Overexpression of human glutathione peroxidase protects transgenic mice against focal cerebral ischemia/reperfusion damage

Weisbrot-Lefkowitz, Miriam; Reuhl, Kenneth R.; Perry, Barbara; Chan, Pak H.; Inouye, Masayori; Mirochnitchenko, Oleg

doi:10.1016/s0169-328x(97)00313-6

Cited by 173 publications

(99 citation statements)

References 26 publications

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“…The experimental procedure was previously described (5,8). These conditions provide reproducible I/R injury in brain of normal and transgenic mice.…”

Section: Focal Cerebral Ischemiamentioning

confidence: 99%

“…Data from detailed histopathologic analysis and quantitative neutrophil counts in brain sections from normal and transgenic mice after I/R are well correlated with MPO measurements and are currently included in a manuscript submitted for publication. 5 Therefore, the results indicate that overexpression of glutathione peroxidase (GP) inhibits neutrophil transmigration after focal I/R.…”

Section: Inhibition Of Neutrophil Migration In Brain Infarcts By Gp Omentioning

confidence: 99%

“…According to our previously reported measurements, GP activity was more than two times higher in purified cortical neurons from GPx1 animals compared with that in normal mice. 5 The ability of antioxidants such as N-acetylcysteine to protect neuronal cells against TNF-␣-induced apoptosis in cell culture has been reported (18). To address this issue we exposed cortical neurons from normal and transgenic mice to an in vitro model of I/R, anoxia/glucose depletion following reoxygenation/high glucose treatment, as well as different concentrations of exogenous TNF-␣ and FasL.…”

Section: Induced Cytotoxicity In Primary Neurons In Vitromentioning

confidence: 99%

“…To address the role of ROS, particularly those sensitive to intracellular glutathione peroxidase (GPx1) activity in brain I/R, we used transgenic mice overexpressing human GPx1 (4). Experiments with GPx1 transgenic mice subjected to intraluminal blockade of the middle cerebral artery (MCA) as a model system have shown that they are protected against brain I/R damage (5). Our GPx1 animals displayed a significant decrease in infarct volume (48%) compared with nontransgenic mice.…”

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confidence: 99%

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Inflammatory Response and Glutathione Peroxidase in a Model of Stroke

Ishibashi

Prokopenko

Reuhl

et al. 2002

The Journal of Immunology

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Stroke is one of the leading causes of death in major industrial countries. Many factors contribute to the cellular damage resulting from ischemia/reperfusion (I/R). Experimental data indicate an important role for oxidative stress and the inflammatory cascade during I/R. We are testing the hypothesis that the mechanism of protection against I/R damage observed in transgenic mice overexpressing human antioxidant enzymes (particularly intracellular glutathione peroxidase) involves the modulation of inflammatory response as well as reduced sensitivity of neurons to cytotoxic cytokines. Transgenic animals show significant reduction of expression of chemokines, IL-6, and cell death-inducing ligands as well as corresponding receptors in a focal cerebral I/R model. Reduction of DNA binding activity of consensus and potential AP-1 binding sites in mouse Fas ligand promoter sequence was observed in nuclear extracts from transgenic mice overexpressing intracellular glutathione peroxidase compared with normal animals following I/R. This effect was accompanied by modulation of the c-Jun N-terminal kinase/stress-activated protein kinase pathway. Cultured primary neurons from the transgenic mice demonstrated protection against hypoxia/reoxygenation injury as well as cytotoxicity after TNF-α and Fas ligand treatment. These results indicate that glutathione peroxidase-sensitive reactive oxygen species play an important role in regulation of cell death during cerebral I/R by modulating intrinsic neuronal sensitivity as well as brain inflammatory reactions.

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“…The experimental procedure was previously described (5,8). These conditions provide reproducible I/R injury in brain of normal and transgenic mice.…”

Section: Focal Cerebral Ischemiamentioning

confidence: 99%

Section: Inhibition Of Neutrophil Migration In Brain Infarcts By Gp Omentioning

confidence: 99%

Section: Induced Cytotoxicity In Primary Neurons In Vitromentioning

confidence: 99%

mentioning

confidence: 99%

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Inflammatory Response and Glutathione Peroxidase in a Model of Stroke

Ishibashi

Prokopenko

Reuhl

et al. 2002

The Journal of Immunology

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“…It is generally agreed that ischemic insult facilitates an excessive generation of hydroxyl radicals and, therefore, GPxs have an important role in the defense against H 2 O 2 -induced damage. [30][31][32][33] Interestingly, experimental data also suggest that an increased production of H 2 O 2 can represent a critical component of the neuroprotective processes that occur during or after ischemic stroke. In particular, the animal study 7 in which pharmacological inhibition of GPx activity significantly reduced brain infarct damage suggested that under reduced oxygen supply, H 2 O 2 may exert either physiological or protective roles in the brain through its metabolic degradation to oxygen by catalase compensating for the lack of oxygen that occurs in the tissue after an ischemic event.…”

