Triheptanoin in acute mouse seizure models

Thomas, Nicola; Willis, Stephen M.; Sweetman, Lawrence; Borges, Karin

doi:10.1016/j.eplepsyres.2011.12.013

Cited by 36 publications

(32 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In the last 10 years there has been accumulating evidence describing the positive effects of triheptanoin, especially in the treatment of diseases associated with derangement of brain cellular metabolism. Triheptanoin has been successfully applied as a ketogenic diet in epilepsy (33,34) and reduces the severity of ischemic strokes (35). A recent study of patients with Huntington disease supplemented with triheptanoin at the early stage of the disease showed an improvement in the metabolic profile of the brain after 1 month of supplementation (36,37).…”

Section: Discussionmentioning

confidence: 99%

Triheptanoin: long-term effects in the very long-chain acyl-CoA dehydrogenase-deficient mouse

Tucci

Floegel

Beermann

et al. 2017

Journal of Lipid Research

View full text Add to dashboard Cite

This article is available online at http://www.jlr.org symptoms include i) severe energy deficiency due to a deficient fatty acid oxidation and subsequent impairment of ketone body biosynthesis and ii) accumulation of toxic long-chain acylcarnitines. Therefore, catabolic situations in which the organism mainly relies on fatty acid oxidation induce symptoms and severe metabolic derangement. The clinical phenotype is very heterogeneous and presents with different severity and age of onset (3), involving organs and tissues that mostly rely on fatty acid -oxidation for energy production. To date, treatment recommendations (5) include a long-chain fat-restricted and fat-modified diet in which long-chain fatty acids are fully or in part replaced by medium-chain triglycerides (MCTs) (1, 5) and the avoidance of prolonged fasting. In contrast to long-chain fatty acids, medium-chain fatty acids (MCFAs) are oxidized by medium-chain acyl-CoA dehydrogenase, bypassing VLCAD; therefore, MCTs may be fully metabolized, supplying the organism with the required energy. Many reports confirm the effectiveness of MCT application in the treatment of cardiomyopathy in long-chain fatty acid oxidation disorders (FAODs) (6-9). In patients with exercise-induced muscle pain, the application of an MCT bolus immediately prior to physical exercise has been proven effective (1, 5). Our own studies on the VLCAD-deficient (VLCAD / ) mouse showed the beneficial effects of MCTs when applied during increased demand (10). Although an MCT diet is considered to be a safe dietary intervention and is applied in different FAODs for longer periods of time, recent reports highlight the adverse effects of an MCT diet in the murine model of VLCAD deficiency (11)(12)(13)(14). A rather new therapeutic approach for the treatment of FAODs is represented by the application of MCTs in the form of Mitochondrial -oxidation is essential for energy production from fat. Deficiency of one of the enzymes involved is associated with life-threatening events and death. Verylong chain acyl-CoA dehydrogenase (VLCAD) deficiency (OMIM 609575) is the second most common disorder of fatty acid oxidation in Europe and the USA, with an incidence of 1:25,000-1:100,000 newborns (1-4). Pathophysiological mechanisms responsible for the development of

show abstract

Section: Discussionmentioning

confidence: 99%

Triheptanoin: long-term effects in the very long-chain acyl-CoA dehydrogenase-deficient mouse

Tucci

Floegel

Beermann

et al. 2017

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…Standard diet (SF11-027) or matched diets (SF11-079) in which 35% of the calories are from either trioctanoin or triheptanoin oil 6 were obtained from Specialty Feeds (Western Australia, Australia). Triheptanoin was a gift from Sasol GmbH (Germany) and trioctanoin from Stepan Lipid Nutrition (Maywood, NJ, USA).…”

Section: Animals and Dietsmentioning

confidence: 99%

“…2 Uneven MCTs are rare in natural foods, but can be chemically produced from natural oils. They are found to be beneficial in several metabolic disorders, 3 anticonvulsant in four mouse seizure models, [4][5][6] and improve cognitive function in a mouse Alzheimer's disease model. 7 However, little is known about the effects of even and uneven MCTs on brain energy metabolism.…”

Section: Introductionmentioning

confidence: 99%

“…Triheptanoin has been found to be anticonvulsant in four rodent seizure models. [4][5][6] The exact mechanisms of the anticonvulsant effects are still unknown for even and uneven MCTs. In the present study, we compared the effects chronic trioctanoin and triheptanoin feeding on glucose and TCA cycle metabolism in the mouse hippocampal formation (HF) and the 6 Hz seizure test.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Alterations of Hippocampal Glucose Metabolism by Even versus Uneven Medium Chain Triglycerides

