Superoxide and nitric oxide cooperation in hypoxia/ reoxygenation-induced neuron injury

Cazevielle, Chantal; Müller, Agnès; Meynier, Françoise; Bonne, C.

doi:10.1016/0891-5849(93)90088-c

Cited by 209 publications

(79 citation statements)

References 31 publications

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“…The number of NMDA receptors in the mature NT2-N neurons is 1 ⁄10 that found in rat brains, but approximately at the same level as that found in fetal human neurons (25). Furthermore, human fetal neurons have a larger capacity of intracellular calciumbuffering systems than cortical rat neurons (35). There are also species differences with respect to the free radical-producing enzyme xanthine oxidase, which is present in rat neurons (15)(16)(17) but absent in human brain (18).…”

Section: Discussionmentioning

confidence: 85%

Neuronal Formation of Free Radicals Plays a Minor Role in Hypoxic Cell Death in Human NT2-N Neurons

Almaas¹,

Saugstad²,

Pleasure

et al. 2002

Pediatr Res

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Free radicals are suggested to play an important role in hypoxic-ischemic neuronal death. However, the importance in human disease is not known. Furthermore, whether posthypoxic free radical formation mainly occurs in endothelium and neutrophils, or whether neuronal production is important, is not finally determined. To study this we differentiated human Ntera2 teratocarcinoma cells into postmitotic NT2-N neurons and exposed them to free radicals, hypoxia, or oxygen and glucose deprivation. These cells are devoid of nitric oxide synthase, and we hypothesized that free radicals are important mediators downstream of N-methyl-D-aspartate stimulation. Production of free radicals, evaluated with the fluorescent dyes dihydrorhodamine and 2',7'-dichlorodihydrofluorescein, was significantly higher in neurons deprived of oxygen and glucose after 40 min of reoxygenation than in normoxic cells. The antioxidant trolox, the flavonoid quercetin, thiopental, and the N-methyl-D-aspartateglutamate receptor antagonist MK-801 reduced the formation of free radicals. Treatment with the flavonoid rutin (86 Ϯ 16% of hypoxic cells without drug, p Ͻ 0.01), trolox (86 Ϯ 20%, p Ͻ 0.01), and MK-801 (57 Ϯ 12%, p Ͻ 0.01) reduced lactate dehydrogenase release after 6 h of hypoxia. Trolox, salicylate, and quercetin also significantly reduced lactate dehydrogenase release after 3 h of oxygen and glucose deprivation. The protection offered by these antioxidants was, however, limited compared with the effect of MK-801. We conclude that oxygen and glucose deprivation causes a moderate increase in the formation of free radicals in NT2-N neurons that can be Several experiments have indicated a role for free radicals in the pathogenesis of hypoxic-ischemic cell death. The xanthine oxidase inhibitor and hydroxyl radical scavenger allopurinol reduces hypoxic-ischemic brain damage in rats (1), and van Bel et al. (2) demonstrated beneficial effects of allopurinol in asphyxiated infants. Infarct size and brain edema after focal cerebral ischemia are attenuated in adult transgenic mice overexpressing CuZn SOD (3). However, brain injury after hypoxia-ischemia was exacerbated in a similar newborn mice model (4).During reperfusion after cerebral ischemia in pigs, superoxide anion is generated (5). Production of free radicals after ischemia has been reported from rat brain microvessels (6) and from fetal bovine endothelial cells (7). A substantial part of posthypoxic free radical formation in endothelium has been attributed to xanthine oxidase (7). On the other hand, ScmidElsaesser et al. (8)

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Section: Discussionmentioning

confidence: 85%

Neuronal Formation of Free Radicals Plays a Minor Role in Hypoxic Cell Death in Human NT2-N Neurons

Almaas¹,

Saugstad²,

Pleasure

et al. 2002

Pediatr Res

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“…However, the ability of oxyhemoglobin to protect HA1 cells from saturated NO-containing medium demonstrates that the reactive nitrogen species involved in producing the cytotoxic response in this cell model originate from NO. NO has been reported to contribute to cytotoxic and cytoprotective reactions in a number of in vitro cell experiments (11)(12)(13)(14)(15)(16)(17)(18). Controversy about the role of endogenous or exogenous NO exists in a number of scenarios including ischemiareperfusion injury (18), neurotoxicity (15)(16)(17), and leukocytemediated and autoimmune diseases (3,27,28).…”

Section: Discussionmentioning

confidence: 99%

“…NO has been reported to contribute to cytotoxic and cytoprotective reactions in a number of in vitro cell experiments (11)(12)(13)(14)(15)(16)(17)(18). Controversy about the role of endogenous or exogenous NO exists in a number of scenarios including ischemiareperfusion injury (18), neurotoxicity (15)(16)(17), and leukocytemediated and autoimmune diseases (3,27,28). Two critical characteristics of NO that may account for the apparent conflicting reports in the literature include the observation that NO is known to exist in a number of oxidation states (29) and that NO is an extremely reactive free radical with a t,,, of 3-5 s in physiologic conditions (4).…”

Section: Discussionmentioning

confidence: 99%

“…investigators have reported that endogenously derived NO, or NO released from pharmacologic agents, can function in cytoprotective responses to injury initiated by ischemiareperfusion or other pathologic conditions (11)(12)(13)(14). Conversely, other investigators report that endogenously generated or exogenously administered NO may initiate or contribute to cytotoxic reactions seen in neural, cardiac, and endothelial tissue after similar experiments designed to evaluate the interactions of NO and ischemia-reperfusion (15)(16)(17)(18). Clearly, NO can have beneficial, as well as cytotoxic, properties depending on the system and initial conditions that are being studied.…”

