Journal of Molecular Neuroscience

, Volume 35, Issue 2, pp 225–234

Neuronal Peroxisome Proliferator-Activated Receptor γ Signaling: Regulation by Mood-Stabilizer Valproate

  • Martin J. Lan
  • Peixiong Yuan
  • Guang Chen
  • Husseini K. Manji
Article

DOI: 10.1007/s12031-008-9056-8

Cite this article as:
Lan, M.J., Yuan, P., Chen, G. et al. J Mol Neurosci (2008) 35: 225. doi:10.1007/s12031-008-9056-8

Abstract

Valproate (Depakote) remains an effective medication for the prevention and treatment of seizures in epilepsy and of mood symptoms in bipolar disorder. Both of these disorders are severe and debilitating, and both warrant further medication options as well as a better understanding of the side effects associated with their current treatments. Although a number of molecular and cellular processes have been found to be altered by valproate, the medication’s therapeutic mechanism has not been fully elucidated. In this paper, peroxisome proliferator-activated receptor (PPAR) signaling was examined to determine valproate’s effects on this transcriptional regulatory system in neuronal tissue. PPAR signaling has been found to affect a number of biochemical processes, including lipid metabolism, cellular differentiation, insulin sensitivity, and cell survival. When primary neuronal cultures were treated with valproate, a significant decrease in PPARγ signaling was observed. This effect was demonstrated through a change in nuclear quantities of PPARγ receptor and decreased DNA binding of the receptor. Valproate also caused gene expression changes and a change to the peroxisome biochemistry consistent with a decrease of PPARγ signaling. These biochemical changes may have functional consequences for either valproate’s therapeutic mechanism or for its neurological side effects and merit further investigation.

Keywords

ValproateBipolar disorderEpilepsyPPAR gammaMetabolism

Abbreviations

ACOX

acyl-coA oxidase

bcl-2

B-cell CLL/lymphoma 2

BAG-1

B-cell CLL/lymphoma 2 associated athanogene 1

ERK

extracellular signal-regulated kinase

FeCl3

iron chloride

GAPDH

glyceraldehyde-3-phosphate dehydrogenase

GSK-3

glycogen synthase kinase-3

H2O2

hydrogen peroxide

HDAC

histone deacetylase

PBS

phosphate buffer saline

PMP-70

peroxisome membrane protein-70

PPAR

peroxisome proliferators-activated receptor

PPRE

PPAR-response element

qPCR

quantitative PCR

SDS

sodium dodecal sulfate

Copyright information

© Humana Press 2008

Authors and Affiliations

  • Martin J. Lan
    • 1
  • Peixiong Yuan
    • 1
  • Guang Chen
    • 1
  • Husseini K. Manji
    • 1
    • 2
  1. 1.Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of HealthBethesdaUSA
  2. 2.Laboratory of Molecular Pathophysiology, Porter Neuroscience Research CenterBethesdaUSA