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Glycogen synthase kinase-3: a putative molecular target for lithium mimetic drugs.
Neuropsychopharmacology. 2005 Jul; 30(7):1223-37.N

Abstract

Despite many decades of clinical use, the therapeutic target of lithium remains uncertain. It is recognized that therapeutic concentrations of lithium, through competition with the similarly sized magnesium cation, inhibit the activity of select enzymes. Among these is glycogen synthase kinase-3 (GSK-3). Recent preclinical evidence, including biochemical, pharmacological, genetic, and rodent behavioral models, supports the hypothesis that inhibition of GSK-3 may represent a target for lithium's mood-stabilizing properties. Specifically, it has been demonstrated that lithium administration regulates multiple GSK-3 targets in vivo and that multiple additional classes of mood-stabilizing and antidepressant drugs regulate GSK-3 signaling. Pharmacological or genetic inhibition of GSK-3 results in mood stabilizer-like behavior in rodent models, and genetic association studies implicate GSK-3 as a possible modulator of particular aspects of bipolar disorder including response to lithium. Furthermore, numerous recent studies have provided a more complete understanding of GSK-3's role in diverse neurological processes strengthening the hypothesis that GSK-3 may represent a therapeutically relevant target of lithium. For example, GSK-3 is a primary regulator of neuronal survival, and cellular responses to glucocorticoids and estrogen may involve GSK-3-regulated pathways. While the preclinical evidence discussed in this review is encouraging, ultimate validation of GSK-3 as a therapeutically relevant target will require clinical trials of selective novel inhibitors. In this regard, as is discussed, there is a major effort underway to develop novel, specific, GSK-3 inhibitors.

Authors+Show Affiliations

Gould TD
Laboratory of Molecular Pathophysiology, National Institute of Mental Health, Bethesda, MD 20892, USA. gouldt@mail.nih.gov
Manji HK
No affiliation info available

MeSH

AnimalsAntidepressive AgentsAntipsychotic AgentsCircadian RhythmDisease Models, AnimalElectroconvulsive TherapyEnzyme InhibitorsGlycogen Synthase Kinase 3HumansLithiumModels, BiologicalMood DisordersNeurotransmitter AgentsSignal TransductionValproic Acid

Pub Type(s)

Journal Article
Research Support, N.I.H., Intramural
Research Support, U.S. Gov't, P.H.S.
Review

Language

eng

PubMed ID

15827567

Citation

Gould, Todd D., and Husseini K. Manji. "Glycogen Synthase Kinase-3: a Putative Molecular Target for Lithium Mimetic Drugs." Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, vol. 30, no. 7, 2005, pp. 1223-37.
Gould TD, Manji HK. Glycogen synthase kinase-3: a putative molecular target for lithium mimetic drugs. Neuropsychopharmacology. 2005;30(7):1223-37.
Gould, T. D., & Manji, H. K. (2005). Glycogen synthase kinase-3: a putative molecular target for lithium mimetic drugs. Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology, 30(7), 1223-37.
Gould TD, Manji HK. Glycogen Synthase Kinase-3: a Putative Molecular Target for Lithium Mimetic Drugs. Neuropsychopharmacology. 2005;30(7):1223-37. PubMed PMID: 15827567.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Glycogen synthase kinase-3: a putative molecular target for lithium mimetic drugs. AU - Gould,Todd D, AU - Manji,Husseini K, PY - 2005/4/14/pubmed PY - 2005/8/10/medline PY - 2005/4/14/entrez SP - 1223 EP - 37 JF - Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology JO - Neuropsychopharmacology VL - 30 IS - 7 N2 - Despite many decades of clinical use, the therapeutic target of lithium remains uncertain. It is recognized that therapeutic concentrations of lithium, through competition with the similarly sized magnesium cation, inhibit the activity of select enzymes. Among these is glycogen synthase kinase-3 (GSK-3). Recent preclinical evidence, including biochemical, pharmacological, genetic, and rodent behavioral models, supports the hypothesis that inhibition of GSK-3 may represent a target for lithium's mood-stabilizing properties. Specifically, it has been demonstrated that lithium administration regulates multiple GSK-3 targets in vivo and that multiple additional classes of mood-stabilizing and antidepressant drugs regulate GSK-3 signaling. Pharmacological or genetic inhibition of GSK-3 results in mood stabilizer-like behavior in rodent models, and genetic association studies implicate GSK-3 as a possible modulator of particular aspects of bipolar disorder including response to lithium. Furthermore, numerous recent studies have provided a more complete understanding of GSK-3's role in diverse neurological processes strengthening the hypothesis that GSK-3 may represent a therapeutically relevant target of lithium. For example, GSK-3 is a primary regulator of neuronal survival, and cellular responses to glucocorticoids and estrogen may involve GSK-3-regulated pathways. While the preclinical evidence discussed in this review is encouraging, ultimate validation of GSK-3 as a therapeutically relevant target will require clinical trials of selective novel inhibitors. In this regard, as is discussed, there is a major effort underway to develop novel, specific, GSK-3 inhibitors. SN - 0893-133X UR - https://www.unboundmedicine.com/medline/citation/15827567/Glycogen_synthase_kinase_3:_a_putative_molecular_target_for_lithium_mimetic_drugs_ DB - PRIME DP - Unbound Medicine ER -