15778-9 · Cited by 158 · see citing works
Matrix Metalloproteinase-Mediated Blood-Brain Barrier Dysfunction in Epilepsy
Rempe, R. G., Hartz, A. M. S., Soldner, E. L. B., Sokola, B. S., Alluri, S. R., Abner, E. L., Kryscio, R. J., Pekcec, A., Schlichtiger, J., & Bauer, B. (2018) · The Journal of Neuroscience · doi:10.1523/jneurosci.2751-17.2018 · Cited by 162 · see citing works
EEG and functional ultrasound imaging in mobile rats
Sieu, L.-A., Bergel, A., Tiran, E., Deffieux, T., Pernot, M., Gennisson, J.-L., Tanter, M., & Cohen, I. (2015) · Nature Methods · doi:10.1038/nmeth.3506 · Cited by 158 · see citing works
Regulation of neuron-astrocyte metabolic coupling across the sleep-wake cycle
Petit, J.-M., & Magistretti, P. J. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2015.12.007 · Cited by 92 · see citing works
Skupio, U., Tertil, M., Bilecki, W., Barut, J., Korostynski, M., Golda, S., Kudla, L., Wiktorowska, L., Sowa, J. E., Siwiec, M., et al. (2020) · Neuropsychopharmacology · doi:10.1038/s41386-019-0450-4 · Cited by 36 · see citing works
Properties of REM sleep alterations with epilepsy
Ikoma, Y., Takahashi, Y., Sasaki, D., & Matsui, K. (2023) · Brain · doi:10.1093/brain/awac499 · Cited by 33 · see citing works
Local brain environment changes associated with epileptogenesis
Ikoma, Y., Sasaki, D., & Matsui, K. (2023) · Brain · doi:10.1093/brain/awac355 · Cited by 26 · see citing works
Dynamics of Neuronal and Astrocytic Energy Molecules in Epilepsy
Furukawa, K., Ikoma, Y., Niino, Y., Hiraoka, Y., Tanaka, K., Miyawaki, A., Hirrlinger, J., & Matsui, K. (2025) · Journal of Neurochemistry · doi:10.1111/jnc.70044 · Cited by 11 · see citing works
Singh, T., Bridgeman, E., Baker, A. J., Noblet, H. A., Yang, K. Y., Kang, S., Lim, K. H., Lee, S. S., Amundsen, N. M., Lee, Y., et al. (2026) · Neurobiology of Disease · doi:10.1016/j.nbd.2025.107246 · Cited by 1 · see citing works
Self-citation
- Authors
- Sada, N., Lee, S., Katsu, T., Otsuki, T., & Inoue, T.
- Affiliations
- Okayama University (JP)
- Department of Hygiene, Kawasaki Medical School, Kurashiki 701-0192, Japan.
- Kawasaki Medical School (JP)
- Corresponding author
- Inoue, Tsuyoshi
- Venue
- Science
- Published
- 2015-03-20
- Volume
- 347
- Issue
- 6228
- Pages
- 1362-1367
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2034688612
- Cited by
- 413
- References
- 6
- Citations by year
- 2026: 37 · 2025: 47 · 2024: 39 · 2023: 36 · 2022: 39 · 2021: 36 · 2020: 33 · 2019: 31 · 2018: 29 · 2017: 36 · 2016: 27 · 2015: 23
- FWCI
- 28.50
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Takeda Science Foundation
- Japan Society for the Promotion of Science (24590114)
- Ryobi-Teien Memory Foundation
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Epilepsy research and treatment
- Health Sciences › Medicine › Physiology › Diet and metabolism studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- lactate dehydrogenase, drug-resistant epilepsy, seizures, astrocyte-neuron lactate shuttle, neuronal energy metabolism, pyruvate, neuronal hyperpolarization, antiepileptic drugs, epileptiform activity, mouse model of epilepsy
- MeSH terms
- Animals, Anticonvulsants, Dioxolanes, Disease Models, Animal, Enzyme Inhibitors, L-Lactate Dehydrogenase, Membrane Potentials, Mice, Inbred ICR, Neurons, Safrole, Seizures, Patch-Clamp Techniques, Subthalamic Nucleus, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
