Neuroprotective Effects of Ebselen Following Forebrain Ischemia: Involvement of Glutamate and Nitric Oxide

Koizumi, Hiroyasu; Fujisawa, Hironori; Suehiro, Eiichi; Shirao, Satoshi; Suzuki, Michiyasu

doi:10.2176/nmc.51.337

Cited by 39 publications

(21 citation statements)

References 36 publications

(55 reference statements)

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“…The similar effect on mitochondrial level and function was observed in SelH overexpressing HT22 cells [88]. Moreover, the SelH elevated the mitochondrial biogenesis through activation of protein kinase A-CREB-PGC-1α and Akt/protein kinase B-CREB-PGC-1α pathways [89].…”

Section: Selenium and Selenoproteins In Neuro-logical Disorderssupporting

confidence: 67%

Selenium in the therapy of neurological diseases. Where is it going?

Dominiak¹,

Wilkaniec²,

Wroczyński³

et al. 2015

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Selenium ( 34 Se), an antioxidant trace element, is an important regulator of brain function. These beneficial properties that Se possesses are attributed to its ability to be incorporated into selenoproteins as an amino acid. Several selenoproteins are expressed in the brain, in which some of them, e.g. glutathione peroxidases (GPxs), thioredoxin reductases (TrxRs) or selenoprotein P (SelP), are strongly involved in antioxidant defence and in maintaining intercellular reducing conditions. Since increased oxidative stress has been implicated in neurological disorders, including Parkinson's disease, Alzheimer's disease, stroke, epilepsy and others, a growing body of evidence suggests that Se depletion followed by decreased activity of Se-dependent enzymes may be important factors connected with those pathologies. Undoubtedly, the remarkable progress that has been made in understanding the biological function of Se in the brain has opened up new potential possibilities for the treatment of neurological diseases by using Se as a potential drug. However, further research in the search for optimal Se donors is necessary in order to achieve an effective and safe therapeutic income.

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Section: Selenium and Selenoproteins In Neuro-logical Disorderssupporting

confidence: 67%

Selenium in the therapy of neurological diseases. Where is it going?

Dominiak¹,

Wilkaniec²,

Wroczyński³

et al. 2015

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“…Ebselen has been extensively used in a variety of experimental animal models of injury/disease [37] and as a neuroprotectant in the treatment of patients following acute ischemic stroke [40–42] and aneurysmal subarachnoid hemorrhage [43]. A clinical trial is currently underway to determine the utility of ebselen in a hearing loss paradigm [44].…”

Section: Discussionmentioning

confidence: 99%

Kinetic characterization of ebselen, chelerythrine and apomorphine as glutaminase inhibitors

Thomas

Rojas

Tanega

et al. 2013

Biochemical and Biophysical Research Communications

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Glutaminase catalyzes the hydrolysis of glutamine to glutamate and plays a central role in the proliferation of neoplastic cells via glutaminolysis, as well as in the generation of excitotoxic glutamate in central nervous system disorders such as HIV-associated dementia (HAD) and multiple sclerosis. Both glutaminase siRNA and glutaminase inhibition have been shown to be effective in in vitro models of cancer and HAD, suggesting a potential role for small molecule glutaminase inhibitors. However, there are no potent, selective inhibitors of glutaminase currently available. The two prototypical glutaminase inhibitors, BPTES and DON, are either insoluble or non-specific. In a search for more drug-like glutaminase inhibitors, we conducted a screen of 1280 in vivo active drugs (Library of Pharmacologically Active Compounds (LOPAC1280)) and identified ebselen, chelerythrine and (R)-apomorphine. The newly identified inhibitors exhibited 10 to 1500-fold greater affinities than DON and BPTES and over 100-fold increased efficiency of inhibition. Although non-selective, it is noteworthy that the affinity of ebselen for glutaminase is more potent than any other activity yet described. It is possible that the previously reported biological activity seen with these compounds is due, in part, to glutaminase inhibition. Ebselen, chelerythrine and apomorphine complement the armamentarium of compounds to explore the role of glutaminase in disease.

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“…However, in these models, NOX2ds-tat was applied via a cranial window, which almost excludes these studies as valuable proof of concepts for NOX inhibition in human therapy of these diseases. Several studies suggested a protection by deleting NOX2 in brain ischemia reperfusion injury, some by applying unspecific inhibitors such as apocynin, DPI (120), or ebselen (90) [reviewed in ref. (140)].…”

Section: Fig 7 Nox Enzymes As Validated Therapeutic Targetsmentioning

confidence: 99%

Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement

Altenhöfer

Radermacher

Kleikers

et al. 2015

Antioxidants & Redox Signaling

439

417

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Significance: Oxidative stress, an excess of reactive oxygen species (ROS) production versus consumption, may be involved in the pathogenesis of different diseases. The only known enzymes solely dedicated to ROS generation are nicotinamide adenine dinucleotide phosphate (NADPH) oxidases with their catalytic subunits (NOX). After the clinical failure of most antioxidant trials, NOX inhibitors are the most promising therapeutic option for diseases associated with oxidative stress. Recent Advances: Historical NADPH oxidase inhibitors, apocynin and diphenylene iodonium, are un-specific and not isoform selective. Novel NOX inhibitors stemming from rational drug discovery approaches, for example, GKT137831, ML171, and VAS2870, show improved specificity for NADPH oxidases and moderate NOX isoform selectivity. Along with NOX2 docking sequence (NOX2ds)-tat, a peptide-based inhibitor, the use of these novel small molecules in animal models has provided preliminary in vivo evidence for a pathophysiological role of specific NOX isoforms. Critical Issues: Here, we discuss whether novel NOX inhibitors enable reliable validation of NOX isoforms' pathological roles and whether this knowledge supports translation into pharmacological applications. Modern NOX inhibitors have increased the evidence for pathophysiological roles of NADPH oxidases. However, in comparison to knockout mouse models, NOX inhibitors have limited isoform selectivity. Thus, their use does not enable clear statements on the involvement of individual NOX isoforms in a given disease. Future Directions: The development of isoform-selective NOX inhibitors and biologicals will enable reliable validation of specific NOX isoforms in disease models other than the mouse. Finally, GKT137831, the first NOX inhibitor in clinical development, is poised to provide proof of principle for the clinical potential of NOX inhibition. Antioxid. Redox Signal. 23, 406-427.

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Neuroprotective Effects of Ebselen Following Forebrain Ischemia: Involvement of Glutamate and Nitric Oxide

Cited by 39 publications

References 36 publications

Selenium in the therapy of neurological diseases. Where is it going?

Selenium in the therapy of neurological diseases. Where is it going?

Kinetic characterization of ebselen, chelerythrine and apomorphine as glutaminase inhibitors

Evolution of NADPH Oxidase Inhibitors: Selectivity and Mechanisms for Target Engagement

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