Lithium Regulates Glycogen Synthase Kinase-3β in Human Peripheral Blood Mononuclear Cells: Implication in the Treatment of Bipolar Disorder

Li, Xiaohua; Friedman, Ari B; Zhu, Wawa; Wang, Li; Boswell, Sherer; May, Roberta S.; Davis, Lori L.; Jope, Richard S.

doi:10.1016/j.biopsych.2006.02.027

Cited by 107 publications

(99 citation statements)

References 22 publications

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“…The observed reduced level of p-GSK3b, thus higher GSK3b activity in bipolar fibroblasts, may also underlie the rationale for lithium treatment of bipolar disorder since lithium directly inhibits GSK3b resulting in N-terminal phosphorylation of GSK3b at serine 9. 61 It was reported that the level of p-GSK3b in peripheral blood mononuclear cells from subjects with bipolar disorder under lithium treatment is significantly higher than that in healthy control subjects, 100 although no difference was detected between lithium-free bipolar and healthy controls. We postulate that the genetically heterogeneous nature of the samples may account for the failure of detecting p-GSK3b level difference between lithiumfree bipolar and healthy controls, as we encountered when including samples from members of non-Amish family 884 in our analysis.…”

Section: Discussionmentioning

confidence: 99%

Assessment of circadian function in fibroblasts of patients with bipolar disorder

et al. 2008

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Previous studies have implicated the circadian system in the pathophysiology of bipolar disorder, but conclusive evidence for altered circadian clocks is lacking. Cultured fibroblasts harbor circadian clocks representative of those in the master clock resident in the suprachiasmatic nuclei, providing a new avenue to investigate the core clock machinery in patients with bipolar illness. We examined the rhythmic expression patterns of core clock genes (BMAL1, PER1, PER2, REV-ERBa, DEC2, DBP) in fibroblasts from 12 bipolar patients and 12 healthy controls. Although we did not detect differences in the circadian period between bipolar patients and controls, the amplitude of rhythmic expression for BMAL1, REVERBa and DBP, as well as the overall mRNA expression level for DEC2 and DBP was reduced in fibroblasts from bipolar patients. Bonferroni's correction for multiple comparisons still resulted in significantly reduced DBP expression level, and trends toward reduced overall expression level of DEC2 and circadian amplitude of BMAL1, in fibroblasts from bipolar patients. We next examined an expanded cohort of 18 bipolar patients and 35 healthy controls for mRNA expression levels of four kinases (CKId, CKIe, GSK3a and GSK3b) and the protein and phosphorylation levels of two of them (GSK3a and GSK3b). We did not detect differences in steady-state mRNA levels or protein levels of these kinases between bipolar patients and controls, but the level of GSK3b phosphorylation was significantly reduced in bipolar patients within an Old Order Amish bipolar kindred. Our results suggest that the reduced amplitudes and overall expression levels of circadian genes, and the decreased phosphorylation level of GSK3b may lead to dysregulation of downstream genes, which could explain some pathological features of bipolar disorder.

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Section: Discussionmentioning

confidence: 99%

Assessment of circadian function in fibroblasts of patients with bipolar disorder

et al. 2008

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“…Akt activity was decreased by 31%, while GSK-3β activity was increased by 53% in patients with major depressive disorder (10 suicide and 10 non-suicide), compared with control subjects (10 suicide and 10 non-suicide); however, Akt and GSK-3α/ 3β protein levels were not changed between depressive patients and control subjects (54). In human peripheral blood mononuclear cells isolated from 23 healthy subjects, 9 bipolar disorder patients treated with lithium and 13 lithium-free bipolar disorder patients, Li et al (55) …”

Section: Depressive Patientsmentioning

confidence: 97%

Lithium and Neuropsychiatric Therapeutics: Neuroplasticity via Glycogen Synthase Kinase-3β, β-Catenin, and Neurotrophin Cascades

