The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1.
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.
Plant
Kathryn E
KE
Centre for Toxicology, Faculty of Health and Medical Sciences, University of Surrey, GU2 7XH, UK. N.Plant@Surrey.ac.uk
Anderson
Elizabeth
E
Simecek
Nicole
N
Brown
Richard
R
Forster
Sam
S
Spinks
Jenny
J
Toms
Nick
N
Gibson
G Gordon
GG
Lyon
Jon
J
Plant
Nick
N
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*
D018692:Antimanic Agents; D018398:Homeodomain Proteins; C099236:SIX1 protein, human; D014635:Valproic Acid; D018021:Lithium Chloride; D019311:Staurosporine