Lithium increases platelet serine-9 phosphorylated GSK-3β levels in drug-free bipolar disorder during depressive episodes

Sousa, Rafael T. de; Zanetti, Marcus V.; Talib, Leda Leme; Chaim, Tiffany M.; Carvalho, André F.; Brunoni, André R.; Busatto, Geraldo F.; Gattaz, Wagner F.; Machado‐Vieira, Rodrigo

doi:10.1016/j.jpsychires.2015.01.016

Cited by 48 publications

(32 citation statements)

References 48 publications

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“…In this protocol, the levels of both GSK3α and GSK3β were increased prior to treatment, while inhibitory serine phosphorylation of the enzyme showed a rise by treatment with lithium, valproate and second generation antipsychotics (SGAs) 16). In a more recently published study similar results were obtained in bipolar subjects experiencing major depressive episodes, in whom serine-9 phosphorylated GSK3β ratios increased after lithium therapy and this correlated with symptomatic improvement in the cohort 17). These investigations confirm the notion that GSK3 is involved in the pathophysiology of affective disorders; additionally, mood stabilizing drugs block the activity of GSK3, with this path being involved in the mechanism of action of psychotropic medications.…”

Section: Main Subjectssupporting

confidence: 52%

Wnt and GSK3 Signaling Pathways in Bipolar Disorder: Clinical and Therapeutic Implications

Muneer

2017

Clin Psychopharmacol Neurosci

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The neurobiology of bipolar disorder, a chronic and systemic ailment is not completely understood. The bipolar phenotype manifests in myriad ways, and psychopharmacological agents like lithium have long term beneficial effects. The enzyme glycogen synthase kinase 3 (GSK3) has come into focus, as lithium and several other mood stabilizing medications inhibit its activity. This kinase and its key upstream modulator, Wnt are dysregulated in mood disorders and there is a growing impetus to delineate the chief substrates involved in the development of these illnesses. In May 2016, a comprehensive literature search was undertaken which revealed that there is over activity of GSK3 in bipolar disorder with deleterious downstream effects like proinflammatory status, increased oxidative stress, and circadian dysregulation leading to declining neurotrophic support and enhanced apoptosis of neural elements. By developing specific GSK3 inhibitors the progressive worsening in bipolar disorder can be forestalled with improved prospects for the sufferers.

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Section: Main Subjectssupporting

confidence: 52%

Wnt and GSK3 Signaling Pathways in Bipolar Disorder: Clinical and Therapeutic Implications

Muneer

2017

Clin Psychopharmacol Neurosci

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“…Due to this phosphorylation the active contractile apparatus [Ca 2+ ] i -dependently develops small paracellular gaps and thus hyper-permeability (Aslam et al, 2010). Lithium is known to inhibit the inositol monophosphatase/glycogen synthase kinase-3-β signaling-pathways including [Ca 2+ ] i in neurons and perhaps other cells (Berridge, 1989, 2014; de Sousa et al, 2015; Bosche et al, 2016). These down-steam pathways may affect MLC phosphorylation; we therefore studied the MLC phosphorylation (with or without lithium) as possible link to endothelial permeability.…”

Section: Resultsmentioning

confidence: 99%

Low-Dose Lithium Stabilizes Human Endothelial Barrier by Decreasing MLC Phosphorylation and Universally Augments Cholinergic Vasorelaxation Capacity in a Direct Manner

et al. 2016

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Lithium at serum concentrations up to 1 mmol/L has been used in patients suffering from bipolar disorder for decades and has recently been shown to reduce the risk for ischemic stroke in these patients. The risk for stroke and thromboembolism depend not only on cerebral but also on general endothelial function and health; the entire endothelium as an organ is therefore pathophysiologically relevant. Regardless, the knowledge about the direct impact of lithium on endothelial function remains poor. We conducted an experimental study using lithium as pharmacologic pretreatment for murine, porcine and human vascular endothelium. We predominantly investigated endothelial vasorelaxation capacities in addition to human basal and dynamic (thrombin-/PAR-1 receptor agonist-impaired) barrier functioning including myosin light chain (MLC) phosphorylation (MLC-P). Low-dose therapeutic lithium concentrations (0.4 mmol/L) significantly augment the cholinergic endothelium-dependent vasorelaxation capacities of cerebral and thoracic arteries, independently of central and autonomic nerve system influences. Similar concentrations of lithium (0.2–0.4 mmol/L) significantly stabilized the dynamic thrombin-induced and PAR-1 receptor agonist-induced permeability of human endothelium, while even the basal permeability appeared to be stabilized. The lithium-attenuated dynamic permeability was mediated by a reduced endothelial MLC-P known to be followed by a lessening of endothelial cell contraction and paracellular gap formation. The well-known lithium-associated inhibition of inositol monophosphatase/glycogen synthase kinase-3-β signaling-pathways involving intracellular calcium concentrations in neurons seems to similarly occur in endothelial cells, too, but with different down-stream effects such as MLC-P reduction. This is the first study discovering low-dose lithium as a drug directly stabilizing human endothelium and ubiquitously augmenting cholinergic endothelium-mediated vasorelaxation. Our findings have translational and potentially clinical impact on cardiovascular and cerebrovascular disease associated with inflammation explaining why lithium can reduce, e.g., the risk for stroke. However, further clinical studies are warranted.

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“…The latter mechanism has been demonstrated by assessing the level of serine-9 phosphorylated GSK3 β in platelets of bipolar patients. After treatment with lithium, the level was higher and related to the clinical improvement [98]. Many effects of lithium can be reconducted to its inhibitory action on GSK3.…”

Section: Methodsmentioning

confidence: 99%

Gsk3 Signalling and Redox Status in Bipolar Disorder: Evidence from Lithium Efficacy

Luca

Calandra

Luca

2016

Oxidative Medicine and Cellular Longevity

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Objective. To discuss the link between glycogen synthase kinase-3 (GSK3) and the main biological alterations demonstrated in bipolar disorder (BD), with special attention to the redox status and the evidence supporting the efficacy of lithium (a GSK3 inhibitor) in the treatment of BD. Methods. A literature research on the discussed topics, using Pubmed and Google Scholar, has been conducted. Moreover, a manual selection of interesting references from the identified articles has been performed. Results. The main biological alterations of BD, pertaining to inflammation, oxidative stress, membrane ion channels, and circadian system, seem to be intertwined. The dysfunction of the GSK3 signalling pathway is involved in all the aforementioned “biological causes” of BD. In a complex scenario, it can be seen as the common denominator linking them all. Lithium inhibition of GSK3 could, at least in part, explain its positive effect on these biological dysfunctions and its superiority in terms of clinical efficacy. Conclusions. Deepening the knowledge on the molecular bases of BD is fundamental to identifying the biochemical pathways that must be targeted in order to provide patients with increasingly effective therapeutic tools against an invalidating disorder such as BD.

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Lithium increases platelet serine-9 phosphorylated GSK-3β levels in drug-free bipolar disorder during depressive episodes

Cited by 48 publications

References 48 publications

Wnt and GSK3 Signaling Pathways in Bipolar Disorder: Clinical and Therapeutic Implications

Wnt and GSK3 Signaling Pathways in Bipolar Disorder: Clinical and Therapeutic Implications

Low-Dose Lithium Stabilizes Human Endothelial Barrier by Decreasing MLC Phosphorylation and Universally Augments Cholinergic Vasorelaxation Capacity in a Direct Manner

Gsk3 Signalling and Redox Status in Bipolar Disorder: Evidence from Lithium Efficacy

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