Anti-epileptic effects of an anaplerotic diet in two chronic mouse epilepsy models

Borges, K., Willis, S., Sweetman, L. and Stoll, J. (2009). Anti-epileptic effects of an anaplerotic diet in two chronic mouse epilepsy models. In: , Epilepsia. Proceedings of: Abstracts from the 2009 Annual Meeting of the American Epilepsy Society. 63rd Annual Meeting of the American-Epilepsy-Society, Boston MA, (131-132). 4-8 December 2009.


Author Borges, K.
Willis, S.
Sweetman, L.
Stoll, J.
Title of paper Anti-epileptic effects of an anaplerotic diet in two chronic mouse epilepsy models
Conference name 63rd Annual Meeting of the American-Epilepsy-Society
Conference location Boston MA
Conference dates 4-8 December 2009
Proceedings title Epilepsia. Proceedings of: Abstracts from the 2009 Annual Meeting of the American Epilepsy Society   Check publisher's open access policy
Journal name Epilepsia   Check publisher's open access policy
Publication Year 2009
DOI 10.1111/j.1528-1167.2009.02377_1.x
ISSN 0013-9580
1528-1167
Volume 50
Issue s11
Start page 131
End page 132
Total pages 1
Language eng
Formatted Abstract/Summary Rationale: The Citric Acid Cycle (CAC) is critical for oxidative metabolism
in the brain. Also, CAC intermediates are the precursor of neurotransmitters.
We hypothesize that impaired CAC activity may lead to
decreases in GABA and ATP and could lead to generation/progression of
epileptic disorders. Anaplerosis is the metabolic replenishment of CAC
catalytic intermediates. Here we researched if an anaplerotic diet may be
anti-convulsant and/or anti-epileptogenic in mice.
Methods: Mice were fed ad libitum either control diet or diet containing
35% calories from triheptanoin - the triglyceride of heptanoate, an
anaplerotic molecule. Body weight and metabolites in blood and brain
were monitored to assess metabolism of triheptanoin. To assess antiepileptic
activity of the diet acute and chronic mouse seizure models
in CD1 and CF1 mice were employed; namely the fluorothyl, pentylenetetrazole
and 6 Hertz acute models, a chronic corneal kindling model and the pilocarpine model with a second hit pentylenetetrazole
seizure threshold test.

Results:
There was no statistically significant difference in body
weights 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-fold
in mice on the triheptanoin diet, demonstrating metabolism of triheptanoin.
The triheptanoin diet showed no significant effects on seizure thresholds
in three acute seizure models; the pentylenetetrazole, 6 Hertz, or the
fluorothyl models, indicating that it is not anti-convulsant in healthy
mice.
In the chronic pilocarpine model, mice that developed SE in response
to pilocarpine were subsequently fed triheptanoin or control diet for three
weeks. Brain metabolite analysis of SE mice on the C7 diet showed statistically
significant increases in the levels of b-hydroxybutyrate and the
anaplerotic CAC precursors, propionyl-CoA and methylmalonyl-CoA
compared to SE mice on control diet. SE mice were significantly more
sensitive than non-SE mice to pentylenetetrazole-induced seizures signifying
epileptogenesis. SE mice fed triheptanoin diet had an increase in
pentylenetetrazole seizure threshold compared to SE mice fed the control
diet (p=0.03; ANOVA, with post-hoc Student-Newman-Keuls test), indicating
an anti-epileptogenic and/or anti-convulsant effect of triheptanoin.
Ongoing experiments will assess if hippocampal neurodegeneration was
also reduced by the diet. In the second chronic model, mice on either diet
were kindled by corneal electroshock twice a day. The anaplerotic diet
produced a statistically significant delay in kindling.

Conclusions:
Taken together, we found that triheptanoin increased
CAC precursor levels in mouse brains and was anti-epileptogenic and/or
anti-convulsant in two chronic epilepsy models. The mechanism of the
anti-epileptic effect remains to be examined and future human trials are
warranted.
We thank CURE for funding.
Subjects 1103 Clinical Sciences
Q-Index Code EX
Q-Index Status Provisional Code
Institutional Status Unknown

Document type: Conference Paper
Collection: School of Biomedical Sciences Publications
 
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Created: Sun, 10 Jan 2010, 00:06:35 EST