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 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. 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.
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 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. 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.
Authors: M Hart; J P Concordet; I Lassot; I Albert; R del los Santos; H Durand; C Perret; B Rubinfeld; F Margottin; R Benarous; P Polakis Journal: Curr Biol Date: 1999-02-25 Impact factor: 10.834
Authors: Andrea de Bartolomeis; Carmine Tomasetti; Maria Cicale; Pei-Xiong Yuan; Husseini K Manji Journal: Eur Neuropsychopharmacol Date: 2012-01-14 Impact factor: 4.600
Authors: Nicole Terbach; Rishita Shah; Rachel Kelemen; Peter S Klein; Dmitri Gordienko; Nigel A Brown; Christopher J Wilkinson; Robin S B Williams Journal: J Cell Sci Date: 2011-06-07 Impact factor: 5.285
Authors: Xuehua Xu; Annette Müller-Taubenberger; Kathryn E Adley; Nadine Pawolleck; Vivian W Y Lee; Claudia Wiedemann; Talvinder S Sihra; Markus Maniak; Tian Jin; Robin S B Williams Journal: Eukaryot Cell Date: 2007-04-13