ER Stress Proteins as Therapeutic Targets in Bipolar Disorder

ER

In our work to identify new targets for mood stabilizers, using both

differential display PCR, we have identified the ER stress proteins as

potentially relevant sites of action for both valproate and lithium.  The three

members of the ER stress protein family, GRP78, GRP95 and calreticulin were all

found to be increased by chronic treatment with valproate in primary cultured

rat cerebral cortex cells, rat brain and C6 glioma cells. These proteins were

also increased by lithium in primary cultured neurons. Since these proteins are

cytoprotective, we also demonstrated an effect of valproate, possibly through

increasing ER stress protein levels to protect cells against oxidative damage as

evidenced lipid peroxidation, protein oxidation and cell death. In further

support of these antioxidant cytoprotective effects of mood stabilizers, using

DNA micoarrays we found that three isozymes of glutathione-S-transferase were

also regulated by valproate in these same cellular models. These data strongly

support the potential clinical relevance to the treatment of bipolar disorder of

the ER stress proteins and their ability to block oxidative damage in brain.

Finally, these findings support the use of novel genomic techniques in the