Targeting LDH enzymes with a stiripentol analog to treat epilepsy

  title={Targeting LDH enzymes with a stiripentol analog to treat epilepsy},
  author={Nagisa Sada and Suni Lee and Takashi Katsu and Takemi Otsuki and Tsuyoshi Inoue},
  pages={1362 - 1367}
Targeting metabolism to tackle seizures About 1% of us suffer from epilepsy. Unfortunately, presently available drugs do not work for a third of epileptic patients. Sada et al. wanted to develop compounds to treat drug-resistant epilepsy (see the Perspective by Scharfman). They focused on a metabolic pathway in the brain, the astrocyte-neuron lactate shuttle. They found that lactate dehydrogenase, a key molecule in nerve cell metabolism, controls brain excitability. Searching for a substance… 

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

  • C. Cho
  • Biology
    Front. Cell. Neurosci.
  • 2015
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, 2015).

Metabolic Control of Epilepsy: A Promising Therapeutic Target for Epilepsy

Epilepsy is a common neurological disease that is not always controlled, and the ketogenic diet shows good antiepileptic effects drug-resistant epilepsy or seizures caused by specific metabolic

Upregulation of lactate dehydrogenase A in a chronic model of temporal lobe epilepsy

It is shown that chronic seizures increase LDHA, and conversely, the inhibition of LDHA suppresses seizures, which supports LDHA as a molecular target for the development of new antiepileptic drugs.

Metabolic Control of Epilepsy: A Promising Therapeutic Target for Epilepsy

Regulation of neuronal excitation via metabolic pathways and antiepileptic therapies targeting metabolic pathways are emphasized to provide insight into the state of the art concerning the brain’s metabolic patterns and their association with epilepsy.

The metabolic basis of epilepsy

Evidence that supports both pathophysiological and therapeutic roles for brain metabolism in epilepsy is reviewed, highlighting the growing recognition that disruptions in cellular metabolism can be both a cause and a consequence of epileptic seizures and how this emerging science might be exploited to develop innovative therapeutic strategies.

Reduction of epileptiform activity in ketogenic mice: The role of monocarboxylate transporters

The results suggest that MCTs not only play an important role in the transport of ketone bodies, but also in the modulation of brain energy metabolism under normal and ketogenic conditions.

Use of the Ketogenic Diet to Treat Intractable Epilepsy in Mitochondrial Disorders

The ketogenic diet and its more palatable formulations has shown promising results and is especially indicated and effective in the treatment of mitochondrial disorders due to complex I deficiency.

Neuregulin 1/ErbB4 signaling contributes to the anti-epileptic effects of the ketogenic diet

A critical role of Nrg1/ErbB4 signaling in mediating KD’s effects on GABAergic activity and seizures is suggested, shedding light on developing new therapeutic interventions to seizure control.

Metabolic control of epilepsy

Seizures may be controlled by targeting inexcitable elements of the nervous system [Also see Report by Sada et al.] It has been assumed that anticonvulsants or antiepileptic drugs, now called



Stiripentol. A novel antiepileptic drug.

STP potentiates central gamma-aminobutyric acid (GABA) transmission and is characterized by nonlinear pharmacokinetics and inhibition of liver microsomal enzymes, and seems a good candidate for adjunctive therapy in intractable epilepsy.

Sweet Sixteen for ANLS

  • L. PellerinP. Magistretti
  • Biology
    Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
  • 2012
The ANLS model now represents a useful, experimentally based framework to better understand the coupling between neuronal activity and energetics as it relates to neuronal plasticity, neurodegeneration, and functional brain imaging.

Discovery of N-hydroxyindole-based inhibitors of human lactate dehydrogenase isoform A (LDH-A) as starvation agents against cancer cells.

New and efficient N-hydroxyindole-based inhibitors of LDH-A are discovered, which are isoform-selective (overLDH-B) and competitive with both the substrate (pyruvate) and the cofactor (NADH) and they proved to be particularly effective under hypoxic conditions.

A ketogenic diet suppresses seizures in mice through adenosine A₁ receptors.

It is shown that ketogenic diet can reduce seizures in mice by increasing activation of adenosine A1 receptors (A1Rs) and that adenosines deficiency may be relevant to human epilepsy and that KD can reducing seizures by increasing A1R-mediated inhibition.

Ketogenic Diet Metabolites Reduce Firing in Central Neurons by Opening KATP Channels

It is proposed that ketone bodies or glycolytic restriction treat epilepsy by augmenting a natural activity-limiting function served by KATP channels in neurons, which is larger for cells that fire more rapidly.

Ketogenic diets, mitochondria, and neurological diseases

There is mounting evidence that the KD and its variants can impact key signaling pathways that evolved to sense the energetic state of the cell, and that help maintain cellular homeostasis, which may lead to future therapeutic strategies aimed at mimicking the pleiotropic neuroprotective effects of the KD.

Seizure Suppression by Adenosine A1 Receptor Activation in a Mouse Model of Pharmacoresistant Epilepsy

In the present study, activation of the adenosine system was applied as a possible treatment for pharmacoresistant epilepsy.