GSK-3 activity in neocortical cells is inhibited by lithium but not carbamazepine or valproic acid

Ryves, William Jonathan, Dalton, Emma Charlotte ORCID: https://orcid.org/0000-0002-3517-0742, Harwood, Adrian John ORCID: https://orcid.org/0000-0003-3124-5169 and Williams, Robin S. B. 2005. GSK-3 activity in neocortical cells is inhibited by lithium but not carbamazepine or valproic acid. Bipolar Disorders , pp. 260-265. 10.1111/j.1399-5618.2005.00194.x

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Abstract

Objectives: Lithium (Li+) has been suggested to target the enzyme glycogen synthase kinase 3 (GSK-3) as a mechanism of mood stabilization. Inhibition of GSK-3 by a second mood-stabilizer, valproic acid (VPA), has also been reported, but this effect is dependent on cell type. It is currently unknown if carbamazepine (CBZ) inhibits GSK-3 activity. We have sought to compare the inhibitory effect of Li+, VPA and CBZ on GSK-3 activity. Methods: We treated rat primary cultured neurones at three times therapeutic drug concentration with CBZ, VPA and Li+ and examined changes in GSK-3 protein levels, activity and phosphorylation of downstream targets. To eliminate a possible direct effect of these drugs at higher concentrations, we also looked for direct inhibition of both GSK-3 isoforms at a range of concentrations. Results: CBZ, VPA and Li+ did not change the levels of the GSK-3 or produce an irreversible in vivo effect on GSK-3 activity. Only Li+ inhibited the phosphorylation of a cytoskeletal target of GSK-3, tau, whereas CBZ and VPA did not. Surprisingly, none of these drugs altered ?-catenin levels in these cells, a process attenuated by GSK-3 activity. Finally, only Li+ directly inhibits GSK-3 activity (both and ? isoforms) at therapeutic levels in direct biochemical assays. Conclusion: Thus we show that neither GSK-3 nor the altered GSK-3 signalling pathway can provide a common mechanism of action of mood-stabilizing drugs in the mammalian brain.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences Neuroscience and Mental Health Research Institute (NMHRI)
Subjects:	Q Science > QH Natural history > QH301 Biology
Uncontrolled Keywords:	bipolar disorder ; carbamazepine ; glycogen synthase kinase-3 ; lithium ; mood-stabilizers ; valproic acid
ISSN:	1398-5647
Last Modified:	17 Oct 2022 08:48
URI:	https://orca.cardiff.ac.uk/id/eprint/1098

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