Attenuation of Phospholipid Signaling Provides a Novel Mechanism for the Action of Valproic Acid

Abstract

Valproic acid (VPA) is used to treat epilepsy and bipolar disorder and to prevent migraine. It is also undergoing trials for cancer therapy. However, the biochemical and molecular biological actions of VPA are poorly understood. Using the social amoeba Dictyostelium discoideum, we show that an acute effect of VPA is the inhibition of chemotactic cell movement, a process partially dependent upon phospholipid signaling. Analysis of this process shows that VPA attenuates the signal-induced translocation of PH Crac -green fluorescent protein from cytosol to membrane, suggesting the inhibition of phosphatidylinositol-(3,4,5)-trisphosphate (PIP 3 ) production. Direct labeling of lipids in vivo also shows a reduction in PIP and PIP 2 phosphorylation following VPA treatment. We further show that VPA acutely reduces endocytosis and exocytosis-processes previously shown to be dependent upon PIP 3 production. These results suggest that in Dictyostelium, VPA rapidly attenuates phospholipid signaling to reduce endocytic trafficking. To examine this effect in a mammalian model, we also tested depolarization-dependent neurotransmitter release in rat nerve terminals, and we show that this process is also suppressed upon application of VPA and an inhibitor of phosphatidylinositol 3-kinase. Although a more comprehensive analysis of the effect of VPA on lipid signaling will be necessary in mammalian systems, these results suggest that VPA may function to reduce phospholipid signaling processes and thus may provide a novel therapeutic effect for this drug.

Bitter tastant responses in the amoeba Dictyostelium correlate with rat and human taste assays

“…It is at this stage, that Dictyostelium has been extensively utilized to investigate a range of fundamental biological processes such as cell migration and signal transduction, as well as a range of pharmacological studies. These include identifying the molecular targets of flavonoids (Waheed et al, 2014), bipolar disorder treatments (Williams et al, 2002;Williams, 2005) and epilepsy treatments including the MCT ketogenic diet (Xu et al, 2007;Chang et al, 2012). In all these cases, discoveries in Dictyostelium have been successfully translated to humans or other mammals (Xu et al, 2007;Chang et al, 2013Chang et al, , 2014.…”

“…These include identifying the molecular targets of flavonoids (Waheed et al, 2014), bipolar disorder treatments (Williams et al, 2002;Williams, 2005) and epilepsy treatments including the MCT ketogenic diet (Xu et al, 2007;Chang et al, 2012). In all these cases, discoveries in Dictyostelium have been successfully translated to humans or other mammals (Xu et al, 2007;Chang et al, 2013Chang et al, , 2014. Finally, Dictyostelium was able to identify pungent (e.g., capsaicin) and bitter (quinine, denatonium, phenylthiourea) tastants (Robery et al, 2013;Otto et al, 2015) and led to the discovery of a novel human receptor implicated in detection of the bitter tastant phenylthiourea (Robery et al, 2013).…”

Lipid Involvement in Viral Infections: Present and Future Perspectives for the Design of Antiviral Strategies

“…This makes drugs interfering this pathway candidates for antiviral design. Along this line, the antiviral properties of valproic acid -a short chain fatty acid commonly used for the treatment of epilepsy and bipolar disorder that impairs multiple aspects of phosphoinositide metabolism [197][198][199] -against a broad panel of enveloped viruses have been reported (Table 4) [145].…”

Dictyostelium discoideum: Novel Insights into the Cellular Biology of Neurological Disorders

“…Early work was able to show that in Dictyostelium, drugs that provide a neuroprotective effect in individuals with bipolar disorder work through a common mechanism involving the activation of MAPK signaling and increased ERK2 phosphorylation by reducing protein kinase A (PKA) signaling (Eickholt et al 2005). More recently, data from Dictyostelium models strongly suggest that VPA rapidly immobilizes phospholipid signaling through the modulation of phosphoinositide levels independent of inositol regulation which coincides with a reduction in endocytic trafficking and that VPA when tested in mammalian cells also abrogates this process as measured through depolarization-dependent neurotransmitter release in rat nerve terminals (Chang et al 2011;Xu et al 2007). The use of Dictyostelium as a model system to understand the common mechanism of action of drugs to treat bipolar disorders will not be discussed any further in this chapter as it has been recently and extensively reviewed (Ludtmann et al 2011) but confirms the existence of conserved drug-sensitive signaling pathways between Dictyostelium and mammalian model systems.…”