Editors' ChoiceEpilepsy

Metabolic sanctions against epilepsy

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Science Translational Medicine  08 Apr 2015:
Vol. 7, Issue 282, pp. 282ec58
DOI: 10.1126/scitranslmed.aab2934

Epilepsy is one of the most common human disorders. About 1% of the population is affected by this disease at some point in life, albeit to a different extent. Epileptic seizures are caused by numerous factors that range from point mutations in ion channels to traumatic brain damage. The diversity of causes for epilepsy represents a major challenge for treatment, and more than 30% of epilepsy patients are treatment-resistant. A recent study from Sada et al. offers an optimistic prospect for treatment of the disease by curbing the neurons’ metabolism.

Neurons in the brain receive their energy from three different sources: glucose, lactate (produced by neighboring astrocytes), and ketone bodies. The authors found that inhibition of lactate dehydrogenase (LDH), an enzyme critical in the metabolic cross-talk between astrocytes and neurons, blocks neuron excitation and seizures in mice. Why would inhibition of LDH have an anti-epileptic effect? It appears that neuronal excitability depends largely on glucose, whereas ketone bodies suppress neuron activity by inducing a hyperpolarized state. The ketone body–induced neuronal hyperpolarization can be reversed by the presence of lactate. The astrocyte-neuronal lactate pathway is mediated by the enzyme LDH, which controls lactate production in astrocytes and lactate metabolism in neurons. The authors used a chemical inhibitor of LDH activity to mimic ketone body–induced hyperpolarization, revealing LDH as a major regulator of neuronal excitability. The authors narrowed the action of LDH inhibition specifically to astrocytes. In the astrocytes, a reduction in lactate production caused hyperpolarization of neighboring excitatory neurons. In support of a therapeutic potential of inhibiting LDH activity in vivo, the researchers found that chemical and antisense oligodeoxynucleotide-based reduction of LDH in the hippocampus attenuated chemically induced acute and chronic seizures in mice.

One of the currently available antiseizure medications, stiripentol, can inhibit LDH, although at a high concentration. By modifying the chemical structure of stiripentol, the authors identified a previously unknown LDH inhibitor, isosafrole, which potently suppressed seizures in mouse models in vivo. These findings may initiate a shift in the therapeutic approach in epilepsy toward targeting the metabolic pathways in neurons and astrocytes.

N. Sada et al., Targeting LDH enzymes with a stiripentol analog to treat epilepsy. Science 347, 1362–1367 (2015). [Abstract]

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