Journal
SCIENCE
Volume 347, Issue 6228, Pages 1362-1367Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aaa1299
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Funding
- Japan Society for the Promotion of Science [24590114]
- Takeda Science Foundation
- Ryobi-Teien Memory Foundation
- Grants-in-Aid for Scientific Research [25253008, 24590114, 25460825] Funding Source: KAKEN
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Neuronal excitation is regulated by energy metabolism, and drug-resistant epilepsy can be suppressed by special diets. Here, we report that seizures and epileptiform activity are reduced by inhibition of the metabolic pathway via lactate dehydrogenase (LDH), a component of the astrocyte-neuron lactate shuttle. Inhibition of the enzyme LDH hyperpolarized neurons, which was reversed by the downstream metabolite pyruvate. LDH inhibition also suppressed seizures in vivo in a mouse model of epilepsy. We further found that stiripentol, a clinically used antiepileptic drug, is an LDH inhibitor. By modifying its chemical structure, we identified a previously unknown LDH inhibitor, which potently suppressed seizures in vivo. We conclude that LDH inhibitors are a promising new group of antiepileptic drugs.
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