TY - JOUR
T1 - The antiepileptic drug valproic acid and other medium-chain fatty acids acutely reduce phosphoinositide levels independently of inositol in Dictyostelium
AU - Chang, Pishan
AU - Orabi, Benoit
AU - Deranieh, Rania M.
AU - Dham, Manik
AU - Hoeller, Oliver
AU - Shimshoni, Jakob A.
AU - Yagen, Boris
AU - Bialer, Meir
AU - Greenberg, Miriam L.
AU - Walker, Matthew C.
AU - Williams, Robin S.B.
PY - 2012/1
Y1 - 2012/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/84862907498
U2 - 10.1242/dmm.008029
DO - 10.1242/dmm.008029
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C2 - 21876211
AN - SCOPUS:84862907498
SN - 1754-8403
VL - 5
SP - 115
EP - 124
JO - DMM Disease Models and Mechanisms
JF - DMM Disease Models and Mechanisms
IS - 1
ER -