The antiepileptic drug valproic acid and other medium-chain fatty acids acutely reduce phosphoinositide levels independently of inositol in Dictyostelium
| Autor: | 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 |
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| Jazyk: | angličtina |
| Rok vydání: | 2012 |
| Předmět: | |
| Zdroj: | Disease Models & Mechanisms, Vol 5, Iss 1, Pp 115-124 (2012) |
| Druh dokumentu: | article |
| ISSN: | 1754-8403 1754-8411 |
| DOI: | 10.1242/dmm.008029 |
| Popis: | SUMMARY 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 PtdInsP2 (also known as PIP2)] 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. |
| Databáze: | Directory of Open Access Journals |
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