Triheptanoin, an oily substance, consists of
glycerol bound to three molecules of heptanoic
acid, a C7 odd-chain
fatty acid. A
triheptanoin-rich diet has anaplerotic effects because heptanoate metabolism yields
succinate which delivers substrates to the Krebs cycle. While previous studies on the effects of
triheptanoin focused on metabolic disorders and
epilepsy, we investigated
triheptanoin's effect on
ischemic stroke. Mice were fed a
triheptanoin-enriched diet for 14days; controls received
soybean oil. Only mice fed
triheptanoin had measurable quantities of odd-numbered
fatty acids in the plasma and brain. Transient
ischemia was induced in the brain by occlusion of the middle cerebral artery (MCAO) for 60min. One day later, mice were tested for neurological function (chimney, rotarod and corner tests) which was found to be better preserved in the
triheptanoin group. Microdialysis demonstrated that the strong, neurotoxic increase of extracellular
glutamate, which was observed in the mouse striatum during MCAO, was strongly reduced in
triheptanoin-fed mice while
glucose levels were not affected.
Triheptanoin diet reduced the
infarct area in stroked mice by about 40%. In ex vivo-experiments with isolated mitochondria,
ischemia was found to cause a reduction of mitochondrial respiratory activity. This reduction was attenuated by
triheptanoin diet in complex II and IV. In parallel measurements,
ATP levels and mitochondrial membrane potential were reduced in control animals but were preserved in
triheptanoin-fed mice. We conclude that
triheptanoin-fed mice which sustained an experimental
stroke had a significantly improved neurological outcome. This beneficial effect is apparently due to an improvement of mitochondrial function and preservation of the cellular energy state. Our findings identify
triheptanoin as a promising new dietary agent for neuroprotection.