Breathing 100% oxygen after global brain ischemia in Mongolian Gerbils results in increased lipid peroxidation and increased mortality.

Mickel, Hubert S.; Vaishnav, Y.N.; Kempski, Oliver; Lubitz, Dag Von; Weiss, Joseph F.; Feuerstein, Giora

doi:10.1161/01.str.18.2.426

Cited by 161 publications

(86 citation statements)

References 21 publications

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“…This practice has been questioned by results obtained with animal models demonstrating improved neurologic outcome using postischemic ventilation with O 2 concentrations as low as 21% [15,16,72]. Our present findings demonstrating reduced hippocampal protein tyrosine nitration and retention of PDHC enzyme activity with normoxic resuscitation support the need for additional preclinical and clinical studies to resolve this issue.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 69%

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

Richards

Rosenthal

Kristián

et al. 2006

Free Radical Biology and Medicine

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The pyruvate dehydrogenase complex (PDHC) is a mitochondrial matrix enzyme that catalyzes the oxidative decarboxylation of pyruvate and represents the sole bridge between anaerobic and aerobic cerebral energy metabolism. Previous studies demonstrating loss of PDHC enzyme activity and immunoreactivity during reperfusion after cerebral ischemia suggest that oxidative modifications are involved. This study tested the hypothesis that hyperoxic reperfusion exacerbates loss of PDHC enzyme activity, possibly due to tyrosine nitration or S-nitrosation. We used a clinically relevant canine ventricular fibrillation cardiac arrest model in which, after resuscitation and ventilation on either 100% O 2 (hyperoxic) or 21-30% O 2 (normoxic), animals were sacrificed at 2 h reperfusion and the brains removed for enzyme activity and immunoreactivity measurements. Animals resuscitated under hyperoxic conditions exhibited decreased PDHC activity and elevated 3-nitrotyrosine immunoreactivity in the hippocampus but not the cortex, compared to nonischemic controls. These measures were unchanged in normoxic animals. In vitro exposure of purified PDHC to peroxynitrite resulted in a dose-dependent loss of activity and increased nitrotyrosine immunoreactivity. These results support the hypothesis that oxidative stress contributes to loss of hippocampal PDHC activity during cerebral ischemia and reperfusion and suggest that PDHC is a target of peroxynitrite. KeywordsMitochondria; Hyperoxia; Nitrotyrosine; Normoxia; Oxidative stress; Global ischemia; Selective vulnerability; Free radicals Global cerebral ischemia and reperfusion cause severe neurochemical alterations, including oxidative modifications to lipids, proteins, and DNA. These and other covalent modifications can impair enzyme activities, including those necessary for energy metabolism. Alterations in these enzyme activities can limit postischemic aerobic metabolism and cellular ATP regeneration, thereby contributing to the pathophysiology of delayed neuronal cell death [1][2][3][4]. One enzyme known to be targeted and inactivated by reactive oxygen species is the pyruvate dehydrogenase complex (PDHC) [5]. Effects of ischemia/reperfusion on the PDHC can be particularly devastating because this enzyme forms the bridge between glycolysis and the Krebs cycle and can be the rate-limiting step in aerobic cerebral energy metabolism. NIH Public Access Author ManuscriptFree Radic Biol Med. Author manuscript; available in PMC 2008 October 21. Published in final edited form as:Free Radic Biol Med. 2006 June 1; 40(11): 1960-1970. doi:10.1016/j.freeradbiomed.2006.01.022. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe PDHC is located exclusively in the mitochondrial matrix and catalyzes the oxidative decarboxylation of pyruvate to form NADH and acetyl coenzyme A-the primary form of carbon that enters the Krebs cycle in the adult brain. Several laboratories have shown that PDHC enzyme activity is lost during cerebral ischemia/reperfusion [6][7][8]. PDHC im...

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Section: Nih-pa Author Manuscriptmentioning

confidence: 69%

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

Richards

Rosenthal

Kristián

et al. 2006

Free Radical Biology and Medicine

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“…Several studies have demonstrated that when animals are hyperoxic during reperfusion following global cerebral ischemia, brain tissue oxidative stress markers, impaired cerebral energy metabolism, neuronal death, and neurologic impairment are greater than what is observed following normoxic reperfusion (Balan et al, 2006;Liu et al, 1998;Mickel et al, 1987;Richards et al, 2006;Vereczki et al, 2006). These findings have led to the concept that brain tissue oxygenation in excess of what is necessary to saturate metabolic O 2 utilization is toxic during early reperfusion, when altered intracellular conditions, e.g., pH, [Ca 2+ ], etc., may either promote the formation of reactive oxygen species (ROS) or inhibit their detoxification (Rosenthal and Fiskum, 2005).…”