Section: Biological Role and Functional Studies Of The Gpx4 Genementioning

confidence: 99%

The C718T polymorphism in the 3′-untranslated region of glutathione peroxidase-4 gene is a predictor of cerebral stroke in patients with essential hypertension

et al. 2011

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In the present study we have investigated the association of three single nucleotide polymorphisms in glutathione peroxidase (GPx) genes GPX1 rs1050450 (P198L), GPX3 rs2070593 (G930A) and GPX4 rs713041 (T718C) with the risk of cerebral stroke (CS) in patients with essential hypertension (EH). A total of 667 unrelated EH patients of Russian origin, including 306 hypertensives (the EH-CS group) who suffered from CS and 361 people (the EH-CS group) who did not have cerebrovascular accidents, were enrolled in the study. The variant allele 718C of the GPX4 gene was found to be significantly associated with an increased risk of CS in hypertensive patients (odds ratio (OR) 1.53, 95% confidence interval (CI) 1.23-1.90, P adj ¼0.0003). The prevalence of the 718TC and 718CC genotypes of the GPX4 gene was higher in the EH-CS group than the EH-alone group (OR¼2.12, 95%CI 1.42-3.16, P adj ¼0.0018). The association of the variant GPX4 genotypes with the increased risk of CS in hypertensives remained statistically significant after adjusting for confounding variables such as sex, body mass index (BMI), blood pressure and antihypertensive medication use (OR¼2.18, 95%CI 1.46-3.27, P¼0.0015). Multiple logistic regression analysis did not reveal any interaction between various combinations of GPX1, GPX3 and GPX4 genotypes regarding the risk of CS in patients with EH. The study demonstrated for the first time that the C718T polymorphism in the 3¢-untranslated region of the GPX4 gene could be considered as a genetic marker of susceptibility to CS in patients with EH.

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Evaluation of neuroprotective activity of digoxin and semisynthetic derivatives against partial chemical ischemia

Gonçalves

Valadares

Alves

et al. 2019

J of Cellular Biochemistry

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Recently, cardiotonic steroids (CTS) have been shown to lead to the activation of Na,K‐ATPase at low concentrations in brain, promoting neuroprotection against ischemia. We report here the results of the use of digoxin and its semisynthetic derivatives BD‐14, BD‐15, and BD‐16 against partial chemical ischemic induction followed by reperfusion in murine neuroblastoma cells neuro‐2a (N2a). For chemical ischemic induction, sodium azide (5 mM) was used for 5 hours, and then reperfusion was induced for 24 hours. Na,K‐ATPase activity and protein levels were analyzed in membrane preparation of N2a cells pretreated with the compounds (150 nM), in the controls and in induced chemical ischemia. In the Na,K‐ATPase activity and protein levels assays, the steroids digoxin and BD‐15 demonstrated a capacity to modulate the activity of the enzyme directly, increasing its levels of expression and activity. Oxidative parameters, such as superoxide dismutase (SOD) activity, lipid peroxidation (thiobarbituric acid reactive substance), glutathione peroxidase (GPx), glutathione (GSH) levels, hydrogen peroxide content, and the amount of free radicals (reactive oxygen species) during induced chemical ischemia were also evaluated. Regarding the redox state, lipid peroxidation, hydrogen peroxide content, and GPx activity, we have observed an increase in the chemical ischemic group, and a reduction in the groups treated with CTS. SOD activity increased in all treated groups when compared to control and GSH levels decreased when treated with sodium azide and did not change with CTS treatments. Regarding the lipid profile, we saw a decrease in the content of phospholipids and cholesterol in the chemical ischemic group, and an increase in the groups treated with CTS. In conclusion, the compounds used in this study demonstrate promising results, since they appear to promote neuroprotection in cells exposed to chemical ischemia.

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Overexpression of human glutathione peroxidase protects transgenic mice against focal cerebral ischemia/reperfusion damage

Cited by 173 publications

References 26 publications

Inflammatory Response and Glutathione Peroxidase in a Model of Stroke

Inflammatory Response and Glutathione Peroxidase in a Model of Stroke

The C718T polymorphism in the 3′-untranslated region of glutathione peroxidase-4 gene is a predictor of cerebral stroke in patients with essential hypertension

Evaluation of neuroprotective activity of digoxin and semisynthetic derivatives against partial chemical ischemia

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