Commentary: Targeting LDH enzymes with a stiripentol analog to treat epilepsy

Citation: Cho C-H (2015) Commentary: Targeting LDH enzymes with a stiripentol analog to treat epilepsy. Meeting energy demands in neurons is critical for proper functions of nervous systems. In addition to glucose, lactate is used as a major energy source in the brain, and a significant amount of lactate is produced through aerobic glycolysis in astrocytes It is reversibly converted to and from pyruvate by lactate dehydrogenase (LDH), and it is transported from astrocytes to neurons via the astrocyte-neuron lactate shuttle (Pellerin and Magistretti, 2012). Lactate is released from astrocytes through monocarboxylate transporters (MCT1 and MCT4), and has been also reported to be released through ion channels yet to be identified (Korn et al., 2005; Sotelo-Hitschfeld et al., 2015). Released lactate is taken into neurons through MCT2 and converted to pyruvate (Bergersen, 2007). Lactate also induces expression of genes (e.g., arc and c-fos) involved in synaptic plasticity (Suzuki et al., 2011; Yang et al., 2014). In epilepsy where abnormal network activities of hyperexcitable neurons are uncontrollably synchronized, abundant energy for these activities has to be supplemented (Bertram et al., 1998). Expectedly, although more studies need to be done, high rates of glucose metabolism and elevated activity of LDH have been shown in people with epilepsy (PWE) and in animal models of epilepsy (Dufour et al., 2003). Increased level of lactate has been reported in some epilepsy cases (Hill et al., 1999). Other glycolytic enzymes are identified as markers for intractable temporal lobe epilepsies (e.g., neuron-specific enolases) and their defects (e.g., malic enzyme 2 and pyruvate dehydrogenase) are also shown either causative or susceptible to certain types of epilepsy (Steinhoff et al., 1999; Greenberg et al., 2005; Prasad et al., 2011). Recently, Tsuyoshi Inoue's group in Japan reported that the anti-epileptic effect of the ketogenic diet (KD) bypass glycolysis (especially LDH), but occur elaborately through K ATP channels– mediated mechanisms (Ma et al., 2007; Sada et al., 2015). They have shown in electrophysiological recordings that switching glucose to ketone bodies [ß–hydroxybutyrate (ß-HB) or acetoacetate] in artificial cerebrospinal fluid hyperpolarized resting membrane potentials in excitatory neurons, and reduced the firing rate of action potentials in acute brain slice preparations. Replacing ß-HB either with glucose or lactate returned the initial level of resting membrane potentials and the firing rate. Electrophysiological data recorded when oxamate, an LDH inhibitor, was included in the recording pipette showed similar effects to the ß-HB's data. This suggests that …