Section: Introductionmentioning

confidence: 99%

Hyperoxia promotes astrocyte cell death after oxygen and glucose deprivation

Danilov

Fiskum

2008

Glia

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Astrocyte dysfunction and death accompany cerebral ischemia/reperfusion and possibly compromise neuronal survival. Animal studies indicate that neuronal death, neurologic injury, and oxidative molecular modifications are worse in animals exposed to hyperoxic compared to normoxic ventilation during reperfusion after global cerebral ischemia. It is unknown, however, whether ambient O 2 affects brain cell survival using in vitro ischemia paradigms where mechanisms of injury to specific cell types can be more thoroughly investigated. This study tested the hypothesis that compared with the supraphysiological level of 20% O 2 normally used in cell culture, lower, more physiological O 2 levels protect astrocytes from death following oxygen and glucose deprivation. Primary rat cortical astrocytes were cultured under either 7 or 20% O 2 , exposed to O 2 , and glucose deprivation for 4 h, and then exposed to normal medium under either 7 or 20% O 2 . Cell death and 3-nitrotyrosine and 8-hydroxy-2-deoxyguanosine immunoreactivities were assessed at different periods of reoxygenation. Astrocytes exposed to low levels of O 2 during reoxygenation undergo less death and exhibit lower levels of protein nitration and nucleic acid oxidation when compared with those under high levels of O 2 during reoxygenation. These results support the hypothesis that the 20% O 2 normally used in cell culture exacerbates astrocyte death and oxidative stress in an in vitro ischemia/reperfusion model compared to levels that more closely approximate those that exist in vivo.

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“…18) Also, breathing 100% oxygen after 15 minutes of global brain ischemia not followed by reperfusion increased lipid peroxidation and mortality in gerbils. 11) On the other hand, HBO did not increase brain lipid peroxidation if administered to rats after 10 minutes of focal brain ischemia not followed by reperfusion, 24) and HBO increased free radicals but not lipid peroxidation if started within 1 minute of reperfusion following cerebral ischemia in a rabbit model. 12) Therefore, we suspect that HBO probably increases free radicals and lipid peroxidation, particularly in patients with embolic stroke in whom recanalization commonly occurs at various times.…”

Section: Discussionmentioning

confidence: 92%

“…With the exception of three studies, 3,15,20) the major criticism of most clinical investigations has been the lack of controlled prospective analysis. 14) Oxygen free radicals, which may be produced by HBO therapy 6) or by breathing 100% oxygen, 11) are likely to be important in the mechanism of damage caused by cerebral ischemia. 22) Edaravone, a novel free radical scavenger, is reported to be effective in the treatment of patients with acute ischemic stroke.…”

Section: Introductionmentioning

confidence: 99%

Hyperbaric Oxygen Combined With Intravenous Edaravone for Treatment of Acute Embolic Stroke: a Pilot Clinical Trial

Imai

Mori

Izumoto

et al. 2006

Neurol. Med. Chir.(Tokyo)

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The efficacy of hyperbaric oxygen (HBO) therapy combined with intravenous edaravone (free radical scavenger) administration was prospectively investigated in patients with acute embolic stroke involving the anterior cerebral circulation. Patients with acute embolic stroke in the anterior cerebral circulation admitted within 48 hours of onset from August 2001 to March 2002 with National Institutes of Health Stroke Scale (NIHSS) scores on admission of 5 or more were assigned randomly to HBO and control groups. The HBO group underwent HBO therapy combined with intravenous edaravone administration for 7 days, whereas the control group received only conventional treatment. The primary endpoint was the modified Rankin Scale score at 90 days (favorable outcome, score 0 or 1). The secondary endpoint was the NIHSS score at 7 days. Analysis was carried out by intention to treat. Six of the 19 patients in the HBO group, but only one of the 19 patients in the control group, had favorable outcomes at 90 days (p º 0.05), although NIHSS score at 7 days did not differ significantly between the two groups. HBO therapy combined with intravenous edaravone administration appears to be effective for the treatment of patients with acute embolic stroke in the anterior cerebral circulation.

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Breathing 100% oxygen after global brain ischemia in Mongolian Gerbils results in increased lipid peroxidation and increased mortality.

Cited by 161 publications

References 21 publications

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

Postischemic hyperoxia reduces hippocampal pyruvate dehydrogenase activity

Hyperoxia promotes astrocyte cell death after oxygen and glucose deprivation

Hyperbaric Oxygen Combined With Intravenous Edaravone for Treatment of Acute Embolic Stroke: a Pilot Clinical Trial

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