In vivo evidence in the brain for lithium inhibition of glycogen synthase kinase-3.
There is considerable interest in the possibility that small-molecule glycogen synthase kinase-3 inhibitors may have utility in the treatment of bipolar disorder, since glycogen synthase kinase-3 is a target of lithium. Although the in vitro inhibition of glycogen synthase kinase-3 by lithium occurs with a K(i) of 1-2 mM, the degree of inhibition of this enzyme in the mammalian brain at therapeutically relevant concentrations has not fully been established. The transcription factor beta-catenin is an established marker of glycogen synthase kinase-3 inactivation because cytoplasmic levels are increased by inhibition of the enzyme. In this study, we measured beta-catenin protein levels after treatment with therapeutically relevant doses of lithium, valproate, and carbamazepine. Western blot revealed that 9 days of treatment with lithium and valproate, but not carbamazepine, increased beta-catenin protein levels in soluble fractions from the frontal cortex. The level of beta-catenin in the particulate fraction, which is not directly regulated by glycogen synthase kinase-3, did not change with any of the three drugs. Furthermore, real-time PCR revealed that lithium significantly decreased beta-catenin mRNA levels, which may represent compensation for an increase in beta-catenin stability. These results strongly suggest that lithium significantly inhibits brain glycogen synthase kinase-3 in vivo at concentrations relevant for the treatment of bipolar disorder.
Gould
Todd D
TD
Laboratory of Molecular Pathophysiology, Mood and Anxiety Disorders Program, National Institute of Mental Health, Bethesda, MD 20892-4405, USA.
Chen
Guang
G
Manji
Husseini K
HK
D000704:Analysis of Variance; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D015153:Blotting, Western; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000201:enzymology; D002220:Carbamazepine / Q000494:pharmacology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016651:Lithium Carbonate / Q000494:pharmacology*; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D011921:Rats, Inbred WKY; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015534:Trans-Activators / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology; D051176:beta Catenin
D000927:Anticonvulsants; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D015534:Trans-Activators; D051176:beta Catenin; D016651:Lithium Carbonate; D002220:Carbamazepine; D014635:Valproic Acid; D038362:Glycogen Synthase Kinase 3