Bipolar Research Today is a free monthly online journal that collates and summarizes the latest research about Bipolar, including details on bipolar disorder, symptoms, treatment, depression, medication.

The effects of central nervous system-active valproic acid constitutional isomers, cyclopropyl analogs, and amide derivatives on neuronal growth cone behavior.

Shimshoni JA, Dalton EC, Jenkins A, Eyal S, Ewan K, Williams RS, Pessah N, Yagen B, Harwood AJ, Bialer M

Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Ein Karem, P.O. Box 12065, Jerusalem 91120, Israel.

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 beta-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 beta-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.

Published 19 February 2007 in Mol Pharmacol, 71(3): 884-92.
Full-text of this article is available online (may require subscription).

© 2004-2008 Bipolar Research Today. All Rights Reserved.