Saturday, December 5, 2009�Poster Session 1�1:00 p.m.-8:00 p.m

Autor: Karin Borges, L. Sweetman, J. Stoll, Sarah Willis
Rok vydání: 2009
Předmět:
Zdroj: Epilepsia. 50:1-158
ISSN: 1528-1167
0013-9580
DOI: 10.1111/j.1528-1167.2009.02377_1.x
Popis: Rationale: The Citric Acid Cycle (CAC) is critical for oxidative metabolismin the brain. Also, CAC intermediates are the precursor of neurotransmitters.We hypothesize that impaired CAC activity may lead todecreases in GABA and ATP and could lead to generation/progression ofepileptic disorders. Anaplerosis is the metabolic replenishment of CACcatalytic intermediates. Here we researched if an anaplerotic diet may beanti-convulsant and/or anti-epileptogenic in mice.Methods: Mice were fed ad libitum either control diet or diet containing35% calories from triheptanoin - the triglyceride of heptanoate, ananaplerotic molecule. Body weight and metabolites in blood and brainwere monitored to assess metabolism of triheptanoin. To assess antiepilepticactivity of the diet acute and chronic mouse seizure modelsin CD1 and CF1 mice were employed; namely the fluorothyl, pentylenetetrazoleand 6 Hertz acute models, a chronic corneal kindling model and the pilocarpine model with a second hit pentylenetetrazoleseizure threshold test.Results: There was no statistically significant difference in bodyweights or kilocalories consumed/kg body weight/day on either diet,indicating that the diets are calorically equivalent. Blood levels of heptanoyl-,pentanoyl- and propionyl-carnitine were elevated three to ten-foldin mice on the triheptanoin diet, demonstrating metabolism of triheptanoin.The triheptanoin diet showed no significant effects on seizure thresholdsin three acute seizure models; the pentylenetetrazole, 6 Hertz, or thefluorothyl models, indicating that it is not anti-convulsant in healthymice.In the chronic pilocarpine model, mice that developed SE in responseto pilocarpine were subsequently fed triheptanoin or control diet for threeweeks. Brain metabolite analysis of SE mice on the C7 diet showed statisticallysignificant increases in the levels of b-hydroxybutyrate and theanaplerotic CAC precursors, propionyl-CoA and methylmalonyl-CoAcompared to SE mice on control diet. SE mice were significantly moresensitive than non-SE mice to pentylenetetrazole-induced seizures signifyingepileptogenesis. SE mice fed triheptanoin diet had an increase inpentylenetetrazole seizure threshold compared to SE mice fed the controldiet (p=0.03; ANOVA, with post-hoc Student-Newman-Keuls test), indicatingan anti-epileptogenic and/or anti-convulsant effect of triheptanoin.Ongoing experiments will assess if hippocampal neurodegeneration wasalso reduced by the diet. In the second chronic model, mice on either dietwere kindled by corneal electroshock twice a day. The anaplerotic dietproduced a statistically significant delay in kindling.Conclusions: Taken together, we found that triheptanoin increasedCAC precursor levels in mouse brains and was anti-epileptogenic and/oranti-convulsant in two chronic epilepsy models. The mechanism of theanti-epileptic effect remains to be examined and future human trials arewarranted.We thank CURE for funding.
Databáze: OpenAIRE
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