Triheptanoin--a medium chain triglyceride with odd chain fatty acids: a new anaplerotic anticonvulsant treatment?

Abstract

The triglyceride of heptanoate (C7 fatty acid), triheptanoin, is a tasteless oil used to treat rare metabolic disorders in USA and France. Heptanoate is metabolized by β-oxidation to provide propionyl-CoA, which after carboxylation can produce succinyl-CoA, resulting in anaplerosis - the refilling of the tricarboxylic acid cycle. Heptanoate is also metabolized by the liver to the C5 ketones, β-ketopentanoate and/or β-hydroxypentanoate, which are released into the blood and thought to enter the brain via monocarboxylate transporters. Oral triheptanoin has recently been discovered to be reproducibly anticonvulsant in acute and chronic mouse seizures models. However, current knowledge on alterations of brain metabolism after triheptanoin administration and anaplerosis via propionyl-CoA carboxylation in the brain is limited. This review outlines triheptanoin's unique anticonvulsant profile and its clinical potential for the treatment of medically refractory epilepsy. Anaplerosis as a therapeutic approach for the treatment of epilepsy is discussed. More research is needed to elucidate the anticonvulsant mechanism of triheptanoin and to reveal its clinical potential for the treatment of epilepsy and other disorders of the brain.

Fig. 1

Anaplerotic pathways. Enzymes are marked by numbers. In the brain, the main anaplerotic pathway is dependent on pyruvate carboxylase (1). The “reverse” reaction from malate is catalysed by malic enzyme, 2). Phosphoenol-pyruvate carboxykinase (3) is considered to work in the decarboyxlation direction. Anaplerosis via the propionyl-CoA carboxylation pathway using branched chain amino acids (BCAA), heptanoate or the “C5 ketones“β-ketopentanoate and β-hydroxypentanoate involves propionyl-CoA carboxylase (4), methylmalonyl-CoA epimerase (5) and methylmalonyl-CoA mutase (6). Abbreviations: BCAA – branched chain amino acids, α-KG – α-ketoglutarate, OAA- oxaloacetate, Co-A-coenzyme A