Antioxidant Status Alters Levels of Fas-Associated Death Domain-Like IL-1B-Converting Enzyme Inhibitory Protein following Neonatal Hypoxia-Ischemia

Payton, Kurlen S.E.; Sheldon, R. A.; Mack, Devin W.; Zhu, Changlian; Blomgren, Klas; Ferriero, Donna M.; Northington, Frances J.

doi:10.1159/000105481

Cited by 14 publications

(7 citation statements)

References 80 publications

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“…After hypoxic ischemic injury, there is some up-regulation of Fas and FLIP in all regions30. The importance of reactive oxygen species in Fas death receptor signaling has been verified in studies showing enhanced antioxidant status protects against Fas death receptor mediated cell death32.…”

Section: Discussionmentioning

confidence: 93%

Glutathione peroxidase activity modulates recovery in the injured immature brain

Tsuru-Aoyagi

Potts

Trivedi

et al. 2009

Annals of Neurology

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Objective Mice subjected to traumatic brain injury (TBI) at postnatal day (pnd) 21 show emerging cognitive deficits that coincide with hippocampal neuronal loss. Here we consider glutathione peroxidase (GPx) activity as a determinant of recovery in the injured immature brain. Methods Wildtype (WT) and transgenic (GPxTg) mice overexpressing GPx were subjected to TBI or sham surgery at pnd 21. Animals were euthanized acutely (3 or 24 hours postinjury) to assess oxidative stress and cell injury in the hippocampus or 4 months postinjury following behavioral assessments. Results In the acutely injured brains, a reduction in oxidative stress markers including nitrotyrosine was seen in the injured GPxTg group relative to WT controls. In contrast, cell injury, with marked vulnerability in the dentate gyrus, was apparent despite no differences between genotypes. Magnetic resonance imaging demonstrated an emerging cortical lesion during brain maturation that was also indistinguishable between injured genotypes. Stereologic analyses of cortical volumes likewise confirmed no genotypic differences between injured groups. However, behavioral tests beginning 3 months after injury demonstrated improved spatial memory learning in the GPxTg group. Moreover, Stereologic analysis within hippocampal subregions revealed a significantly greater number of neurons within the dentate of the GPx group. Interpretation Our results implicate GPx in recovery of spatial memory after TBI. This recovery may be in part attributed to a reduction in early oxidative stress and selective, long-term sparing of neurons in the dentate.

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Section: Discussionmentioning

confidence: 93%

Glutathione peroxidase activity modulates recovery in the injured immature brain

Tsuru-Aoyagi

Potts

Trivedi

et al. 2009

Annals of Neurology

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“…After hypoxic‐ischemic injury, there is some upregulation of Fas and Fas‐associated death‐domain–like interleukin‐1β converting enzyme inhibitory protein in all regions 30. The importance of reactive oxygen species in Fas death receptor signaling has been verified in studies showing enhanced antioxidant status protects against Fas death receptor–mediated cell death 32…”

Section: Discussionmentioning

confidence: 97%

The predictive value of apoptosis protease‐activating factor 1 in rectal tumors treated with preoperative, high‐dose‐rate brachytherapy

Zlobec

Vuong

Compton

2005

Cancer

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Objective Mice subjected to traumatic brain injury at postnatal day 21 show emerging cognitive deficits that coincide with hippocampal neuronal loss. Here we consider glutathione peroxidase (GPx) activity as a determinant of recovery in the injured immature brain. Methods Wild‐type and transgenic (GPxTg) mice overexpressing GPx were subjected to traumatic brain injury or sham surgery at postnatal day 21. Animals were killed acutely (3 or 24 hours after injury) to assess oxidative stress and cell injury in the hippocampus or 4 months after injury after behavioral assessments. Results In the acutely injured brains, a reduction in oxidative stress markers including nitrotyrosine was seen in the injured GPxTg group relative to wild‐type control mice. In contrast, cell injury, with marked vulnerability in the dentate gyrus, was apparent despite no differences between genotypes. Magnetic resonance imaging demonstrated an emerging cortical lesion during brain maturation that was also indistinguishable between injured genotypes. Stereological analyses of cortical volumes likewise confirmed no genotypic differences between injured groups. However, behavioral tests beginning 3 months after injury demonstrated improved spatial memory learning in the GPxTg group. Moreover, stereological analysis within hippocampal subregions demonstrated a significantly greater number of neurons within the dentate of the GPx group. Interpretation Our results implicate GPx in recovery of spatial memory after traumatic brain injury. This recovery may be attributed, in part, to a reduction in early oxidative stress and selective, long‐term sparing of neurons in the dentate. Ann Neurol 2009;65:540–549

