An epileptic target

Science 347, 1362–1367 (2015)

There are several drugs that are effective for treatment of epilepsy, but in some cases where these fail to prevent seizures, a ketogenic diet has provided effective management of the disease. This diet switches the brain's energy source from glucose to ketone bodies, which suppress seizures via modulation of neuronal ATP-sensitive K⁺ (K_ATP) channels and adenosine A₁ receptors, but the metabolic events that lead to this suppression are not known. To further explore the connection between metabolism and epilepsy, Sada et al. examined neuronal activity following a switch from glucose to ketone-body utilization. They found that STN cells of the basal ganglia, known to be important for some forms of seizures, are hyperpolarized during the switch in energy source. This hyperpolarization could be completely reversed with lactate, indicating that the hyperpolarization during the switch is due to depletion of glucose and a subsequent lack of conversion into lactate, a neuronal glucose metabolite that is known to be important for regulating various brain functions. Indeed, lactate concentrations in the hippocampus were lower in mice fed a ketogenic diet. Spurred by the idea that the lactate pathway is involved in the hyperpolarization seen during the change in energy source, the authors tested the effects of oxamate, an inhibitor of lactate dehydrogenase (LDH), and found that oxamate treatment also induced hyperpolarization. This could be reversed by addition of the downstream LDH metabolites pyruvate and oxaloacetate as well as by K_ATP inhibition. The oxamate-induced hyperpolarization occurred only in neuronal cell types in which there is a putative link between the downstream metabolites of LDH and K_ATP channels. LDH inhibition by oxamate or by knockdown could suppress seizures and epileptiform activity in two mouse models. Finally, the authors found that the anti-epileptic drug stiripentol and a related compound, isosafrole, inhibited LDH activity. These results suggest that LDH inhibition suppresses epilepsy by mimicking the effects of a ketogenic diet and identified the first anti-epileptic drug known to act on a metabolic pathway.