Received for publication September 6, 2006.
Revised December 13, 2006.
Accepted for publication December 13, 2006.

The effects of CNS-active Valproic acid constitutional isomers, cyclopropyl analogues and amide derivatives on neuronal growth cone behaviour

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 (HDACs) activates Wnt signaling via elevated -catenin expression and causes teratogenicity. Given the VPA chemical structure, it may be possible to design VPA derivatives and analogues that modulate specific protein targets, but leave the others unaffected. Indeed it has been shown that some non-teratogenic VPA derivatives retain antiepileptic and inositol signaling effects. In this study, we describe a further set of VPA analogues 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 (PIA) and diisopropylacetic acid (DIA), but not their corresponding amides, and N-methyl-2,2,3,3-tetramethylcyclopropanecarboaxamide (MTMCD) 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 CNS-active VPA analogues that specifically target bipolar disorder.

Key words: Structure-activity relationships and modeling, Structure/function/mechanism, Anti-depressants

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