Impairment of synaptic transmission by transient hypoxia in hippocampal slices: Improved recovery in glutathione peroxidase transgenic mice

Furling, Denis; Ghribi, Othman; Lahsaini, Ahmed; Mirault, Marc-Édouard; Massicotte, Guy

doi:10.1073/pnas.060574597

Cited by 45 publications

(20 citation statements)

References 37 publications

(40 reference statements)

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“…In the mature brain, studies with other strains of GPX1 overexpressing transgenic mice have found protection in different models of oxidative stress, such as adult focal cerebral ischemia/reperfusion (14,15,25,26) and transient hypoxia in hippocampal slices (27). This is the first study to report that GPX1 overexpression protects the neonatal brain after HI.…”

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confidence: 71%

Manipulation of Antioxidant Pathways in Neonatal Murine Brain

et al. 2004

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To assess the role of brain antioxidant capacity in the pathogenesis of neonatal hypoxic-ischemic brain injury, we measured the activity of glutathione peroxidase (GPX) in both humansuperoxide dismutase-1 (hSOD1) and human-GPX1 overexpressing transgenic (Tg) mice after neonatal hypoxia-ischemia (HI). We have previously shown that mice that overexpress the hSOD1 gene are more injured than their wild-type (WT) littermates after HI, and that H 2 O 2 accumulates in HI hSOD1-Tg hippocampus. We hypothesized that lower GPX activity is responsible for the accumulation of H 2 O 2 . Therefore, increasing the activity of this enzyme through gene manipulation should be protective. We show that brains of hGPX1-Tg mice, in contrast to those of hSOD-Tg, have less injury after HI than WT littermates: hGPX1-Tg, median injury score ϭ 8 (range, 0 -24) versus WT, median injury score ϭ 17 (range, 2-24), p Ͻ 0.01. GPX activity in hSOD1-Tg mice, 2 h and 24 h after HI, showed a delayed and bilateral decline in the cortex 24 h after HI (36.0 Ϯ 1.2 U/mg in naive hSOD1-Tg versus 29.1 Ϯ 1.7 U/mg in HI cortex and 29.2 Ϯ 2.0 for hypoxic cortex, p Ͻ 0.006). On the other hand, GPX activity in hGPX1-Tg after HI showed a significant increase by 24 h in the cortex ipsilateral to the injury (48.5 Ϯ 5.2 U/mg, compared with 37.2 Ϯ 1.5 U/mg in naive hGPX1-Tg cortex, p Ͻ 0.008). These findings support the hypothesis that the immature brain has limited GPX activity and is more susceptible to oxidative damage and may explain the paradoxical effect seen in ischemic neonatal brain when SOD1 is overexpressed. (Pediatr Res 56: 656-662, 2004) Abbreviations CCA, common carotid artery GPX, glutathione peroxidase GSH, glutathione HI, hypoxia-ischemia P, postnatal day red-ox, oxidation-reduction reaction ROS, reactive oxygen species SOD1, copper-zinc superoxide dismutase Tg, transgenic WT, wild-typeThe developing brain faces unique challenges from oxidative stress, and has responses to injury and protective mechanisms that are different from the mature nervous system. The developmental profile of the activity of the endogenous antioxidant enzymes SOD1 and selenium-dependent GPX have been described for both rats (1-3) and mice (4). In the mouse brain, GPX activity is almost exclusively due to the classic, cellular glutathione peroxidase GPX1 (EC 1.11.1.9) (5). In the CD1 mouse, the outbred background strain used in this study, SOD1 activity decreases around the time of birth, and then remains unchanged to weaning. GPX activity, on the other hand, rises steeply around birth but declines sharply in the first few days of life and then remains low through weaning. Protein levels for both enzymes, however, show a steady increase during early development (4). We have shown that, in the CD1 mouse brain, adult levels of GPX activity are reached by weaning (6). Therefore, maturational differences may impact the response of the newborn brain to injury. It has been shown that the adult and juvenile brain attempts to compensate during oxidative stress in response to stroke (...

