The antiapoptotic actions of mood stabilizers: molecular mechanisms and therapeutic potentials.
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.
Chuang
De-Maw
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
D000339:Affect / Q000187:drug effects*; D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D006801:Humans; D008094:Lithium / Q000494:pharmacology / Q000627:therapeutic use; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors / Q000633:toxicity; D051381:Rats; D020521:Stroke / Q000188:drug therapy / Q000473:pathology; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use
D018692:Antimanic Agents; D018690:Excitatory Amino Acid Agonists; D014635:Valproic Acid; D016202:N-Methylaspartate; D008094:Lithium