Protein kinase C substrate activators: potential as novel antidepressants

Abstract

AbstractDepression and mood disorders are major public health concerns. Emerging evidence suggests that abnormal functions of protein kinase C (PKC) isozymes, ubiquitous in the central nervous system, may play a critical role in the pathogenesis of major depression and mood disorders. PKC activity and expression in the brain regions that are involved in mood regulation are reduced in suicide victims and are sensitive to stress‐related damage. PKC isozyme dysfunction may contribute to mood dysfunction, while PKC activators exhibit antidepressant pharmacology. Restoration of PKC activity thus represents an important therapeutic goal in antidepressant therapy. PKC substrate activators, therefore, may have important therapeutic value for the treatment of depression, especially when fine‐tuning of selective isoform activity can be effectively achieved pharmacologically. The success of antidepressant therapy with bryostatin‐1‐like agents that act on PKC signaling cascades depends on whether such agents at their effective doses would significantly disrupt or interfere with other vital functions that rely on a narrow range of PKC activities. Drug Dev. Res. 65:156–169, 2005. © 2005 Wiley‐Liss, Inc.