Early effects of mood stabilizers on the Akt/GSK-3beta signaling pathway and on cell survival and proliferation.
BACKGROUND
Lithium, some of the anticonvulsants, and several second-generation antipsychotic drugs are common medications widely prescribed to treat bipolar disorder. Molecular targets and cellular events that mediate their effects have been described for these drugs but are only partially unraveled. Few comparative studies have been performed.


OBJECTIVE
We evaluated seven mood stabilizers (MS) in the same in vitro system and found several differences and similarities in their cellular mechanisms (proliferation and cell survival). As some MS were previously shown to activate the Akt/GSK-3beta axis, this pathway was explored for other drugs.


METHODS
The SH-SY5Y cells were cultured in RPMI-1640 medium. Effects of MS drugs on serum-induced cell proliferation and on slowing of cell death were analyzed. Phosphorylation and expression of Akt-1 and GSK-3beta mRNA and protein were assessed for the seven drugs as well.


RESULTS
Lithium, Valproate, Olanzapine, and Clozapine enhance proliferation and protect cells against serum withdrawal-induced injury. These drugs also activate Akt-1 and GSK-3beta phosphorylation. Interestingly, gene expression of Akt-1 mRNA and protein, but not GSK-3beta, was increased. The other drugs Lamotrigine, Haloperidol, and Carbamazepine did not affect cellular events nor activate Akt/GSK-3beta axis.


CONCLUSIONS
Valproate and atypical antipsychotics (Olanzapine and Clozapine) regulate SH-SY5Y cell proliferation and survival, activate the Akt/GSK-3beta axis, and stimulate gene expression of Akt-1 mRNA and protein, as does Lithium. The other medications have no effect. The study shows the importance of the Akt/GSK-3 axis in MS actions but also pinpoints a different dependence of these drugs on this signaling axis.
Department of Psychiatry, Bipolar Program, Geneva University Hospitals and University of Geneva, 6-8 rue du 31 Décembre, CH-1207 Geneva, Switzerland.
Jean-Michel
JM
Aubry
Michèle
M
Schwald
Eladia
E
Ballmann
Félicien
F
Karege
D000927:Anticonvulsants / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011619:Psychotropic Drugs / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*
D000927:Anticonvulsants; D011619:Psychotropic Drugs; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3