Abstract
Using differential display PCR, we found that chronic treatment with mood stabilizer valproate at a therapeutically relevant concentration increased expression of 78-kDa glucose-regulated protein (GRP78), an endoplasmic reticulum (ER) stress protein, in rat brain. Chronic valproate treatment not only increased GRP78 mRNA level, but also increased GRP78 gene transcription and protein levels. Chronic treatment with lithium, the most commonly used mood stabilizer, also increased GRP78 mRNA and protein levels in primary cultured rat cerebral cortical cells. Unlike the classic GRP78 inducer thapsigargin, an inhibitor of the ER Ca 2+-ATPase, both lithium and valproate moderately increase GRP78 expression in neuronal cells without effecting basal intracellular free Ca 2+ concentration and cell viability, indicating that these two drugs increase GRP78 expression without causing cell stress. Since GRP78 exhibits molecular chaperone activity, binds calcium and folds damage proteins, and has been shown to inhibit oxidative stress and apoptosis, our findings suggest that both lithium and valproate generate a neuroprotective effect against cell damage. Expression of two other closely related ER stress proteins, GRP94 and calreticulin, has also been shown to increase by chronic treatment with lithium and valproate. Consequences of ER stress protein regulation by mood stabilizers, and its implications for mood stabilizer treatment, are discussed in this review.
Published Version
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