Molecular basis of lithium action: integration of lithium-responsive signaling and gene expression networks

Lenox, Robert H.; Wang, Le

doi:10.1038/sj.mp.4001306

Cited by 125 publications

(79 citation statements)

References 108 publications

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“…Recent studies have shown that antidepressants and mood stabilizers regulate a variety of genes involved in cell survival and cell death, such as CREB, BDNF, Bcl-2, MAP kinases, and GSK-3beta (Manji and Duman, 2001;Lenox and Wang, 2003). Lithium carbonate, the major drug used to treat bipolar disorder, protects cultured rat brain neurons from NMDA-mediated excitotoxicity via mechanisms that include increased expression of Bcl-2 (Chuang et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

DNA fragmentation is increased in non-GABAergic neurons in bipolar disorder but not in schizophrenia

Buttner

Bhattacharyya

Walsh

et al. 2007

Schizophrenia Research

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Apoptosis is thought to contribute to neuronal loss in bipolar disorder and schizophrenia, although empiric evidence in support of this idea has been lacking. In this study, we investigated whether or not apoptosis is associated with GABAergic interneurons in the anterior cingulate cortex in schizophrenia (n = 14) and bipolar disorder (n = 14) when compared to normal controls (n = 14). A double-labeling technique using the Klenow method of in situ end-labeling (ISEL) of single-stranded DNA breaks was combined with an in situ hybridization localization of mRNA for the 67 kiloDalton (kDa) isoform of glutamate decarboxylase (GAD67) and applied to the anterior cingulate cortex of 14 normal controls, 14 schizophrenics, and 14 patients with bipolar disorder matched for age and postmortem interval. An increase in Klenow-positive, GAD67-negative nuclei was observed in layer V/VI of patients with bipolar disorder, but not schizophrenics. Klenow-positive cells that were also positive for GAD67 mRNA did not show differences in either patient group. Conclusions: This is the first demonstration that there is more DNA fragmentation in cells showing no detectable GAD67 mRNA in patients with bipolar disorder than in schizophrenics or controls. These findings suggest that non-GABAergic cells may be selectively vulnerable to oxidative stress in patients with bipolar disorder.

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Section: Discussionmentioning

confidence: 99%

DNA fragmentation is increased in non-GABAergic neurons in bipolar disorder but not in schizophrenia

Buttner

Bhattacharyya

Walsh

et al. 2007

Schizophrenia Research

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“…One possibility to explain this paradoxical fact is illustrated on Fig. 2: lithium interferes with the intracellular production of inositol triphosphate (IP3), via a specific inhibition of the enzyme inositol monophosphatase (IMPase) (16). The final effect of lithium on parathyroid chief cells might be the result of a balance between a weak activation at the level of the CASR and a stronger inhibition of intracellular pathways at the level of the IMPase.…”

Section: Mechanism Of Action Of Lithium On Parathyroid Cellsmentioning

confidence: 99%

Lithium-associated hyperparathyroidism: report of four cases and review of the literature

Szalat¹,

Mazeh²,

Freund³

2009

European Journal of Endocrinology

110

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Context: Lithium-associated hyperparathyroidism (LAH) was first described in 1973 but many issues remain in question regarding the pathophysiology as well as the appropriate management of this condition. Objective: Report of four new cases and review of the literature. Results: We describe two males and two females, treated for more than 10 years with lithium due to bipolar disorder, who developed LAH. All underwent parathyroidectomy. In three cases (75%), pathology revealed multiglandular disease, with hyperplasia or two parathyroid adenomas. We observed a cure status in three (75%) of the operated patients. The fourth patient had a residual disease, but had controlled hypercalcemia under the calcimimetic drug cinacalcet. We also observed the association of LAH with incidental papillary thyroid carcinoma in two patients. Review of the literature identified a higher prevalence of LAH in women than men (four out of one) and a controversy in regard to the prevalence of multiglandular disease. As a result, there is no consensus regarding the preferred surgical procedure. The use of cinacalcet as an effective treatment of LAH was previously described in only five cases. Conclusion: In our view, there are apparently two different mechanisms leading to LAH: exacerbation of a pre-existing state of hyperparathyroidism and multiglandular disease. For uncontrolled hypercalcemia, parathyroidectomy is recommended. The issue of routine four-gland exploration and subtotal parathyroidectomy versus intraoperative PTH-determination-guided excision of enlarged glands is still unresolved. The use of the recently developed calcimimetics may offer an alternative to patients who are not candidates for surgery.

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“…The deficit of new drugs based on lithium is partly due to a complex mechanism of action; lithium affects several enzymes and cellular pathways simultaneously, making its most relevant molecular mechanism in the treatment of BD difficult to disentangle [310]. Nonetheless, it has become increasingly clear over the last 2 decades that one of the relevant (though by no means exclusive) mechanisms of action of lithium within the CNS is inhibition of GSK3, which mimics activation of Wnt/β-catenin signaling [311].…”

Section: Concluding Remarks: Therapeutic Considerationsmentioning

confidence: 99%

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

Mulligan

Cheyette

2016

Complex Psychiatry

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Mounting evidence indicates that Wnt signaling is relevant to pathophysiology of diverse mental illnesses including schizophrenia, bipolar disorder, and autism spectrum disorder. In the 35 years since Wnt ligands were first described, animal studies have richly explored how downstream Wnt signaling pathways affect an array of neurodevelopmental processes and how their disruption can lead to both neurological and behavioral phenotypes. Recently, human induced pluripotent stem cell (hiPSC) models have begun to contribute to this literature while pushing it in increasingly translational directions. Simultaneously, large-scale human genomic studies are providing evidence that sequence variation in Wnt signal pathway genes contributes to pathogenesis in several psychiatric disorders. This article reviews neurodevelopmental and postneurodevelopmental functions of Wnt signaling, highlighting mechanisms, whereby its disruption might contribute to psychiatric illness, and then reviews the most reliable recent genetic evidence supporting that mutations in Wnt pathway genes contribute to psychiatric illness. We are proponents of the notion that studies in animal and hiPSC models informed by the human genetic data combined with the deep knowledge base and tool kits generated over the last several decades of basic neurodevelopmental research will yield near-term tangible advances in neuropsychiatry.

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Molecular basis of lithium action: integration of lithium-responsive signaling and gene expression networks

Cited by 125 publications

References 108 publications

DNA fragmentation is increased in non-GABAergic neurons in bipolar disorder but not in schizophrenia

DNA fragmentation is increased in non-GABAergic neurons in bipolar disorder but not in schizophrenia

Lithium-associated hyperparathyroidism: report of four cases and review of the literature

Neurodevelopmental Perspectives on Wnt Signaling in Psychiatry

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