ER
Stress Proteins as Therapeutic Targets in Bipolar Disorder
L. Trevor
Young
University
of Toronto, Toronto, Ontario, Canada
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
identification of targets for mood stabilizers.