Publication Date:
2015-03-21
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sada, Nagisa -- Lee, Suni -- Katsu, Takashi -- Otsuki, Takemi -- Inoue, Tsuyoshi -- New York, N.Y. -- Science. 2015 Mar 20;347(6228):1362-7. doi: 10.1126/science.aaa1299.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Biophysical Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan. ; Department of Hygiene, Kawasaki Medical School, Kurashiki 701-0192, Japan. ; Department of Biophysical Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan. tinoue@pharm.okayama-u.ac.jp.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25792327" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Anticonvulsants/chemistry/*pharmacology/therapeutic use
;
Dioxolanes/chemistry/*pharmacology/therapeutic use
;
Disease Models, Animal
;
Enzyme Inhibitors/chemistry/*pharmacology/therapeutic use
;
L-Lactate Dehydrogenase/*antagonists & inhibitors
;
Membrane Potentials/drug effects
;
Mice
;
Mice, Inbred ICR
;
Neurons/enzymology/physiology
;
Patch-Clamp Techniques
;
Safrole/chemistry/*pharmacology/therapeutic use
;
Seizures/*drug therapy
;
Subthalamic Nucleus/enzymology
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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