The Effects of Central Nervous System-Active Valproic Acid Constitutional Isomers, Cyclopropyl Analogs, and Amide Derivatives on Neuronal Growth Cone Behavior

Abstract

Valproic acid (VPA) is an effective antiepileptic drug with an additional activity for the treatment of bipolar disorder. It has been assumed that both activities arise from a common target. At the molecular level, VPA targets a number of distinct proteins that are involved in signal transduction. VPA inhibition of inositol synthase reduces the cellular concentration of myo-inositol, an effect common to the mood stabilizers lithium and carbamazepine. VPA inhibition of histone deacetylases activates Wnt signaling via elevated ␤-catenin expression and causes teratogenicity. Given the VPA chemical structure, it may be possible to design VPA derivatives and analogs that modulate specific protein targets but leave the others unaffected. Indeed, it has been shown that some nonteratogenic VPA derivatives retain antiepileptic and inositol signaling effects. In this study, we describe a further set of VPA analogs and derivatives that separate anticonvulsant activity from effects on neuronal growth cone morphology. Lithium, carbamazepine, and VPA induce inositol-dependent spread of neuronal growth cones, providing a cell-based assay that correlates with mood-stabilizing activity. We find that two constitutional isomers of VPA, propylisopropylacetic acid and diisopropylacetic acid, but not their corresponding amides, and N-methyl-2,2,3,3-tetramethyl-cyclopropanecarboaxamide are more effective than VPA in increasing growth cone spreading. We show that these effects are associated with inositol depletion, and not changes in ␤-catenin-mediated Wnt signaling. These results suggest a route to a new generation of central nervous system-active VPA analogs that specifically target bipolar disorder.

Pharmacogenetics of Lithium Long-Term Treatment: Focus on Initiation and Adaptation Mechanisms

“…There is a set of evidence that considers the neurotrophic factors as the most relevant adapted mediators after chronic lithium exposure. This is consistent with the ability of lithium to protect cells promoting anti-apoptotic paths, and to inhibit the collapse of sensory neuron growth cones and increase the growth cone area along with other mood stabilizers (valproic acid and carbamazepine) [82] . Intriguingly, this event has been reported to be sensitive to disruption of the inositol orchestration [83] .…”

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

“…Finally, some of the neuroprotective effects of VPA may result from its effects on mitogen-activated protein kinase/extracellular signal-regulated kinase signaling (5,18), which modulates processes such as neuronal differentiation, neuronal survival, and long-term neuroplasticity. In addition to these effects, we have previously shown that prolonged VPA treatment attenuates inositol-(1,4,5)-trisphosphate (InsP 3 ) signaling (12,50,62) using the eukaryotic model system Dictyostelium discoideum, and this effect also occurs in primary rat dorsal root ganglia neurons (12,62). These data support a role for VPA in the inositol depletion theory of bipolar disorder drug action as proposed by Berridge et al (3).…”

The mood stabiliser lithium suppresses PIP3 signalling in Dictyostelium and human cells

“…First, propylisopropylacetic acid (PIA), a specific inhibitor of myo-inositol synthesis (Shimshoni et al, 2007), has a similar effect on chemotaxis to lithium (Fig. 1B).…”