Targeting LDH enzymes with a stiripentol analog to treat epilepsy

Nagisa Sada, Suni Lee, Takashi Katsu, Takemi Otsuki, Tsuyoshi Inoue

Research output: Contribution to journalArticlepeer-review

193 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1362-1367
Number of pages6
JournalScience
Volume347
Issue number6228
DOIs
Publication statusPublished - Mar 20 2015

ASJC Scopus subject areas

  • General

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