Epilepsy treatment. Targeting LDH enzymes with a stiripentol analog to treat epilepsy.

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Sada N, Lee S, Katsu T, Otsuki T, Inoue T

Epilepsy treatment. Targeting LDH enzymes with a stiripentol analog to treat epilepsy.

Science. 2015 Mar 20;347(6228):1362-7. doi: 10.1126/science.aaa1299.

PubMed ID

25792327 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Drugs

Stiripentol

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Stiripentol	L-lactate dehydrogenase A chain	Protein	Humans	Yes	Inhibitor	Details
Stiripentol	L-lactate dehydrogenase B chain	Protein	Humans	Yes	Inhibitor	Details