title: Epilepsy treatment. Targeting LDH enzymes with a stiripentol analog to treat epilepsy.
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.
authors: Department of Biophysical Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
authors: Nagisa
authors: N
authors: Sada
authors: Department of Hygiene, Kawasaki Medical School, Kurashiki 701-0192, Japan.
authors: Suni
authors: S
authors: Lee
authors: Department of Biophysical Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan.
authors: Takashi
authors: T
authors: Katsu
authors: Department of Hygiene, Kawasaki Medical School, Kurashiki 701-0192, Japan.
authors: Takemi
authors: T
authors: Otsuki
authors: Department of Biophysical Chemistry, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8530, Japan. tinoue@pharm.okayama-u.ac.jp.
authors: Tsuyoshi
authors: T
authors: Inoue
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004148:Dioxolanes / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D007770:L-Lactate Dehydrogenase / Q000037:antagonists & inhibitors*; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D009474:Neurons / Q000201:enzymology / Q000502:physiology; D018408:Patch-Clamp Techniques; D012451:Safrole / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D012640:Seizures / Q000188:drug therapy*; D020531:Subthalamic Nucleus / Q000201:enzymology
chemical_list: D000927:Anticonvulsants; D004148:Dioxolanes; D004791:Enzyme Inhibitors; D007770:L-Lactate Dehydrogenase; C021092:stiripentol; D012451:Safrole; C015959:isosafrole