• Nagisa Sada, Suni Lee, Takashi Katsu, Takemi Otsuki, and Tsuyoshi Inoue.
• Department of Biophysical Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
• Science. 2015 Mar 20;347(6228):1362-7.

AbstractNeuronal 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.Copyright © 2015, American Association for the Advancement of Science.

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