Anticonvulsant effects of a triheptanoin diet in two mouse chronic seizure models

We hypothesized that in epileptic brains citric acid cycle intermediate levels may be deficient leading to hyperexcitability. Anaplerosis is the metabolic refilling of deficient metabolites. Our goal was to determine the anticonvulsant effects of feeding triheptanoin, the triglyceride of anaplerotic heptanoate. CF1 mice were fed 0-35% calories from triheptanoin. Body weights and dietary intake were similar in mice fed triheptanoin vs. standard diet. Triheptanoin feeding increased blood propionyl-carnitine levels, signifying its metabolism. 35%, but not 20%, triheptanoin delayed development of corneal kindled seizures. After pilocarpine-induced status epilepticus (SE), triheptanoin feeding increased the pentylenetetrazole tonic seizure threshold during the chronically epileptic stage. Mice in the chronically epileptic stage showed various changes in brain metabolite levels, including a reduction in malate. Triheptanoin feeding largely restored a reduction in propionyl-CoA levels and increased methylmalonyl-CoA levels in SE mice. In summary, triheptanoin was anticonvulsant in two chronic mouse models and increased levels of anaplerotic precursor metabolites in epileptic mouse brains. The mechanisms of triheptanoin's effects and its efficacy in humans suffering from epilepsy remain to be determined.

Research Highlights►A new 35% (cal) triheptanoin diet was developed that is well tolerated in mice and was anticonvulsant in two chronic mouse seizure models, corneal kindling and the pilocarpine model. ►Brain metabolite levels were changed in the chronic epileptic stage of pilocarpine-status epilepticus mice, including reductions in the levels of malate and propionyl-CoA. ►Triheptanoin feeding largely restored the reduction in propionyl-CoA and increased methylmalonyl-CoA levels, both anaplerotic metabolites in mice in the chronic stage of epilepsy. ►If effective in human epilepsy patients, this new diet may represent a palatable alternative to the ketogenic diet in children and adults.