isosafrole and Disease-Models--Animal

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.

Topics: Animals; Anticonvulsants; Dioxolanes; Disease Models, Animal; Enzyme Inhibitors; L-Lactate Dehydrogenase; Membrane Potentials; Mice; Mice, Inbred ICR; Neurons; Patch-Clamp Techniques; Safrole; Seizures; Subthalamic Nucleus