Wada

2009

J Pharmacol Sci

125

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Abstract. Mood disorders are not merely attributed to the functional defect of neurotransmission, but also are due to the structural impairment of neuroplasticity. Chronic stress decreases neurotrophin levels, precipitating or exacerbating depression; conversely, antidepressants increase expression of various neurotrophins (e.g., brain-derived neurotrophic factor and vascular endothelial growth factor), thereby blocking or reversing structural and functional pathologies via promoting neurogenesis. Since the worldwide approval of lithium therapy in 1970, lithium has been used for its anti-manic, antidepressant, and anti-suicidal effects, yet the therapeutic mechanisms at the cellular level remain not-fully defined. During the last five years, multiple lines of evidence have shown that the mood stabilization and neurogenesis by lithium are due to the lithium-induced inhibition of glycogen synthase kinase-3β (GSK-3β), allowing accumulation of β-catenin and β-catenin-dependent gene transcriptional events. Altered levels of GSK-3β and β-catenin are associated with various neuropsychiatric and neurodegenerative diseases, while various classical neuropsychiatric drugs inhibit GSK-3β and up-regulate β-catenin expression. In addition, evidence has emerged that insulin-like growth factor-I enhances antidepression, antianxiety, memory, neurogenesis, and angiogenesis; antidepressants up-regulate expression of insulin-like growth factor-I, while insulin-like growth factor-I up-regulates brain-derived neurotrophic factor expression and its receptor TrkB level, as well as brain-derived neurotrophic factor-induced synaptic protein levels. More importantly, physical exercise and healthy diet raise transport of peripheral circulating insulin-like growth factor I into the brain, reinforcing the expression of neurotrophins (e.g., brain-derived neurotrophic factor) and the strength of cell survival signalings (e.g., phosphoinositide 3-kinase / Akt / GSK-3β pathway). This review will focus on the rapidly advancing new trends in the last five years about lithium, GSK-3β/ β-catenin, and neurotrophin cascades.

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“…However, at a therapeutic concentration of lithium, which is approximately 1 mM, GSK3 is only moderately inhibited because lithium's Ki for inhibition of GSK3 is approximately 2 mM. However, in addition to this direct inhibitory action of lithium on GSK3, treatment with lithium of mice, cultured cells, or human blood cells increases the inhibitory serine-phosphorylation of GSK3 [49,50;reviewed in Ref. 51].…”

Section: Psychiatric Diseases: Gsk3 and Mood Disordersmentioning

confidence: 99%

“…These are all difficult questions to address experimentally, so most evidence is based on correlative data. For example, lithium inhibits GSK3 both in mouse brain [49] and in human blood cells [50], which has led to the hypothesis that lithium also inhibits GSK3 in human brain. Since impaired serotonergic activity has long been linked to depression, the finding that enhanced serotonergic activity or anti-depressants acting on serotonergic systems cause inhibition of GSK3 in mouse brain in vivo lends further support to the possibility that impaired control of GSK3 is a component of mood disorders [54].…”

Section: Psychiatric Diseases: Gsk3 and Mood Disordersmentioning

confidence: 99%

Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics

2006

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Deciphering what governs inflammation and its effects on tissues is vital for understanding many pathologies. The recent discovery that glycogen synthase kinase-3 (GSK3) promotes inflammation reveals a new component of its well-documented actions in several prevalent diseases which involve inflammation, including mood disorders, Alzheimer's disease, diabetes, and cancer. Involvement in such disparate conditions stems from the widespread influences of GSK3 on many cellular functions, with this review focusing on its regulation of inflammatory processes. GSK3 promotes the production of inflammatory molecules and cell migration, which together make GSK3 a powerful regulator of inflammation, while GSK3 inhibition provides protection from inflammatory conditions in animal models. The involvement of GSK3 and inflammation in these diseases are highlighted. Thus, GSK3 may contribute not only to primary pathologies in these diseases, but also to the associated inflammation, suggesting that GSK3 inhibitors may have multiple effects influencing these conditions.

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Lithium Regulates Glycogen Synthase Kinase-3β in Human Peripheral Blood Mononuclear Cells: Implication in the Treatment of Bipolar Disorder

Cited by 107 publications

References 22 publications

Assessment of circadian function in fibroblasts of patients with bipolar disorder

Assessment of circadian function in fibroblasts of patients with bipolar disorder

Lithium and Neuropsychiatric Therapeutics: Neuroplasticity via Glycogen Synthase Kinase-3β, β-Catenin, and Neurotrophin Cascades

Glycogen Synthase Kinase-3 (GSK3): Inflammation, Diseases, and Therapeutics

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