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confidence: 99%

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Nitric Oxide-Induced Cytotoxicity: Involvement of Cellular Resistance to Oxidative Stress and the Role of Glutathione in Protection

et al. 1995

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A series of experiments were designed to examine the potential cytotoxicity of nitric oxide (NO), or reactive species derived from NO, in HA1 fibroblasts and H202-resistant variants of this cell line, designated OC14 cells. A 1-h exposure at 37OC to a 1.7 mM bolus dose of NO, prepared in N2-gassed medium, significantly reduced clonogenic survival in the HA1 fibroblasts line to 60% of control cells treated with N2-gassed medium alone. The OC14 cells were found to be completely resistant (100% survival) to NO-mediated injury in comparable experiments. A second set of experiments was designed to determine the role of the intracellular antioxidant, glutathione, in protection against NO-mediated injury. Depletion of total glutathione resulted in a significant reduction in HA1 and OC14 clonogenic survival to 8% and 50% when compared with respective control cells. The effect of total glutathione depletion on NO-initiated toxicity in HA1 cells was dose-and cell-density dependent and was observed to occur within 5 min of exposure to NO. Further evidence of cytotoxicity was demonstrated by loss of trypan blue dye exclusion properties in glutathione-depleted HA1 cells after NO is a free radical molecule endogenously produced by a variety of cell types. NO has been demonstrated to participate in physiologic reactions involving regulation of vasomotor tone, neurotransmission, immune system function, and platelet aggregation (1-4). Recent clinical trials have demonstrated some efficacy for inhaled NO in treatment of neonatal pulmonary hypertension and adult respiratory distress syndrome (5-7). Paradoxically, elevated concentrations of atmospheric NO are known to be harmful in many animal models, and lethal exposures at high concentrations have been reported in both animals and humans (8-10). This same paradoxical beneficial and/or toxic effect of NO has been observed in vitro. Several Received August 10, 1993; accepted July 8, 1994. Correspondence: Dr. M. Whit Walker, Department of Neonatology, Greenville Hospital Systems, 701 Grove Road, Greenville, SC 29605.Supported by National Institutes of Health Grants HL42057, HL08841, HL51469, CA.51116, HD28810, GM08260, and DK38924.NO exposure. Other experiments demonstrated that nitrate and nitrite exposure produced no cytotoxicity in glutathione-depleted HA1 cells and that coincubation of NO-saturated medium with oxyhemoglobin inhibited NO-induced cytotoxicity in glutathione-depleted HA1 cells. These results demonstrate that 1 ) nitric oxide, or an NO-derived reactive nitrogen species other than nitrites or nitrates, is responsible for reduction in clonogenic survival and trypan blue dye exclusion capabilities in vitro; 2) biochemical pathways associated with cellular resistance to oxidative stress also confer resistance to NO-mediated injury in this cell model; and 3) total glutathione content determines a significant portion of cell sensitivity to NO-mediated cytotoxicity.

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“…49 Moreover, the role of free radicals in NMDA receptor-mediated glutamate excitotoxicity is well established in various experimental conditions. 50,51 Thus, given that oxidative stress seems to be involved in mechanisms of excitotoxicity, 52,53 it is not unexpected that neuronal COX-2 activity may contribute to neurodegeneration via oxidative mechanisms 11 ; this COX-2 influence may not necessarily be closely linked to PG production. 54 Oxidative stress resulting from COX-2 activity may have important implications for neurodegenerative diseases such as AD, in which an elevated glutamatergic tone, also defined as disinhibition syndrome, may be responsible for a widespread pattern of neurodegeneration.…”

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confidence: 99%

Potentiation of Excitotoxicity in Transgenic Mice Overexpressing Neuronal Cyclooxygenase-2

Kelley

Winger

et al. 1999

The American Journal of Pathology

210

133

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In this study we describe the generation of a transgenic mouse model with neuronal overexpression of the human cyclooxygenase-2 , h(COX)-2 , to explore its role in excitotoxicity. We report that overexpression of neuronal hCOX-2 potentiates the intensity and lethality of kainic acid excitotoxicity in coincidence with potentiation of expression of the immediate early genes c-fos and zif-268. In vitro studies extended the in vivo findings and revealed that glutamate excitotoxicity is potentiated in primary cortico-hippocampal neurons derived from hCOX-2 transgenic mice , possibly through potentiation of mitochondrial impairment. This study is the first to demonstrate a cause-effect relationship between neuronal COX-2 expression and excitotoxicity. This model system will allow the systematic examination of the role of COX-2 in mechanisms of neurodegeneration that involve excitatory amino acid pathways. (Am J Pathol 1999, 155:995-1004) Cyclooxygenase (COX) is the rate-limiting enzyme in the production of prostaglandins and, as such, a key target for anti-inflammatory drugs. Indeed, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are COX inhibitors.

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Superoxide and nitric oxide cooperation in hypoxia/ reoxygenation-induced neuron injury

Cited by 209 publications

References 31 publications

Neuronal Formation of Free Radicals Plays a Minor Role in Hypoxic Cell Death in Human NT2-N Neurons

Neuronal Formation of Free Radicals Plays a Minor Role in Hypoxic Cell Death in Human NT2-N Neurons

Nitric Oxide-Induced Cytotoxicity: Involvement of Cellular Resistance to Oxidative Stress and the Role of Glutathione in Protection

Potentiation of Excitotoxicity in Transgenic Mice Overexpressing Neuronal Cyclooxygenase-2

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