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

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 lacta...

Full description

Saved in:
Bibliographic Details
Published in:Science (American Association for the Advancement of Science) 2015-03, Vol.347 (6228), p.1362-1367
Main Authors: Sada, Nagisa, Lee, Suni, Katsu, Takashi, Otsuki, Takemi, Inoue, Tsuyoshi
Format: Article
Language:English
Subjects:
Animals
Anticonvulsants - chemistry
Anticonvulsants - pharmacology
Anticonvulsants - therapeutic use
Dioxolanes - chemistry
Dioxolanes - pharmacology
Dioxolanes - therapeutic use
Disease Models, Animal
Enzyme Inhibitors - chemistry
Enzyme Inhibitors - pharmacology
Enzyme Inhibitors - therapeutic use
L-Lactate Dehydrogenase - antagonists & inhibitors
Membrane Potentials - drug effects
Mice
Mice, Inbred ICR
Neurons - enzymology
Neurons - physiology
Patch-Clamp Techniques
Safrole - chemistry
Safrole - pharmacology
Safrole - therapeutic use
Seizures - drug therapy
Subthalamic Nucleus - enzymology
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1095-9203
DOI:10.1126/SCIENCE.AAA1299