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.
References
Sada, N. et al. Targeting LDH enzymes with a stiripentol analog to treat epilepsy. Science 347, 1362–1367 (2015)
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Crunkhorn, S. LDH inhibition suppresses seizures. Nat Rev Drug Discov 14, 312 (2015). https://doi.org/10.1038/nrd4631
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DOI: https://doi.org/10.1038/nrd4631