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Regulation of ER stress proteins by valproate: therapeutic implications


Corresponding author: L Trevor Young, MD, PhD, McMaster University, Department of Psychiatry and Behavioural Neurosciences, HSC-4N77A, 1200 Main Street West, Hamilton, Ontario, Canada, L8N 3Z5. Fax: +1 (905) 522-8804; e-mail:


Objectives: This paper reviews results of our studies examining the regulation of endoplasmic reticulum (ER) stress proteins by valproate (VPA), and discusses the possible implications in bipolar disorder.

Methods: Our previous studies in the field are reviewed along with relevant literature.

Results: Using differential display PCR, we identified GRP78 as a VPA-regulated gene in rat cerebral cortex. We also showed that other members of the ER stress proteins family, GRP94 and calreticulin, are also upregulated by VPA. Immunohistochemistry identified that ER stress proteins are increased in frontal and parietal cortex, as well as regions of the hippocampus in rat brain following chronic treatment with VPA.

Conclusions: Regulation of ER stress proteins by VPA may prove to be important to the mechanism of action of the drug. The neuroprotective role of these proteins may also prove to be involved in the pathophysiology of bipolar disorder.