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The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1

Plant, Kathryn E.; Anderson, Elizabeth; Simecek, Nicole; Brown, Richard; Forster, Sam; Spinks, Jenny; Toms, Nick; Gibson, G. Gordon; Lyon, Jon; Plant, Nick

Authors

Kathryn E. Plant

Nicole Simecek

Richard Brown

Sam Forster

Jenny Spinks

Nick Toms

G. Gordon Gibson

Jon Lyon

Nick Plant



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 1mM lithium chloride or 1mM sodium valproate for 6h or 72h, 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. © 2008 Elsevier Inc. All rights reserved.

Journal Article Type Article
Publication Date Feb 15, 2009
Journal Toxicology and Applied Pharmacology
Print ISSN 0041-008X
Electronic ISSN 1096-0333
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 235
Issue 1
Pages 124-134
DOI https://doi.org/10.1016/j.taap.2008.10.019
Keywords bipolar disorder, neuroprotection, lithium chloride, sodium valproate, microarray, apoptosis
Public URL https://uwe-repository.worktribe.com/output/998684
Publisher URL http://dx.doi.org/10.1016/j.taap.2008.10.019