A safe lithium mimetic for bipolar disorder

Singh, Nisha; Halliday, Amy C.; Thomas, Jonathan; Кузнецова, О. В.; Baldwin, Rhiannon; Woon, Esther C. Y.; Aley, Parvinder K.; Antoniadou, Ioanna; Sharp, Trevor; Vasudevan, Sridhar R.; Churchill, Grant C.

doi:10.1038/ncomms2320

Cited by 234 publications

(212 citation statements)

References 60 publications

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“…injection to C57BL/6 mice (58) or was directly suspended in water for oral administration to humans (72). The ebselen that was delivered in both ways was absorbed to blood and even crossed the blood-brain barrier (58,72). Since ebselen is included in the National Institutes of Health Clinical Collection (3), it has a history of use in human clinical trials and known safety profiles (www.nihchinicalcollection.com).…”

Section: Discussionmentioning

confidence: 99%

Glutathione Peroxidase Mimic Ebselen Improves Glucose-Stimulated Insulin Secretion in Murine Islets

Wang

Yun²,

Lei³

2014

Antioxidants & Redox Signaling

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Aims: Glutathione peroxidase (GPX) mimic ebselen and superoxide dismutase (SOD) mimic copper diisopropylsalicylate (CuDIPs) were used to rescue impaired glucose-stimulated insulin secretion (GSIS) in islets of GPX1 and(or) SOD1-knockout mice. Results: Ebselen improved GSIS in islets of all four tested genotypes. The rescue in the GPX1 knockout resulted from a coordinated transcriptional regulation of four key GSIS regulators and was mediated by the peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1a)-mediated signaling pathways. In contrast, CuDIPs improved GSIS only in the SOD1 knockout and suppressed gene expression of the PGC-1a pathway. Innovation: Islets from the GPX1 and(or) SOD1 knockout mice provided metabolically controlled intracellular hydrogen peroxide (H 2 O 2 ) and superoxide conditions for the present study to avoid confounding effects. Bioinformatics analyses of gene promoters and expression profiles guided the search for upstream signaling pathways to link the ebselen-initiated H 2 O 2 scavenging to downstream key events of GSIS. The RNA interference was applied to prove PGC-1a as the main mediator for that link. Conclusion: Our study revealed a novel metabolic use and clinical potential of ebselen in rescuing GSIS in the GPX1-deficient islets and mice, along with distinct differences between the GPX and SOD mimics in this regard. These findings highlight the necessities and opportunities of discretional applications of various antioxidant enzyme mimics in treating insulin secretion disorders. Redox Signal. 20,[191][192][193][194][195][196][197][198][199][200][201][202][203]

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Section: Discussionmentioning

confidence: 99%

Glutathione Peroxidase Mimic Ebselen Improves Glucose-Stimulated Insulin Secretion in Murine Islets

Wang

Yun²,

Lei³

2014

Antioxidants & Redox Signaling

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“…Advances in disease biology often lead to the identification of new druggable pharmaceutical targets, and the newly identified therapeutic target can be subjected to target-based screening such as enzymatic HTS assays [14,59]. In AD, this approach has had limited success as the majority of target-based approaches have focused on development of high-affinity novel compounds that can potently inhibit known AD targets such as secretases.…”

Section: Target-based Approachesmentioning

confidence: 99%

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

Kim

2015

Neurotherapeutics

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Summary Alzheimer's disease (AD) is the most common cause of dementia and represents one of the highest unmet needs in medicine today. Drug development efforts for AD have been encumbered by largely unsuccessful clinical trials in the last decade. Drug repositioning, a process of discovering a new therapeutic use for existing drugs or drug candidates, is an attractive and timely drug development strategy especially for AD. Compared with traditional de novo drug development, time and cost are reduced as the safety and pharmacokinetic properties of most repositioning candidates have already been determined. A majority of drug repositioning efforts for AD have been based on positive clinical or epidemiological observations or in vivo efficacy found in mouse models of AD. More systematic, multidisciplinary approaches will further facilitate drug repositioning for AD. Some experimental approaches include unbiased phenotypic screening using the library of available drug collections in physiologically relevant model systems (e.g. stem cell-derived neurons or glial cells), computational prediction and selection approaches that leverage the accumulating data resulting from RNA expression profiles, and genome-wide association studies. This review will summarize several notable strategies and representative examples of drug repositioning for AD.

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“…The recent identification of the failed stroke treatment antioxidant ebselen as a potential lithium mimetic-obtained from screening of 450 compounds from the National Institutes of Health Clinical Collection-is an elegant and comprehensive approach using several targets, which now needs clinical evaluation. 98 Acceleration of the development of novel treatments needs improved validation strategies for preclinical targets and the development of innovative biomarkers and intermediate outcomes for use in early-phase clinical trials. 99 Validation strategies might include neuroimaging, cognitive or biochemical measures, and molecular genetic studies.…”

Section: Future Directionsmentioning

confidence: 99%

The Treatment of Bipolar Disorder

Möller¹,

Nasrallah²

2017

Oxford Medicine Online

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We review recent developments in the acute and long-term treatment of bipolar disorder and identify promising future routes to therapeutic innovation. Overall, advances in drug treatment remain quite modest. Antipsychotic drugs are effective in the acute treatment of mania; their efficacy in the treatment of depression is variable with the clearest evidence for quetiapine. Despite their widespread use, considerable uncertainty and controversy remains about the use of antidepressant drugs in the management of depressive episodes. Lithium has the strongest evidence for long-term relapse prevention; the evidence for anticonvulsants such as divalproex and lamotrigine is less robust and there is much uncertainty about the longer term benefits of antipsychotics. Substantial progress has been made in the development and assessment of adjunctive psychosocial interventions. Long-term maintenance and possibly acute stabilisation of depression can be enhanced by the combination of psychosocial treatments with drugs. The development of future treatments should consider both the neurobiological and psychosocial mechanisms underlying the disorder. We should continue to repurpose treatments and to recognise the role of serendipity. We should also investigate optimum combinations of pharmacological and psychotherapeutic treatments at different stages of the illness. Clarification of the mechanisms by which different treatments affect sleep and circadian rhythms and their relation with daily mood fluctuations is likely to help with the treatment selection for individual patients. To be economically viable, existing psychotherapy protocols need to be made briefer and more efficient for improved scalability and sustainability in widespread implementation.

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A safe lithium mimetic for bipolar disorder

Cited by 234 publications

References 60 publications

Glutathione Peroxidase Mimic Ebselen Improves Glucose-Stimulated Insulin Secretion in Murine Islets

Glutathione Peroxidase Mimic Ebselen Improves Glucose-Stimulated Insulin Secretion in Murine Islets

Drug Repositioning Approaches for the Discovery of New Therapeutics for Alzheimer's Disease

The Treatment of Bipolar Disorder

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