Triheptanoin reduces seizure susceptibility in a syndrome-specific mouse model of generalized epilepsy

Kim, So Yeon; Borges, Karin; Petrou, Steven; Reid, Christopher A.

doi:10.1016/j.eplepsyres.2012.09.016

Cited by 33 publications

(30 citation statements)

References 18 publications

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“…Triheptanoin was previously tested for therapeutic effects in inherited metabolic disorders such as pyruvate carboxylase deficiency, adult polyglucosan body disease or various fatty acid oxidation disorders (Mochel et al, 2005;Roe et al, 2010;Spiekerkoetter et al, 2010), as well as in Huntington's disease (Mochel et al, 2010). Borges described beneficial effects of a triheptanoin-rich diet (35% of calories) in several epileptic models (Willis et al, 2010;Thomas et al, 2012;Kim et al, 2013). To our knowledge, this is the first investigation of the effects of triheptanoin in an experimental stroke model.…”

Section: Introductionmentioning

confidence: 89%

Reduced severity of ischemic stroke and improvement of mitochondrial function after dietary treatment with the anaplerotic substance triheptanoin

2015

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Section: Introductionmentioning

confidence: 89%

Reduced severity of ischemic stroke and improvement of mitochondrial function after dietary treatment with the anaplerotic substance triheptanoin

2015

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“…Ketone bodies are able to supply the majority of fuel to the human brain during low-carbohydrate, high-fat ketogenic diets. 10,[25][26][27][28][29][30] Triheptanoin has been used in various metabolic disorders at the same or similar doses 31,32 in glucose transporter 1 deficiency [33][34][35] and in children with epilepsy. 16, but see Ref.…”

Section: Introductionmentioning

confidence: 99%

Randomized trial of add‐on triheptanoin vs medium chain triglycerides in adults with refractory epilepsy

et al. 2019

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Summary Objective To investigate the feasibility, safety, and tolerability of add‐on treatment of the triglycerides of heptanoate (triheptanoin) vs the triglycerides of octanoate and decanoate (medium chain triglycerides [MCTs]) in adults with treatment‐refractory epilepsy. Methods After an 8‐week prospective baseline period, people with drug‐resistant epilepsy were randomized in a double‐blind fashion to receive triheptanoin or MCTs. Treatment was titrated over 3 weeks to a maximum of 100 mL/d to be distributed over 3 meals and mixed into food, followed by 12‐week maintenance before tapering. The primary aims were to assess the following: (a) safety by comparing the number of intervention‐related adverse events with triheptanoin vs MCT treatment and (b) adherence, measured as a percentage of the prescribed treatment doses taken. Results Thirty‐four people were randomized (17 to MCT and 17 to triheptanoin). There were no differences regarding (a) the number of participants completing the study (11 vs 9 participants), (b) the time until withdrawal, (c) the total number of adverse events or those potentially related to treatment, (d) median doses of oils taken (59 vs 55 mL/d, P = 0.59), or (e) change in seizure frequency (54% vs 102%, P = 0.13). Please note that people with focal unaware seizures were underrepresented in the triheptanoin treatment arm (P = 0.04). The most common adverse events were gastrointestinal disturbances (47% and 62.5% of participants). Five people taking on average 0.73 mL/kg body weight MCTs (0.64 mL/kg median) and one person taking 0.59 mL/kg triheptanoin showed >50% reduction in seizure frequency, specifically focal unaware seizures. Significance Add‐on treatment with MCTs or triheptanoin was feasible, safe, and tolerated for 12 weeks in two‐thirds of people with treatment‐resistant epilepsy. Our results indicate a protective effect of MCTs on focal unaware seizures. This warrants further study.

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“…Its anticonvulsant property in the syndrome‐specific genetic mouse model of generalized absence epilepsy was also reported recently (Kim et al . ). Furthermore, triheptanoin added to a ketogenic diet reduced the velocity of propagation of cortical spreading depression similar to ketogenic diet in young rats (de Almeida Rabello Oliveira et al .…”

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confidence: 97%

Triheptanoin partially restores levels of tricarboxylic acid cycle intermediates in the mouse pilocarpine model of epilepsy

Hadera

Smeland

McDonald

et al. 2013

Journal of Neurochemistry

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Triheptanoin, the triglyceride of heptanoate, is anticonvulsant in various epilepsy models. It is thought to improve energy metabolism in the epileptic brain by re-filling the tricarboxylic acid (TCA) cycle with C4-intermediates (anaplerosis). Here, we injected mice with [1,2-13 C]glucose 3.5-4 weeks after pilocarpine-induced status epilepticus (SE) fed either a control or triheptanoin diet. Amounts of metabolites and incorporations of 13 C were determined in extracts of cerebral cortices and hippocampal formation and enzyme activity and mRNA expression were quantified. The percentage enrichment with two 13 C atoms in malate, citrate, succinate, and GABA was reduced in hippocampal formation of control-fed SE compared with control mice. Except for succinate, these reductions were not found in triheptanoin-fed SE mice, indicating that triheptanoin prevented a decrease of TCA cycle capacity. Compared to those on control diet, triheptanoin-fed SE mice showed few changes in most other metabolite levels and their 13 C labeling. Reduced pyruvate carboxylase mRNA and enzyme activity in forebrains and decreased [2,3-13 C]aspartate amounts in cortex suggest a pyruvate carboxylation independent source of C-4 TCA cycle intermediates. Most likely anaplerosis was kept unchanged by carboxylation of propionyl-CoA derived from heptanoate. Further studies are proposed to fully understand triheptanoin's effects on neuroglial metabolism and interaction.

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Triheptanoin reduces seizure susceptibility in a syndrome-specific mouse model of generalized epilepsy

Cited by 33 publications

References 18 publications

Reduced severity of ischemic stroke and improvement of mitochondrial function after dietary treatment with the anaplerotic substance triheptanoin

Reduced severity of ischemic stroke and improvement of mitochondrial function after dietary treatment with the anaplerotic substance triheptanoin

Randomized trial of add‐on triheptanoin vs medium chain triglycerides in adults with refractory epilepsy

Triheptanoin partially restores levels of tricarboxylic acid cycle intermediates in the mouse pilocarpine model of epilepsy

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