title: The antiepileptic drug valproic acid and other medium-chain fatty acids acutely reduce phosphoinositide levels independently of inositol in Dictyostelium.
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.
authors.affiliation: Centre for Biomedical Sciences, School of Biological Sciences, Royal Holloway University of London, Egham, TW20 0EX, UK.
authors.forename: Pishan
authors.initials: P
authors.lastname: Chang
authors.forename: Benoit
authors.initials: B
authors.lastname: Orabi
authors.forename: Rania M
authors.initials: RM
authors.lastname: Deranieh
authors.forename: Manik
authors.initials: M
authors.lastname: Dham
authors.forename: Oliver
authors.initials: O
authors.lastname: Hoeller
authors.forename: Jakob A
authors.initials: JA
authors.lastname: Shimshoni
authors.forename: Boris
authors.initials: B
authors.lastname: Yagen
authors.forename: Meir
authors.initials: M
authors.lastname: Bialer
authors.forename: Miriam L
authors.initials: ML
authors.lastname: Greenberg
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Walker
authors.forename: Robin S B
authors.initials: RS
authors.lastname: Williams
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004023:Dictyostelium / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004827:Epilepsy / Q000188:drug therapy / Q000473:pathology; D007294:Inositol / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014635:Valproic Acid / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D010716:Phosphatidylinositols; D007294:Inositol; D014635:Valproic Acid; D019869:Phosphatidylinositol 3-Kinases