Regulation of glycogen synthase kinase-3 during bipolar mania treatment

Beijing Anding Hospital, Capital Medical University, 1720 Seventh Avenue South, Beijing, China.
Bipolar Disorders (Impact Factor: 4.89). 11/2010; 12(7):741-52. DOI: 10.1111/j.1399-5618.2010.00866.x
Source: PubMed

ABSTRACT Bipolar disorder is a debilitating psychiatric illness presenting with recurrent mania and depression. The pathophysiology of bipolar disorder is poorly understood, and molecular targets in the treatment of bipolar disorder remain to be identified. Preclinical studies have suggested that glycogen synthase kinase-3 (GSK3) is a potential therapeutic target in bipolar disorder, but evidence of abnormal GSK3 in human bipolar disorder and its response to treatment is still lacking.
This study was conducted in acutely ill type I bipolar disorder subjects who were hospitalized for a manic episode. The protein level and the inhibitory serine phosphorylation of GSK3 in peripheral blood mononuclear cells of bipolar manic and healthy control subjects were compared, and the response of GSK3 to antimanic treatment was evaluated.
The levels of GSK3α and GSK3β in this group of bipolar manic subjects were higher than healthy controls. Symptom improvement during an eight-week antimanic treatment with lithium, valproate, and atypical antipsychotics was accompanied by a significant increase in the inhibitory serine phosphorylation of GSK3, but not the total level of GSK3, whereas concomitant electroconvulsive therapy treatment during a manic episode appeared to dampen the response of GSK3 to pharmacological treatment.
Results of this study suggest that GSK3 can be modified during the treatment of bipolar mania. This finding in human bipolar disorder is in agreement with preclinical data suggesting that inhibition of GSK3 by increasing serine phosphorylation is a response of GSK3 to psychotropics used in bipolar disorder, supporting the notion that GSK3 is a promising molecular target in the pharmacological treatment of bipolar disorder.

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    • "Selective dopamine transporter (DAT) inhibitors – i.e. GBR12909 – or DAT knockdown have been used to model long-lasting behavioural profiles in mice consistent with manic phenotypes in patients with BD, that however differ from those induced by amphetamine administration (Perry et al., 2009; Ralph-Williams et al., 2003; Young et al., 2010a, 2011) (Table 1). These observations may suggest that the dysregulation in dopamine homeostasis in patients with BD could mainly rely on impairments in dopamine reuptake mechanisms, rather than on altered presynaptic functions. "
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    ABSTRACT: Aberrant synaptic plasticity, originating from abnormalities in dopamine and/or glutamate transduction pathways, may contribute to the complex clinical manifestations of bipolar disorder (BD). Dopamine and glutamate systems cross-talk at multiple levels, such as at the postsynaptic density (PSD). The PSD is a structural and functional protein mesh implicated in dopamine and glutamate-mediated synaptic plasticity. Proteins at PSD have been demonstrated to be involved in mood disorders pathophysiology and to be modulated by antipsychotics and mood stabilizers. On the other side, post-receptor effectors such as protein kinase B (Akt), glycogen synthase kinase-3 (GSK-3) and the extracellular signal-regulated kinase (Erk), which are implicated in both molecular abnormalities and treatment of BD, may interact with PSD proteins, and participate in the interplay of the dopamine-glutamate signalling pathway. In this review, we describe emerging evidence on the molecular cross-talk between dopamine and glutamate signalling in BD pathophysiology and pharmacological treatment, mainly focusing on dysfunctions in PSD molecules. We also aim to discuss future therapeutic strategies that could selectively target the PSD-mediated signalling cascade at the crossroads of dopamine-glutamate neurotransmission.
    Journal of Psychopharmacology 02/2014; 28(6). DOI:10.1177/0269881114523864 · 2.81 Impact Factor
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    • "—Lithium, an inorganic element administered as a salt for the treatment of BD, is a powerful inhibitor of GSK3β. Lithium can inhibit GSK3β directly via competition with magnesium and indirectly by increasing inhibitory serine-phosphorylation of GSK3 through Akt (Li et al., 2010b) (reviewed in Beaulieu and Gainetdinov, 2011; Polter et al., 2010) (Figure 3). Together, these GSK3 inhibitory mechanisms likely mediate the behavioral effects of lithium (Beaulieu et al., 2004) and it is thus possible that myelination is involved in its mechanism of action (Azim and Butt, 2011) (reviewed in Bartzokis, 2011b) (Figure 3). "
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    ABSTRACT: Current psychiatric diagnostic schema segregate symptom clusters into discrete entities, however, large proportions of patients suffer from comorbid conditions that fit neither diagnostic nor therapeutic schema. Similarly, psychotropic treatments ranging from lithium and antipsychotics to serotonin reuptake inhibitors (SSRIs) and acetylcholinesterase inhibitors have been shown to be efficacious in a wide spectrum of psychiatric disorders ranging from autism, schizophrenia (SZ), depression, and bipolar disorder (BD) to Alzheimer's disease (AD). This apparent lack of specificity suggests that psychiatric symptoms as well as treatments may share aspects of pathophysiology and mechanisms of action that defy current symptom-based diagnostic and neuron-based therapeutic schema. A myelin-centered model of human brain function can help integrate these incongruities and provide novel insights into disease etiologies and treatment mechanisms. Available data are integrated herein to suggest that widely used psychotropic treatments ranging from antipsychotics and antidepressants to lithium and electroconvulsive therapy share complex signaling pathways such as Akt and glycogen synthase kinase-3 (GSK3) that affect myelination, its plasticity, and repair. These signaling pathways respond to neurotransmitters, neurotrophins, hormones, and nutrition, underlie intricate neuroglial communications, and may substantially contribute to the mechanisms of action and wide spectra of efficacy of current therapeutics by promoting myelination. Imaging and genetic technologies make it possible to safely and non-invasively test these hypotheses directly in humans and can help guide clinical trial efforts designed to correct myelination abnormalities. Such efforts may provide insights into novel avenues for treatment and prevention of some of the most prevalent and devastating human diseases.
    Neuropharmacology 01/2012; 62(7):2137-53. DOI:10.1016/j.neuropharm.2012.01.015 · 4.82 Impact Factor
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    ABSTRACT: OBJECTIVES. More than 60 years have passed since the introduction of lithium into modern psychiatry and special issues of Bipolar Disorders in 2009 and Neuropsychobiology in 2010 were devoted to this anniversary. Notwithstanding such a long tradition, a number of key articles on the neuropsychiatric aspects of lithium have appeared in recent years. METHODS. This update was based on the most important original papers and reviews on lithium published in recent years. The main topics were the efficacy of lithium in mood disorders, with a special focus on cognitive functions, the neuroprotective effects of this ion and the potential of using lithium in neurology. RESULTS. Clinical studies and reviews point to lithium being still a cornerstone for the prophylaxis of mood disorders, especially bipolar. The pro-cognitive and antisuicidal properties of lithium have been confirmed as an augmentation of antidepressants in treatment-resistant depression. The neuroprotective effects of lithium have been evidenced in both experimental research and in clinical studies using brain imaging. The possible use of lithium in the prophylaxis of dementia and in neurodegenerative disorders, such as Huntington's disease and amyotrophic lateral sclerosis is discussed. CONCLUSIONS. Although not promoted by pharmaceutical companies, lithium remains a highly important drug in neuropsychiatry.
    The World Journal of Biological Psychiatry 03/2011; 12(5):340-8. DOI:10.3109/15622975.2011.559274 · 4.23 Impact Factor
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