Abstract
Recent advances in cellular and molecular biology have resulted in the identification
of two 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 lithium treatment has been demonstrated to markedly increase the
levels of the major neuroprotective protein, bcl-2 in rat frontal cortex, hippocampus,
and striatum. Similar lithium-induced increases in bcl-2 are also observed in cells
of human neuronal origin, and are observed in rat frontal cortex at lithium levels
as low as ∼0.3 mmol/L. Bcl-2 is widely regarded as a major neuroprotective protein,
and genetic strategies that increase bcl-2 levels have demonstrated not only robust
protection of neurons against diverse insults, but have also demonstrated an increase
the regeneration of mammalian CNS axons. Lithium has also been demonstrated to inhibit glycogen synthase
kinase 3β (GSK-3β), an enzyme known to regulate the levels of phosphorylated tau and β-catenin (both of which may play a role in the neurodegeneration observed in
Alzheimer’s disease). Consistent with the increases in bcl-2 levels and inhibition
of GSK-3β, lithium 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 disorders
via underappreciated neuroprotective effects. To date, lithium remains the only medication
demonstrated to markedly increase bcl-2 levels in several brain areas; in the absence
of other adequate treatments, the potential efficacy of lithium in the long term treatment
of certain neurodegenerative disorders may be warranted.
Keywords
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Article info
Publication history
Accepted:
June 23,
1999
Received in revised form:
June 14,
1999
Received:
February 17,
1999
Identification
Copyright
© 1999 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
