Neuronal excitation is regulated by energy metabolism, and specific diets have been shown to suppress seizures in some patients with epilepsy. Targeting brain metabolism may therefore represent a new antiepileptic strategy. Here, Sada et al. report that blocking a key metabolic pathway in the brain — the astrocyte–neuron lactate shuttle — by inhibiting or knocking down lactate dehydrogenase (LDH) hyperpolarizes neurons and suppresses seizures in mouse seizure models. The authors optimized the structure of the antiepileptic agent stiripentol — which they found to inhibit LDH — to produce isosafrole, which potently suppressed seizures in the mouse kainate epilepsy model.