Lithium up-regulates the cytoprotective protein bcl-2 in the CNS in vivo: A role for neurotrophic and neuroprotective effects in manic depressive illness

Although mood disorders have traditionally been conceptualized as "neuroche mical disorders," considerable literature from a variety of sources demonst rates significant reductions in regional central nervous system (CNS) volum e and cell numbers (both neurons and glia) in persons with mood disorders. It is noteworthy that recent advances in cellular and molecular biology hav e resulted in the identification of 2 novel, hitherto completely unexpected targets of lithium's actions, discoveries that may have a major impact on the future use of this unique cation in biology and medicine. Chronic lithi um treatment has been demonstrated to markedly increase the levels of the m ajor neuroprotective protein bcl-2 in rat frontal cortex, hippocampus, and striatum. Similar lithium-induced increases in bcl-2 are also observed in c ells of human neuronal origin and are observed in rat frontal cortex at lit hium levels as low as similar to 0.3 mM. Bcl-2 is widely regarded as a majo r neuroprotective protein, and genetic strategies that increase bcl-2 level s have demonstrated not only robust protection of neurons against diverse i nsults, but have also demonstrated an increase in the regeneration of mamma lian CNS axons. Lithium has also been demonstrated to inhibit glycogen synt hase kinase 3 beta (GSK-3 beta), an enzyme known to regulate the levels of phosphorylated tau and beta-catenin (both of which may play a role in the n eurodegeneration observed in certain forms of Alzheimer's disease). Consist ent with the increases in bcl-2 levels and inhibition of GSK-3 beta, lithiu m has been demonstrated to exert robust protective effects against diverse insults both in vitro and in vivo. These findings suggest that lithium may exert some of its long-term beneficial effects in the treatment of mood dis orders via underappreciated neurotrophic and neuroprotective effects. To da te, lithium remains the only medication demonstrated to markedly increase b cl-2 levels in several brain areas; in the absence of other adequate treatm ents, an investigation of the potential efficacy of lithium in the long-ter m treatment of several neurodegenerative disorders is warranted. Additional ly, we suggest that a reconceptualization of the use of lithium in mood dis orders may be warranted-namely, that the use of lithium as a neurotrophic/n europrotective agent should be considered in the long-term treatment of moo d disorders, irrespective of the "primary" treatment modality being used fo r the condition.