Targeting Brain Metabolism Could Offer New Way To Treat Epilepsy

For about one-third of patients with epilepsy, existing drugs do little to relieve symptoms such as chronic seizures. When they do work, these drugs stop neurons from becoming overexcited by targeting ion channels and other receptors on the cells.

Now, researchers in Japan report a novel antiepilepsy target outside neurons. The team demonstrates that inhibiting a metabolic pathway in neuron-helper cells called astrocytes can suppress seizures in mice.

“This is a major discovery that will revolutionize the field,” says Detlev Boison, the director of neurobiology at Legacy Research Institute in Portland, Ore., who was not involved in the study. “This study shows that there are other ways to look at treating epilepsy.”

The new target is the enzyme lactate dehydrogenase (LDH). It plays a role in how brain cells generate energy from glucose. In one part of the process, astrocytes use enzymes, including LDH, to turn glucose into lactate, which they then shuttle to neurons. The nerve cells convert lactate to pyruvate, which enters the citric acid cycle, a major metabolic pathway that produces chemical energy for the cell.

Tsuyoshi Inoue of Okayama University and colleagues focused on inhibiting LDH because some epileptic patients find relief from seizures when they switch to a low-carbohydrate, high-fat diet that makes brain cells skip the LDH-driven astrocyte process. This ketogenic diet forces the brain to switch from burning glucose to burning fat metabolites called ketone bodies, which get pushed directly into the citric acid cycle.

The researchers found that blocking LDH directly mimics the ketogenic diet’s effects (Science 2015, DOI: 10.1126/science.aaa1299). When they injected an LDH inhibitor into the hippocampus of mice with epilepsy-like symptoms, they observed fewer high-voltage spikes, a cellular sign of seizures, than seen in mice receiving a saline injection.

The Okayama team also found that an antiepileptic drug used in Europe called stiripentol inhibits LDH, although that was not part of the molecule’s design. The researchers tested an analog of the compound, isosafrole, and found it was a better LDH inhibitor and suppressed high-voltage spikes to a greater degree compared with stiripentol.

The scientists think compounds such as isosafrole could lead to new treatments for drug-resistant epilepsy.