Cellular and Molecular Life Sciences

, Volume 64, Issue 16, pp 2090–2103

The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees?


DOI: 10.1007/s00018-007-7079-x

Cite this article as:
Rosenberg, G. Cell. Mol. Life Sci. (2007) 64: 2090. doi:10.1007/s00018-007-7079-x


After more than 40 years of clinical use, the mechanisms of action of valproate in epilepsy, bipolar disorder and migraine are still not fully understood. However, recent findings reviewed here shed new light on the cellular effects of valproate. Beyond the enhancement of γ-aminobutyric acid-mediated neurotransmission, valproate has been found to affect signalling systems like the Wnt/β-catenin and ERK pathways and to interfere with inositol and arachidonate metabolism. Nevertheless, the clinical relevance of these effects is not always clear. Valproate treatment also produces marked alterations in the expression of multiple genes, many of which are involved in transcription regulation, cell survival, ion homeostasis, cytoskeletal modifications and signal transduction. These alterations may well be relevant to the therapeutic effects of valproate, and result from its enhancement of activator protein-1 DNA binding and direct inhibition of histone deacetylases, and possibly additional, yet unknown, mechanism(s). Most likely, both immediate biochemical and longer-term genomic influences underlie the effects of valproate in all three indications.


Valproateantiepilepticmigrainebipolar disorderhistone deacetylaseneuroprotectionsignal transduction

Copyright information

© Birkhäuser Verlag, Basel 2007

Authors and Affiliations

  1. 1.D-Pharm Ltd.Kiryat Weizman Science ParkRehovotIsrael