Lithium ion, commonly used as the carbonate salt in the treatment of bipolar disorders, has been identified as an inhibitor of several kinases, including Glycogen Synthase Kinase-3β, for almost 20 years.
Although Glycogen synthase kinase 3 beta (GSK3β) has been suggested to play a role in the pathophysiology of BD since it is inhibited by lithium, it remains unknown how GSK3β activity might be involved.
Recent studies have identified GSK-3β as a potential therapeutic target in Alzheimer´s disease, bipolar disorder, stroke, more than 15 types of cancer, and diabetes.
Lithium (Li), a mood stabilizer used to treat bipolar disorder (BP) symptoms has important anti-inflammatory effects by downregulation of glycogen synthase kinase-3 beta (GSK-3β).
Lithium chloride, a classical treatment for bipolar disorder, has shown neuroprotective effects through glycogen synthase kinase-3β inhibition in a variety of central nervous system diseases, including stroke.
Baseline mRNA levels of glycogen synthase kinase 3 beta (GSK3β) and collapsin response mediator protein 1 (CRMP1) genes were significantly associated with BD status and with severity of mood symptoms.
In a prospective 6-12 month follow-up study, GSK- 3β activity in peripheral blood mononuclear cells was measured concurrently with cognitive performance assessed using a comprehensive test battery in 27 patients with BD-I in early and late remission following a manic or mixed episode.
The single nucleotide polymorphism (SNP) rs334558 on the glycogen synthase kinase-3β (GSK3β) gene has been identified as a genetic risk loci associated with schizophrenia and bipolar disorder.
We studied whether lymphocyte GSK-3β activity measured indirectly in lithium- or valproate (VPA)-treated euthymic patients with bipolar disorder is different from controls.
These studies show region-specific abnormalities of both protein and mRNA expression of GSK-3β and β-catenin in postmortem brains of subjects with BP but not subjects with SZ.
The aim of this study is to investigate the effects of ongoing long-term lithium treatment and GSK-3β promoter rs334558 polymorphism on regional gray matter (GM) volumes of patients with BD.
The GSK-3β gene, GSK3B, codes for an enzyme that is a target for the action of mood stabilizers, lithium and possibly valproic acid.In this study, the relationship between haplotypes consisting of single nucleotide polymorphisms (SNPs) of GSK3B -50T/C and -1727A/T and the effect of lithium was studied among Japanese bipolar disorder lithium nonresponders and responders.The distributions of the GSK3B haplotypes (-50T/C and -1727A/T) showed a trend for significant difference between the lithium nonresponders and responders (global P=0.07074).
In summary, here we confirmed significant association of the GSK3B CNV and bipolar disorder pointing out that the copy number and extension of the CNV varies among individuals.
In summary, here we confirmed significant association of the GSK3B CNV and bipolar disorder pointing out that the copy number and extension of the CNV varies among individuals.
We suggest that GSK3-β inhibition and lithium could counteract the detrimental influences of BD on WM structure, with specific benefits resulting from effects on specific WM tracts contributing to the functional integrity of the brain and involving interhemispheric, limbic, and large frontal, parietal, and fronto-occipital connections.
The findings suggest that seemingly disparate candidate genes for SZ and BD can be incorporated into a common molecular network revolving around GSK3β/β-catenin signaling.