Hypoxia activates glycogen synthase kinase-3 in mouse brain in vivo: protection by mood stabilizers and imipramine.
BACKGROUND
Glycogen synthase kinase-3 (GSK3), which is primarily regulated by an inhibitory phosphorylation of an N-terminal serine, has been implicated as contributing to mood disorders by the finding that it is inhibited by the mood stabilizer lithium.


METHODS
This study tested if the antidepressant imipramine or the mood stabilizers lithium and sodium valproate regulated pathophysiological serine-dephosphorylation of GSK3 caused by hypoxia in mouse brain in vivo.


RESULTS
Hypoxia caused rapid serine-dephosphorylation of both isoforms of GSK3, GSK3beta and GSK3alpha, in mouse cerebral cortex, hippocampus, and striatum. Pretreatment of mice with imipramine, sodium valproate, or lithium attenuated hypoxia-induced serine-dephosphorylation of GSK3beta and GSK3alpha in all three brain regions.


CONCLUSIONS
These results demonstrate that imipramine and mood stabilizers are capable of blocking pathophysiologically induced serine-dephosphorylation of GSK3, supporting the hypothesis that stabilization of serine-phosphorylation of GSK3 contributes to their therapeutic effects.
Roh
Myoung-Sun
MS
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0017, USA.
Eom
Tae-Yeon
TY
Zmijewska
Anna A
AA
De Sarno
Patrizia
P
Roth
Kevin A
KA
Jope
Richard S
RS
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D000929:Antidepressive Agents, Tricyclic / Q000627:therapeutic use*; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D002245:Carbon Dioxide / Q000009:adverse effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004789:Enzyme Activation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000860:Hypoxia / Q000139:chemically induced / Q000201:enzymology / Q000517:prevention & control*; D007099:Imipramine / Q000627:therapeutic use*; D015151:Immunoblotting / Q000379:methods; D007150:Immunohistochemistry / Q000379:methods; D008094:Lithium / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009584:Nitrogen / Q000009:adverse effects; D010766:Phosphorylation / Q000187:drug effects; D012694:Serine / Q000378:metabolism; D013997:Time Factors; D014635:Valproic Acid / Q000494:pharmacology
D000927:Anticonvulsants; D000929:Antidepressive Agents, Tricyclic; D002245:Carbon Dioxide; D012694:Serine; D014635:Valproic Acid; D008094:Lithium; D038362:Glycogen Synthase Kinase 3; D009584:Nitrogen; D007099:Imipramine