Abstract |
Valproic acid (VPA) is the most widely prescribed epilepsy treatment worldwide, but its mechanism of action remains unclear. Our previous work identified a previously unknown effect of VPA in reducing phosphoinositide production in the simple model Dictyostelium followed by the transfer of data to a mammalian synaptic release model. In our current study, we show that the reduction in phosphoinositide [ PtdInsP (also known as PIP) and PtdInsP(2) (also known as PIP(2))] production caused by VPA is acute and dose dependent, and that this effect occurs independently of phosphatidylinositol 3-kinase (PI3K) activity, inositol recycling and inositol synthesis. In characterising the structural requirements for this effect, we also identify a family of medium-chain fatty acids that show increased efficacy compared with VPA. Within the group of active compounds is a little-studied group previously associated with seizure control, and analysis of two of these compounds ( nonanoic acid and 4-methyloctanoic acid) shows around a threefold enhanced potency compared with VPA for protection in an in vitro acute rat seizure model. Together, our data show that VPA and a newly identified group of medium-chain fatty acids reduce phosphoinositide levels independently of inositol regulation, and suggest the reinvestigation of these compounds as treatments for epilepsy.
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Authors | Pishan Chang, Benoit Orabi, Rania M Deranieh, Manik Dham, Oliver Hoeller, Jakob A Shimshoni, Boris Yagen, Meir Bialer, Miriam L Greenberg, Matthew C Walker, Robin S B Williams |
Journal | Disease models & mechanisms
(Dis Model Mech)
Vol. 5
Issue 1
Pg. 115-24
(Jan 2012)
ISSN: 1754-8411 [Electronic] England |
PMID | 21876211
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Anticonvulsants
- Phosphatidylinositols
- Inositol
- Valproic Acid
- Phosphatidylinositol 3-Kinases
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Topics |
- Animals
- Anticonvulsants
(chemistry, pharmacology, therapeutic use)
- Dictyostelium
(drug effects, enzymology, metabolism)
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Epilepsy
(drug therapy, pathology)
- Inositol
(metabolism)
- Models, Biological
- Mutation
(genetics)
- Phosphatidylinositol 3-Kinases
(metabolism)
- Phosphatidylinositols
(metabolism)
- Rats
- Signal Transduction
(drug effects)
- Time Factors
- Valproic Acid
(chemistry, pharmacology, therapeutic use)
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