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

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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.

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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

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Acknowledgment

We would like to thank Dr. Sabine Bahn and Dr. Jing Du for their thoughtful conversations and advice throughout this work. Thank you also to Dr. Alfred Volkl for his generous gift of the ACOX antibody. Ioline Henter provided outstanding editorial assistance. Martin Lan is the recipient of an NIH-Cambridge health science scholarship.

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Authors and Affiliations

  1. Laboratory of Molecular Pathophysiology, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, USA

    Martin J. Lan, Peixiong Yuan, Guang Chen & Husseini K. Manji

  2. Laboratory of Molecular Pathophysiology, Porter Neuroscience Research Center, Building 35, Room 1C-917, 35 Convent Drive, MSC 3711, Bethesda, MD, 20892-3711, USA

    Husseini K. Manji

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  1. Martin J. Lan
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  2. Peixiong Yuan
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  3. Guang Chen
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  4. Husseini K. Manji
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Correspondence to Husseini K. Manji.

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Lan, M.J., Yuan, P., Chen, G. et al. Neuronal Peroxisome Proliferator-Activated Receptor γ Signaling: Regulation by Mood-Stabilizer Valproate. J Mol Neurosci 35, 225–234 (2008). https://doi.org/10.1007/s12031-008-9056-8

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