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Lithium neuroprotection: molecular mechanisms and clinical implications

Published online by Cambridge University Press:  18 October 2004

Michael K. Rowe
Affiliation:
Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health Building 10, Room 4C206, 10 Center Drive, MSC 1363, Bethesda, MD 20892-1363, USA.
De-Maw Chuang
Affiliation:
Molecular Neurobiology Section, National Institute of Mental Health, National Institutes of Health Building 10, Room 4C206, 10 Center Drive, MSC 1363, Bethesda, MD 20892-1363, USA.

Abstract

Lithium has emerged as a neuroprotective agent efficacious in preventing apoptosis-dependent cellular death. Lithium neuroprotection is provided through multiple, intersecting mechanisms, although how lithium interacts with these mechanisms is still under investigation. Lithium increases cell survival by inducing brain-derived neurotrophic factor and thereby stimulating activity in anti-apoptotic pathways, including the phosphatidylinositol 3-kinase/Akt and the mitogen-activated protein kinase pathways. In addition, lithium reduces pro-apoptotic function by directly and indirectly inhibiting glycogen synthase kinase-3β activity and indirectly inhibiting N-methyl-D-aspartate (NMDA)-receptor-mediated calcium influx. Lithium-induced regulation of anti- and pro-apoptotic pathways alters a wide variety of downstream effectors, including β-catenin, heat shock factor 1, activator protein 1, cAMP-response-element-binding protein, and the Bcl-2 protein family. Lithium neuroprotection has a wide variety of clinical implications. Beyond its present use in bipolar mood disorder, lithium's neuroprotective abilities imply that it could be used to treat or prevent brain damage following traumatic injury, such as stroke, and neurodegenerative diseases such as Huntington's and Alzheimer's diseases.

Type
Review Article
Copyright
© Cambridge University Press 2004

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