Lithium neuroprotection: molecular mechanisms and clinical implications.
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-3beta 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 beta-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.
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. mrowe@mail.nih.gov
Michael K
MK
Rowe
De-Maw
DM
Chuang
D018692:Antimanic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001714:Bipolar Disorder / Q000188:drug therapy; D001925:Brain Damage, Chronic / Q000209:etiology / Q000517:prevention & control; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008094:Lithium / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D009419:Nerve Tissue Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D020521:Stroke / Q000150:complications / Q000188:drug therapy
D018692:Antimanic Agents; D018691:Excitatory Amino Acid Antagonists; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; D008094:Lithium