Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder
Top Cited Papers
Open Access
- 8 January 2013
- journal article
- review article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Pharmacological Reviews
- Vol. 65 (1), 105-142
- https://doi.org/10.1124/pr.111.005512
Abstract
The mood stabilizers lithium and valproic acid (VPA) are traditionally used to treat bipolar disorder (BD), a severe mental illness arising from complex interactions between genes and environment that drive deficits in cellular plasticity and resiliency. The therapeutic potential of these drugs in other central nervous system diseases is also gaining support. This article reviews the various mechanisms of action of lithium and VPA gleaned from cellular and animal models of neurologic, neurodegenerative, and neuropsychiatric disorders. Clinical evidence is included when available to provide a comprehensive perspective of the field and to acknowledge some of the limitations of these treatments. First, the review describes how action at these drugs’ primary targets—glycogen synthase kinase-3 for lithium and histone deacetylases for VPA—induces the transcription and expression of neurotrophic, angiogenic, and neuroprotective proteins. Cell survival signaling cascades, oxidative stress pathways, and protein quality control mechanisms may further underlie lithium and VPA’s beneficial actions. The ability of cotreatment to augment neuroprotection and enhance stem cell homing and migration is also discussed, as are microRNAs as new therapeutic targets. Finally, preclinical findings have shown that the neuroprotective benefits of these agents facilitate anti-inflammation, angiogenesis, neurogenesis, blood-brain barrier integrity, and disease-specific neuroprotection. These mechanisms can be compared with dysregulated disease mechanisms to suggest core cellular and molecular disturbances identifiable by specific risk biomarkers. Future clinical endeavors are warranted to determine the therapeutic potential of lithium and VPA across the spectrum of central nervous system diseases, with particular emphasis on a personalized medicine approach toward treating these disorders.Keywords
This publication has 187 references indexed in Scilit:
- Inflammation Induced by Infection Potentiates Tau Pathological Features in Transgenic MiceThe American Journal of Pathology, 2011
- Lithium protects against oxidative stress‐mediated cell death in α‐synuclein‐overexpressing in vitro and in vivo models of Parkinson's diseaseJournal of Neuroscience Research, 2011
- Stem cell technology for neurodegenerative diseasesAnnals of Neurology, 2011
- Role of ubiquitin–proteasome-mediated proteolysis in nervous system diseaseBiochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms, 2011
- Tau Phosphorylation and Cleavage in Ethanol-Induced Neurodegeneration in the Developing Mouse BrainNeurochemical Research, 2010
- Age-dependent cognitive impairment in a Drosophila Fragile X model and its pharmacological rescueBiogerontology, 2009
- Overexpression of glycogen synthase kinase 3β sensitizes neuronal cells to ethanol toxicityJournal of Neuroscience Research, 2009
- Promoting Optic Nerve Regeneration in Adult Mice with Pharmaceutical ApproachNeurochemical Research, 2008
- Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and TherapeuticsNeurochemical Research, 2006
- Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndromeCell, 1991