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Manipulation of Antioxidant Pathways in Neonatal Murine Brain

et al. 2004

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“…Control slices subjected to hypoxia suffered an irreversible loss of EPSPs with an inability to generate LTP. GPx overexpression resulted in a significant recovery of synaptic transmission and LTP (141). In addition, GPx overexpression has been shown to be beneficial to TBI-induced cognitive deficits in the absence of any effect on the lesion anatomy and brain volume.…”

Section: Catalasementioning

confidence: 93%

Reactive Oxygen Species in the Regulation of Synaptic Plasticity and Memory

Massaad

Klann

2011

Antioxidants & Redox Signaling

469

350

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The brain is a metabolically active organ exhibiting high oxygen consumption and robust production of reactive oxygen species (ROS). The large amounts of ROS are kept in check by an elaborate network of antioxidants, which sometimes fail and lead to neuronal oxidative stress. Thus, ROS are typically categorized as neurotoxic molecules and typically exert their detrimental effects via oxidation of essential macromolecules such as enzymes and cytoskeletal proteins. Most importantly, excessive ROS are associated with decreased performance in cognitive function. However, at physiological concentrations, ROS are involved in functional changes necessary for synaptic plasticity and hence, for normal cognitive function. The fine line of role reversal of ROS from good molecules to bad molecules is far from being fully understood. This review focuses on identifying the multiple sources of ROS in the mammalian nervous system and on presenting evidence for the critical and essential role of ROS in synaptic plasticity and memory. The review also shows that the inability to restrain either age-or pathology-related increases in ROS levels leads to opposite, detrimental effects that are involved in impairments in synaptic plasticity and memory function.

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“…In both mature and neonatal brain, studies with GPx-1-overexpressing mice have shown significant neuroprotection against focal cerebral ischemia as well as hypoxia (Weisbrot-Lefkowitz et al, 1998;Furling et al, 2000;Ishibashi et al, 2002;Sheldon et al, 2004). Truelove et al (1994) also provided evidence that microinfusion of catalase reduces neuronal damage following repetitive ischemic insult.…”

Section: Discussionmentioning

confidence: 89%

Ischemic preconditioning in the rat hippocampus increases antioxidant activities but does not affect the level of hydroxyl radicals during subsequent severe ischemia

et al. 2007

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Several studies have demonstrated that ischemic preconditioning increases superoxide dismutase activity, but it is unclear how ischemic preconditioning affects events downstream of hydrogen peroxide production during subsequent severe ischemia and reperfusion in the hippocampus. To answer this question, we investigated whether ischemic preconditioning in the hippocampal CA1 region increases the activities of antioxidant enzymes glutathione peroxidase and catalase, resulting in a decrease in the level of hydroxyl radicals during subsequent severe ischemia-reperfusion. Transient forebrain ischemia was induced by four-vessel occlusion in rats. Ischemic preconditioning for 3 min or a sham operation was performed and a 15-min severe ischemia was induced three days later. Ischemic preconditioning preserved the CA1 hippocampal neurons following severe ischemia. The concentration of 2,3-dihydroxybenzoic acid, an indicator of hydroxyl radical, was measured using in vivo microdialysis technique combined with HPLC. The ischemia-induced increase in the ratio of 2,3-dihydroxybenzoic acid concentration relative to baseline did not differ significantly between preconditioned and control groups. On the other hand, activities of the antioxidant enzymes glutathione peroxidase-1 and catalase were significantly increased at 3 days after ischemic preconditioning in the hippocampus. Our results suggest that, in preconditioned rats, while hydrogen peroxide is generated from severe ischemia, the activity of catalase and glutathione peroxidase-1 is correspondingly increased to eliminate the excessive hydrogen peroxide. However, our results show that the enhanced activity of these antioxidant enzymes in preconditioned rats is not sufficient to decrease hydroxyl radical levels during subsequent severe ischemia-reperfusion.

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Impairment of synaptic transmission by transient hypoxia in hippocampal slices: Improved recovery in glutathione peroxidase transgenic mice

Cited by 45 publications

References 37 publications

Manipulation of Antioxidant Pathways in Neonatal Murine Brain

Manipulation of Antioxidant Pathways in Neonatal Murine Brain

Reactive Oxygen Species in the Regulation of Synaptic Plasticity and Memory

Ischemic preconditioning in the rat hippocampus increases antioxidant activities but does not affect the level of hydroxyl radicals during subsequent severe ischemia

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