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“…Consequently, it has recently been shown in hGPx-tg mice after HI compared with Wt that the overall degree of injury seen correlates well with changes in expression of Fas death receptor signaling proteins favoring neuroprotection, i.e. increased FLIP expression (36). Thus, the mechanism by which antioxidant status alters FLIP levels after neonatal HI may be related to the relative abilities of the hGPx-tg mice compared with their Wt littermates to detoxify H 2 O 2 produced after neonatal HI.…”

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confidence: 99%

Hypoxic Preconditioning Reverses Protection After Neonatal Hypoxia-Ischemia in Glutathione Peroxidase Transgenic Murine Brain

et al. 2007

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ABSTRACT:The effect of hypoxic preconditioning (PC) on hypoxic-ischemic (HI) injury was explored in glutathione peroxidase (GPx)-overexpressing mice (human GPx-transgenic [hGPx-tg]) mice. Six-day-old hGPx-tg mice and wild-type (Wt) littermates were preconditioned with hypoxia for 30 min and subjected to the Vannucci procedure of HI 24 h after the PC stimulus. Histopathological injury was determined 5 d later (P12). Additional animals were killed 2 h or 24 h after HI and ipsilateral cerebral cortices assayed for GPx activity, glutathione (GSH), and hydrogen peroxide (H 2 O 2 ). In line with previous studies, hypoxic PC reduced injury in the Wt brain. Preconditioned Wt brain had increased GPx activity, but reduced GSH, relative to naive 24 h after HI. Hypoxic PC did not reduce injury to hGPx-tg brain and even reversed the protection previously reported in the hGPx-tg. GPx activity and GSH in hGPx-tg cortices did not change. Without PC, hGPx-tg cortex had less H 2 O 2 accumulation than Wt at both 2 h and 24 h. With PC, H 2 O 2 remained low in hGPx-tg compared with Wt at 2 h, but at 24 h, there was no longer a difference between hGPx-tg and Wt cortices. T he developing brain is particularly susceptible to oxidative stress, more so than the mature brain (1). One reason for this susceptibility may be the different developmental profiles of antioxidant enzymes in the newborn brain compared with the mature brain. For example, total GPx activity increases sharply between E18 and P1, declines in the early postnatal period, then stabilizes through P21 (2). GSH levels also increase between E18 and P1, but remain lower than P21 (2). One consequence of this difference is that the developing brain accumulates H 2 O 2 after HI, whereas the mature brain does not (3). H 2 O 2 accumulation has also been associated with increased injury in superoxide dismutase-overexpressing neonatal murine brain (4), and greater cell death is seen when immature neurons are exposed to H 2 O 2 compared with mature neurons (5). Increased H 2 O 2 accumulation may be the result of relative insufficiency of the endogenous enzyme GPx. Under physiologic circumstances, the brain has efficient antioxidant defense mechanisms, including GPx, which converts potentially harmful H 2 O 2 to oxygen and water at the expense of reduced GSH. Under oxidative stress, in the immature brain, endogenous levels of GPx may be inadequate for converting excess H 2 O 2 . Transgenic mice that overexpress GPx (hGPx-tg), when subjected to HI have less histologic brain injury than their Wt littermates (6). In addition, the cortex exhibits increased GPx enzyme activity at 24 h, whereas GPx activity remains unaltered in the Wt brain. In addition, neurons cultured from GPx-tg brain are resistant to injury from exogenously applied H 2 O 2 (7). Neurons cultured from hippocampus and cortex that are transfected with genes for catalase and GPx also show protection from neurotoxic insults and a corresponding decrease in H 2 O 2 accumulation (8). These findings indicate that adequate GPx ac...

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Antioxidant Status Alters Levels of Fas-Associated Death Domain-Like IL-1B-Converting Enzyme Inhibitory Protein following Neonatal Hypoxia-Ischemia

Cited by 14 publications

References 80 publications

Glutathione peroxidase activity modulates recovery in the injured immature brain

Glutathione peroxidase activity modulates recovery in the injured immature brain

The predictive value of apoptosis protease‐activating factor 1 in rectal tumors treated with preoperative, high‐dose‐rate brachytherapy

Hypoxic Preconditioning Reverses Protection After Neonatal Hypoxia-Ischemia in Glutathione Peroxidase Transgenic Murine Brain

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