GSK-3 activity in neocortical cells is inhibited by lithium but not carbamazepine or valproic acid.
OBJECTIVE
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 beta-catenin levels in these cells, a process attenuated by GSK-3 activity. Finally, only Li(+) directly inhibits GSK-3 activity (both alpha and beta isoforms) at therapeutic levels in direct biochemical assays.


CONCLUSIONS
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.
Jonathan Ryves
W
W
MRC LMCB, University College London, London, UK.
Dalton
Emma C
EC
Harwood
Adrian J
AJ
Williams
Robin Sb
RS
D000818:Animals; D018692:Antimanic Agents / Q000494:pharmacology*; D002220:Carbamazepine / Q000494:pharmacology; D002478:Cells, Cultured; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008094:Lithium / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D014635:Valproic Acid / Q000494:pharmacology
D018692:Antimanic Agents; D007527:Isoenzymes; D002220:Carbamazepine; D014635:Valproic Acid; D008094:Lithium; D038362:Glycogen Synthase Kinase 3