McDonald

Tan

Hodson

et al. 2013

J Cereb Blood Flow Metab

Self Cite

View full text Add to dashboard Cite

Medium chain triglycerides (MCTs) are used to treat neurologic disorders with metabolic impairments, including childhood epilepsy and early Alzheimer's disease. However, the metabolic effects of MCTs in the brain are still unclear. Here, we studied the effects of feeding even and uneven MCTs on brain glucose metabolism in the mouse. Adult mice were fed 35% (calories) of trioctanoin or triheptanoin (the triglycerides of octanoate or heptanoate, respectively) or a matching control diet for 3 weeks. Enzymatic assays and targeted metabolomics by liquid chromatography tandem mass spectrometry were used to quantify metabolites in extracts from the hippocampal formations (HFs). Both oils increased the levels of b-hydroxybutyrate, but no other significant metabolic alterations were observed after triheptanoin feeding. The levels of glucose 6-phosphate and fructose 6-phosphate were increased in the HF of mice fed trioctanoin, whereas levels of metabolites further downstream in the glycolytic pathway and the pentose phosphate pathway were reduced. This indicates that trioctanoin reduces glucose utilization because of a decrease in phosphofructokinase activity. Trioctanoin and triheptanoin showed similar anticonvulsant effects in the 6 Hz seizure model, but it remains unknown to what extent the anticonvulsant mechanism(s) are shared. In conclusion, triheptanoin unlike trioctanoin appears to not alter glucose metabolism in the healthy brain.

show abstract

“…Corneal electroshocks from a rodent electroshock unit (Ugo Basile, Varese, Italy; 6 Hz, 3 s, 0.2 millisecond rectangular pulse width) were given starting at 14 mA (Samala et al, 2008). Using the up down method we determined the critical current at which 50% of mice seized (Thomas et al, 2012). …”

Section: Liquid Chromatography Tandem Mass Spectrometry (Lc-ms/ms)mentioning

confidence: 99%

The role of complement in epilepsy: a specific focus on C5ar1 and its role in seizure initiation and disease development

Benson¹

View full text Add to dashboard Cite

Neuroinflammation and its role in seizure initiation and epilepsy disease development is being investigated, specifically the role of innate immune complement activation through the C5a receptor, C5ar1.C5ar1 expression was found to be significantly upregulated during epilepsy disease progression in several experimental mouse models, in addition to other complement components such as C3, the precursor to C5a. Building upon existing studies supporting the role of inflammation and other complement components in epilepsy, this finding indicates a contribution of C5a and complement activation in this disease. This lead to creation of the primary hypothesis of this thesis; inhibition of C5ar1 activation is potentially neuroprotective and anticonvulsant in epilepsy.To test this hypothesis a small peptide antagonist of C5ar1, PMX53, was used. It was shown to be anticonvulsant in two acute and two chronic seizure models. PMX53 increased the seizure threshold significantly in both the 6Hz test and the corneal kindling model, as well as reduced EEG seizure power in the pilocarpine-induced SE model, indicating anticonvulsant actions. Studies using the chronic intrahippocampal kainate model combined with EEG, showed that PMX53 was acutely anticonvulsant after a single peripheral administration, significantly reducing total time in seizure by >50% as well as EEG seizure power. In addition, treatment of mice with PMX53 during pilocarpine-SE lead to a vast reduction in EEG seizure power highlighting further anticonvulsant effects. These results suggest inhibition of C5ar1 is beneficial in increasing seizure thresholds in several mouse models of epilepsy.Further studies using inert structural analogues of PMX53 and C5ar1-deficient mice in the 6Hz model showed that PMX53's anticonvulsant effect is C5ar1-dependent. This confirms my hypothesis that antagonism of C5ar1 is anticonvulsant. To determine if C5ar1-mediated anticonvulsant effects lead to changes in subsequent cellular damage, neuronal cell death in the hippocampal formation was evaluated acutely after pilocarpine-induced SE. In both PMX53-treated animals and mice lacking the C5ar1 receptor, significant reductions in neuronal degeneration and loss were evident in key hippocampal areas including CA1 and CA3 pyramidal cell layers.iii In addition, the explicit role of C5ar1 expression on microglial cells was investigated, given that consistent upregulation of the receptor was shown at varying stages post-epileptic insult in mice. Specifically microglial activation phenotypes were assessed, based on expression patterns of inflammatory and activation markers. M1 phenotype is considered to be more inflammatory in nature and is detected through expression of pro-inflammatory cytokines, i.e. IL-1β, TNFα, IL-6 and classical activation markers, i.e. CD16, CD86. M2 phenotype is defined as being more reparative in nature, with markers such as Arginase1 (Arg1) and Chitinase-like-3 (Ym1) being associated with this phenotype, all linked to different aspects of cell repair, as wel...

show abstract

Triheptanoin in acute mouse seizure models

Cited by 36 publications

References 22 publications

Triheptanoin: long-term effects in the very long-chain acyl-CoA dehydrogenase-deficient mouse

Triheptanoin: long-term effects in the very long-chain acyl-CoA dehydrogenase-deficient mouse

Alterations of Hippocampal Glucose Metabolism by Even versus Uneven Medium Chain Triglycerides

The role of complement in epilepsy: a specific focus on C5ar1 and its role in seizure initiation and disease development

Contact Info

Product

Resources

About