Researchers working on ways to duplicate the anticonvulsant effects of the ketogenic diet in patients with drug-resistant epilepsy have found that a diet containing a large amount of the triglyceride triheptanoin significantly reduced susceptibility to chronic seizures in two separate mouse models of epilepsy.
But the triglyceride, which has been used to treat hereditary metabolic disorders, did not appear to have an effect on the level of particular citric acid cycle intermediates and metabolites in the brain, Sarah Willis of Texas Tech University and her colleagues reported (Neurobiol. Dis. 2010;40:565-72).
When mice were fed a diet containing 35% triheptanoin for 3 weeks before undergoing seizure induction via corneal kindling, the compound delayed the development of kindled seizures, in comparison with mice that were fed a standard diet.
Triheptanoin replaced sucrose and some of the complex carbohydrates that are contained in the standard diet. Elimination of sucrose altogether or use of a 20% triheptanoin diet had nonsignificant effects.
However, if a 35% triheptanoin diet was introduced after the mice became fully kindled, the compound had no effect on seizure severity.
When Ms. Willis and her associates tried the diet in another group of mice 2 weeks after the animals were given pilocarpine to induce status epilepticus (SE), triheptanoin halved the susceptibility of the mice to tonic extension seizures that were induced with an injection of pentylenetetrazole (PTZ). They observed similar reductions in susceptibility to tonic extension seizures when the diet was initiated immediately after pilocarpine.
SE mice that were given the standard diet 2 weeks after receiving pilocarpine had significant changes in the brain levels of particular citric acid cycle metabolites (including acetyl-CoA), as well as the neurotransmitters aspartate and gamma-aminobutyric acid, compared with mice that did not develop SE.
The level of propionyl-CoA, a metabolite of triheptanoin, declined in SE mice that were fed a standard diet. However, the triheptanoin diet increased levels of propionyl-CoA in SE mice.
Despite the fact that propionyl-CoA can be used to replenish levels of the citric acid cycle intermediate succinyl-CoA, the triheptanoin diet had no effect on the levels of citric acid cycle intermediates, including acetyl-CoA and succinyl-CoA. These effects indicated that the metabolism of triheptanoin is different in epileptic brain tissue, compared with normal brain tissue, which suggests that triheptanoin “may have more pronounced effects in 'diseased' compared to normal brain tissue,” the authors wrote.
The research was funded by Citizens United for Research in Epilepsy and the National Institutes of Health. The investigators filed a provisional patent in the United States for their discovery.
Seizure development was delayed in mice fed a diet containing 35% triheptanoin (right) for 3 weeks, compared with mice fed a standard, sucrose-containing diet (left).
Source Photos Courtesy Karin Borges, Ph.D.