The neuroprotective efficacy of ebselen (a glutathione peroxidase mimic) on brain damage induced by transient focal cerebral ischaemia in the rat

Dawson, Deborah A.; Masayasu, Hiroyuki; Graham, David I.; Macrae, I. Mhairi

doi:10.1016/0304-3940(94)11226-9

Cited by 143 publications

(77 citation statements)

References 27 publications

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“…Ebselen, a seleno-organic compound that mimics the enzymatic function of GPX1 [41], was used to determine whether the decreased UCP2 protein levels in the OE islets were related to the enhanced GPX1 activity. Islets isolated from three WT mice were pooled and divided into three groups (200 islets per sample, n=3 per treatment): medium only (RPMI 1640, 10 mmol/l glucose and 10% [vol./vol.]…”

Section: Methodsmentioning

confidence: 99%

Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice

et al. 2008

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Aims/hypothesis We previously observed hyperglycaemia, hyperinsulinaemia, insulin resistance and obesity in Gpx1-overexpressing mice (OE). Here we determined whether these phenotypes were eliminated by diet restriction, subsequently testing whether hyperinsulinaemia was a primary effect of Gpx1 overexpression and caused by dysregulation of pancreatic duodenal homeobox 1 (PDX1) and uncoupling protein-2 (UCP2) in islets. Methods First, 24 male OE and wild-type (WT) mice (2 months old) were given 3 g (diet-restricted) or 5 g (fullfed) feed per day for 4 months to compare their glucose metabolism. Thereafter, several mechanistic experiments were conducted with pancreas and islets of the two genotypes (2 or 6 months old) to assay for beta cell mass, reactive oxygen species (ROS) levels, mitochondrial membrane potential (Δ= m ) and expression profiles of regulatory proteins. A functional assay of islets was also performed. Results Diet restriction eliminated obesity but not hyperinsulinaemia in OE mice. These mice had greater pancreatic beta cell mass (more than twofold) and pancreatic insulin content (40%) than the WT, along with an enhanced Δ= m and glucose-stimulated insulin secretion in islets. With diminished ROS production, the OE islets displayed hyperacetylation of H3 and H4 histone in the Pdx1 promoter, elevated PDX1 and decreased UCP2. Conclusions/interpretation Overproduction of the major antioxidant enzyme, glutathione peroxidase 1, caused seemingly beneficial changes in pancreatic PDX1 and UCP2, but eventually led to chronic hyperinsulinaemia by dysregulating islet insulin production and secretion.

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Section: Methodsmentioning

confidence: 99%

Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice

et al. 2008

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“…Furthermore, extracellular glutamate and dopamine levels accumulate (Bogaert et al, 2000), and peri-infarct depolarizations occur (Kleeberg et al, 2004). ET-1-induced ischemic injury can also be attenuated by strategies known to be protective during intraluminal suture MCAO, such as blockade of NMDA receptors (MK801 [(ϩ)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate]) (Sharkey et al, 1994), voltage-gated sodium channels (AM-36) (Callaway et al, 2004), and voltage-gated calcium channels (nimodipine) (Bogaert et al, 2001), as well as by free radical scavengers (ebselen and coenzyme Q10) (Dawson et al, 1995;Ostrowski et al, 1998), and hypothermia (Van Hemelrijck et al, 2003). In this study, ET-1 was directly injected into the cortical parenchyma to create a localized and reproducible region of ischemia.…”

Section: Loss Of Nrf2 Function Abrogates Tbhq-mediated Neuroprotectiomentioning

confidence: 99%

A Small-Molecule-Inducible Nrf2-Mediated Antioxidant Response Provides Effective Prophylaxis against Cerebral IschemiaIn Vivo

Shih¹,

Li²,

Murphy³

2005

J. Neurosci.

390

289

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The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) coordinates expression of genes required for free radical scavenging, detoxification of xenobiotics, and maintenance of redox potential. Previously, activation of this pleiotropic response was neuroprotective in cell culture models that simulate components of stroke damage. However, the role of Nrf2 in limiting stroke damage in vivo remained unclear. We report that Nrf2 activation protects the brain from cerebral ischemia in vivo. Acute (1-3 d) intracerebroventricular or intraperitoneal pretreatment with tert-butylhydroquinone (tBHQ), an Nrf2 activity inducer, reduced cortical damage and sensorimotor deficit at 24 h and even 1 month after ischemia-reperfusion in rats. Cortical glutathione levels robustly increased with tBHQ administration to rats and Nrf2-expressing mice, but not Nrf2 Ϫ/Ϫ mice. Basal and inducible activities of antioxidant/detoxification enzymes in Nrf2Ϫ/Ϫ mice were reduced when compared with Nrf2 ϩ/ϩ controls. Interestingly, larger infarcts were observed in Nrf2 Ϫ/Ϫ mice at 7 d after stroke, but not at 24 h, suggesting that Nrf2 may play a role in shaping the penumbra well after the onset of ischemia. Neuronal death caused by a "penumbral" model of stroke, using intracortical endothelin-1 microinjection, was attenuated by tBHQ administration to Nrf2 ϩ/ϩ , but not to Nrf2 Ϫ/Ϫ mice, confirming the Nrf2-specific action of tBHQ in vivo. We conclude that Nrf2 plays a role in modulating ischemic injury in vivo. Accordingly, Nrf2 activation by small molecule inducers may be a practical preventative treatment for stroke-prone patients.

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“…Unlike other selenium compounds, ebselen possesses a very low toxicity because of its unique stability in structure and because its selenium moiety is not liberated during biotransformation and therefore does not enter the selenium metabolism of the organism (7)(8)(9). In more recent animal model studies, ebselen was shown to reduce oxidative stress in ischemiareperfusion in heart (10) and to have neuroprotective effects in brain (11)(12)(13)(14). More importantly, ebselen has been demonstrated to have beneficial effects in clinical trials for the treatment of patients with delayed neurological deficits after aneurysmal subarachnoid hemorrhage (15) and acute ischemic stroke (16,17).…”

mentioning

confidence: 99%

A Novel Antioxidant Mechanism of Ebselen Involving Ebselen Diselenide, a Substrate of Mammalian Thioredoxin and Thioredoxin Reductase

Zhao

Holmgren

2002

Journal of Biological Chemistry

177

103

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The neuroprotective efficacy of ebselen (a glutathione peroxidase mimic) on brain damage induced by transient focal cerebral ischaemia in the rat

Cited by 143 publications

References 27 publications

Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice

Molecular mechanisms for hyperinsulinaemia induced by overproduction of selenium-dependent glutathione peroxidase-1 in mice

A Small-Molecule-Inducible Nrf2-Mediated Antioxidant Response Provides Effective Prophylaxis against Cerebral IschemiaIn Vivo

A Novel Antioxidant Mechanism of Ebselen Involving Ebselen Diselenide, a Substrate of Mammalian Thioredoxin and Thioredoxin Reductase

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