Glycogen synthase kinase-3: a putative molecular target for lithium mimetic drugs

Despite many decades of clinical use, the therapeutic target of lithium remains uncertain. It is recognized that therapeutic concentrations of lithium, through competition with the similarly sized magnesium cation, inhibit the activity of select enzymes. Among these is glycogen synthase kinase-3 (GSK-3). Recent preclinical evidence, including biochemical, pharmacological, genetic, and rodent behavioral models, supports the hypothesis that inhibition of GSK-3 may represent a target for lithium's mood-stabilizing properties. Specifically, it has been demonstrated that lithium administration regulates multiple GSK-3 targets in vivo and that multiple additional classes of mood-stabilizing and antidepressant drugs regulate GSK-3 signaling. Pharmacological or genetic inhibition of GSK-3 results in mood stabilizer-like behavior in rodent models, and genetic association studies implicate GSK-3 as a possible modulator of particular aspects of bipolar disorder including response to lithium. Furthermore, numerous recent studies have provided a more complete understanding of GSK-3's role in diverse neurological processes strengthening the hypothesis that GSK-3 may represent a therapeutically relevant target of lithium. For example, GSK-3 is a primary regulator of neuronal survival, and cellular responses to glucocorticoids and estrogen may involve GSK-3-regulated pathways. While the preclinical evidence discussed in this review is encouraging, ultimate validation of GSK-3 as a therapeutically relevant target will require clinical trials of selective novel inhibitors. In this regard, as is discussed, there is a major effort underway to develop novel, specific, GSK-3 inhibitors.