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The antiapoptotic actions of mood stabilizers: molecular mechanisms and therapeutic potentials.
Ann N Y Acad Sci. 2005 Aug; 1053:195-204.AN

Abstract

Two primary drugs used to treat bipolar mood disorder are lithium and valproate. Emerging evidence supports the notion that both mood stabilizers have neuroprotective effects. In primary cultures of rat cerebellar granule cells and cortical neurons, lithium and valproate robustly and potently protect against glutamate-induced, N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity. The neuroprotective mechanisms involve inactivation of NMDA receptors through inhibition of NR2B tyrosine phosphorylation, activation of cell survival factors such as the PI 3-kinase/Akt signaling pathway, and induction of neurotrophic/neuroprotective proteins, including brain-derived neurotrophic factor, heat-shock protein (HSP), and Bcl-2. Both drugs are also effective against other forms of insults such as ER stress in neurally related cell types. The molecular targets likely involve glycogen synthase kinase-3 (GSK-3) and histone deacetylase (HDAC) for lithium and valproate, respectively. In a rat cerebral artery occlusion model of stroke, postinsult treatment with lithium or valproate reduces ischemia-induced brain infarction, caspase-3 activation, and neurological deficits, and these neuroprotective effects are associated with HSP70 upregulation and, in the case of valproate, HDAC inhibition. In a rat excitotoxic model of Huntington's disease in which an excitotoxin is infused into the striatum to activate NMDA receptors, short-term lithium pretreatment is sufficient to protect against DNA damage, caspase activation, and apoptosis of striatal neurons, and this neuroprotection is concurrent with Bcl-2 induction. Moreover, lithium treatment increases cell proliferation near the site of striatal injury, and some newborn cells have phenotypes of neurons and astroglia. Thus, lithium and valproate are potential drugs for treating some forms of neurodegenerative diseases.

Authors+Show Affiliations

Chuang DM
Molecular Neurobiology Section, Biological Psychiatry Branch, Mood and Anxiety Disorders Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1363, USA. chuang@mail.nih.gov

MeSH

AffectAnimalsAntimanic AgentsApoptosisExcitatory Amino Acid AgonistsHumansLithiumN-MethylaspartateRatsStrokeValproic Acid

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

16179524

Citation

Chuang, De-Maw. "The Antiapoptotic Actions of Mood Stabilizers: Molecular Mechanisms and Therapeutic Potentials." Annals of the New York Academy of Sciences, vol. 1053, 2005, pp. 195-204.
Chuang DM. The antiapoptotic actions of mood stabilizers: molecular mechanisms and therapeutic potentials. Ann N Y Acad Sci. 2005;1053:195-204.
Chuang, D. M. (2005). The antiapoptotic actions of mood stabilizers: molecular mechanisms and therapeutic potentials. Annals of the New York Academy of Sciences, 1053, 195-204.
Chuang DM. The Antiapoptotic Actions of Mood Stabilizers: Molecular Mechanisms and Therapeutic Potentials. Ann N Y Acad Sci. 2005;1053:195-204. PubMed PMID: 16179524.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The antiapoptotic actions of mood stabilizers: molecular mechanisms and therapeutic potentials. A1 - Chuang,De-Maw, PY - 2005/9/24/pubmed PY - 2006/6/7/medline PY - 2005/9/24/entrez SP - 195 EP - 204 JF - Annals of the New York Academy of Sciences JO - Ann N Y Acad Sci VL - 1053 N2 - Two primary drugs used to treat bipolar mood disorder are lithium and valproate. Emerging evidence supports the notion that both mood stabilizers have neuroprotective effects. In primary cultures of rat cerebellar granule cells and cortical neurons, lithium and valproate robustly and potently protect against glutamate-induced, N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity. The neuroprotective mechanisms involve inactivation of NMDA receptors through inhibition of NR2B tyrosine phosphorylation, activation of cell survival factors such as the PI 3-kinase/Akt signaling pathway, and induction of neurotrophic/neuroprotective proteins, including brain-derived neurotrophic factor, heat-shock protein (HSP), and Bcl-2. Both drugs are also effective against other forms of insults such as ER stress in neurally related cell types. The molecular targets likely involve glycogen synthase kinase-3 (GSK-3) and histone deacetylase (HDAC) for lithium and valproate, respectively. In a rat cerebral artery occlusion model of stroke, postinsult treatment with lithium or valproate reduces ischemia-induced brain infarction, caspase-3 activation, and neurological deficits, and these neuroprotective effects are associated with HSP70 upregulation and, in the case of valproate, HDAC inhibition. In a rat excitotoxic model of Huntington's disease in which an excitotoxin is infused into the striatum to activate NMDA receptors, short-term lithium pretreatment is sufficient to protect against DNA damage, caspase activation, and apoptosis of striatal neurons, and this neuroprotection is concurrent with Bcl-2 induction. Moreover, lithium treatment increases cell proliferation near the site of striatal injury, and some newborn cells have phenotypes of neurons and astroglia. Thus, lithium and valproate are potential drugs for treating some forms of neurodegenerative diseases. SN - 0077-8923 UR - https://www.unboundmedicine.com/medline/citation/16179524/The_antiapoptotic_actions_of_mood_stabilizers:_molecular_mechanisms_and_therapeutic_potentials_ DB - PRIME DP - Unbound Medicine ER -