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Cited by 11Epilepsy research and treatmentDiet and metabolism studiesNeuroscience and Neuropharmacology Research

Glycolytic lactate production supports status epilepticus in experimental animals

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Skwarzynska, Daria, Sun, Huayu, Kasprzak, Izabela, Sharma, Supriya, Williamson, John, Kapur, Jaideep·2023·Annals of Clinical and Translational Neurology
DOI 10.1002/acn3.51881PMC PMC10578888
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Abstract

Objective: Status epilepticus (SE) requires rapid intervention to prevent cerebral injury and mortality. The ketogenic diet, which bypasses glycolysis, is a promising remedy for patients with refractory SE. We tested the role of glycolytic lactate production in sustaining SE. Methods: Extracellular lactate and glucose concentration during a seizure and SE in vivo was measured using lactate and glucose biosensors. A lactate dehydrogenase inhibitor, oxamate, blocked pyruvate to lactate conversion during SE. Video‐EEG recordings evaluated seizure duration, severity, and immunohistochemistry was used to determine neuronal loss. Genetically encoded calcium indicator GCaMP7 was used to study the effect of oxamate on CA1 pyramidal neurons in vitro. Spontaneous excitatory postsynaptic currents (sEPSCs) were recorded from CA1 neurons to study oxamate's impact on neurotransmission. Results: The extracellular glucose concentration dropped rapidly during seizures, and lactate accumulated in the extracellular space. Inhibition of pyruvate to lactate conversion with oxamate terminated SE in mice. There was less neuronal loss in treated compared to control mice. Oxamate perfusion decreased tonic and phasic neuronal activity of GCaMP7‐expressing CA1 pyramidal neurons in vitro. Oxamate application reduced the frequency, but not amplitude of sEPSCs recorded from CA1 neurons, suggesting an effect on the presynaptic glutamatergic neurotransmission. Interpretation: A single seizure and SE stimulate lactate production. Diminishing pyruvate to lactate conversion with oxamate terminated SE and reduced associated neuronal death. Oxamate reduced neuronal excitability and excitatory neurotransmission at the presynaptic terminal. Glycolytic lactate production sustains SE and is an attractive therapeutic target.

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  • 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 Skwarzynska et al., 2023

    The Results sections report that oxamate terminated status epilepticus in mice and reduced tonic and phasic activity of hippocampal CA1 neurons in vitro (page numbers unavailable). The Discussion says LDH inhibition blocks conversion of pyruvate to lactate and may favor its conversion to acetyl-CoA, but the paper does not show enhanced pyruvate levels or establish that as the cause of seizure suppression. (LLM, conf=0.88)

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Cited by

Sorted by citations

Authors
Skwarzynska, D., Sun, H., Kasprzak, I., Sharma, S., Williamson, J., & Kapur, J.
Affiliations
  • Neuroscience Graduate Program University of Virginia Charlottesville Virginia 22908 USA
  • University of Virginia (US)
Corresponding author
Kapur, Jaideep
ORCID
Venue
Annals of Clinical and Translational Neurology
Publisher
Wiley
Published
2023-08-25
Volume
10
Issue
10
Pages
1873-1884
ISSN
2328-9503 (ISSN-L)
DOI
10.1002/acn3.51881
PMC
PMC10578888
OpenAlex
W4386188371
Cited by
11
References
0
Citations by year
2026: 4 · 2025: 4 · 2024: 3
FWCI
2.12
Type
journal article
Language
en
Open access
Licence
Locations
  • Annals of Clinical and Translational Neurology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institutes of Health (R01NS120945, R37 NS119012, RO1 NS040337)
  • Brain Institute, University of Virginia
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
status epilepticus, pyruvate to lactate conversion, oxamate, lactate dehydrogenase inhibition, extracellular glucose, neuronal loss, CA1 pyramidal neurons, excitatory postsynaptic currents, glutamatergic neurotransmission, ketogenic diet, seizure termination, neuronal excitability
MeSH terms
Animals, Glucose, Glycolysis, Humans, Pyruvates, Seizures, Status Epilepticus, Lactic Acid, Mice

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