title: The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1.
abstract: The mood stabilizing agents lithium chloride (LiCl) and sodium valproate (VPA) have recently gained interest as potential neuroprotective therapeutics. However, exploitation of these therapeutic applications is hindered by both a lack of molecular understanding of the mode of action, and a number of sub-optimal properties, including a relatively small therapeutic window and variable patient response. Human neuroblastoma cells (SH-SY5Y) were exposed to 1 mM lithium chloride or 1 mM sodium valproate for 6 h or 72 h, and transcriptomes measured by Affymetrix U133A/B microarray. Statistically significant gene expression changes were identified using SAM software, with selected changes confirmed at transcript (TaqMan) and protein (Western blotting) levels. Finally, anti-apoptotic action was measured by an in vitro fluorescent assay. Exposure of SH-SY5Y cells to therapeutically relevant concentrations of either lithium chloride or sodium valproate elicited 936 statistically significant changes in gene expression. Amongst these changes we observed a large (maximal 31.3-fold) increase in the expression of the homeodomain protein Six1, and have characterized the time- and dose-dependent up-regulation of this gene in response to both drugs. In addition, we demonstrate that, like LiCl or VPA treatment, Six1 over-expression protects SH-SY5Y cells from staurosporine-induced apoptosis via the blockade of caspsase-3 activation, whereas removal of Six1 protein via siRNA antagonises the ability of LiCl and VPA to protect SH-SY5Y cells from STS-induced apoptosis. These results provide a novel mechanistic rationale underlying the neuroprotective mechanism of LiCl and VPA, suggesting exciting possibilities for the development of novel therapeutic agents against neurodegenerative diseases such as Alzheimer's or Parkinsonism.
authors.affiliation: Centre for Toxicology, Faculty of Health and Medical Sciences, University of Surrey, GU2 7XH, UK. N.Plant@Surrey.ac.uk
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Plant
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Anderson
authors.forename: Nicole
authors.initials: N
authors.lastname: Simecek
authors.forename: Richard
authors.initials: R
authors.lastname: Brown
authors.forename: Sam
authors.initials: S
authors.lastname: Forster
authors.forename: Jenny
authors.initials: J
authors.lastname: Spinks
authors.forename: Nick
authors.initials: N
authors.lastname: Toms
authors.forename: G Gordon
authors.initials: GG
authors.lastname: Gibson
authors.forename: Jon
authors.initials: J
authors.lastname: Lyon
authors.forename: Nick
authors.initials: N
authors.lastname: Plant
mesh_terms: D018692:Antimanic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling; D020868:Gene Silencing; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D018021:Lithium Chloride / Q000378:metabolism / Q000494:pharmacology*; D009447:Neuroblastoma / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D015854:Up-Regulation; D014635:Valproic Acid / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D018692:Antimanic Agents; D018398:Homeodomain Proteins; C099236:SIX1 protein, human; D014635:Valproic Acid; D018021:Lithium Chloride; D019311:Staurosporine