8-epi-prostaglandin-f2alpha and Brain-Injuries

Sudden cardiac arrest is a leading cause of death worldwide. Three-fourths of cardiac arrest patients die before hospital discharge or experience significant neurological damage. Hydrogen-rich saline, a portable, easily administered, and safe means of delivering hydrogen gas, can exert organ-protective effects through regulating oxidative stress, inflammation, and apoptosis. We designed this study to investigate whether hydrogen-rich saline treatment could improve survival and neurological outcome after cardiac arrest and cardiopulmonary resuscitation, and the mechanism responsible for this effect.. Sprague-Dawley rats were subjected to 8 minutes of cardiac arrest by asphyxia. Different doses of hydrogen-rich saline or normal saline were administered IV at 1 minute before cardiopulmonary resuscitation, followed by injections at 6 and 12 hours after restoration of spontaneous circulation, respectively. We assessed survival, neurological outcome, oxidative stress, inflammation biomarkers, and apoptosis.. Hydrogen-rich saline treatment dose dependently improved survival and neurological function after cardiac arrest/resuscitation. Moreover, hydrogen-rich saline treatment dose dependently ameliorated brain injury after cardiac arrest/resuscitation, which was characterized by the increase of survival neurons in hippocampus CA1, reduction of brain edema in cortex and hippocampus, preservation of blood-brain barrier integrity, as well as the decrease of serum S100β and neuron-specific enolase. Furthermore, we found that the beneficial effects of hydrogen-rich saline treatment were associated with decreased levels of oxidative products (8-iso-prostaglandin F2α and malondialdehyde) and inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, and high-mobility group box protein 1), as well as the increased activity of antioxidant enzymes (superoxide dismutase and catalase) in serum and brain tissues. In addition, hydrogen-rich saline treatment reduced caspase-3 activity in cortex and hippocampus after cardiac arrest/resuscitation.. Hydrogen-rich saline treatment improved survival and neurological outcome after cardiac arrest/resuscitation in rats, which was partially mediated by reducing oxidative stress, inflammation, and apoptosis.

Topics: Administration, Intravenous; Animals; Antioxidants; Apoptosis; Biomarkers; Blood-Brain Barrier; Brain; Brain Injuries; Cardiopulmonary Resuscitation; Caspase 3; Cytokines; Dinoprost; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Fluid Therapy; Heart Arrest; Hydrogen; Inflammation Mediators; Male; Malondialdehyde; Neurons; Neuroprotective Agents; Oxidative Stress; Phosphopyruvate Hydratase; Rats; Rats, Sprague-Dawley; S100 Calcium Binding Protein beta Subunit; Sodium Chloride; Time Factors

8-Iso-Prostaglandin F2α (8-iso-PGF2α) is considered as a gold standard for measuring oxidative stress in vivo. The present study was undertaken to investigate plasma 8-iso-PGF2α concentrations in severe human traumatic brain injury (TBI) and to analyze its correlation with disease outcome.. One hundred six healthy subjects and 106 severe TBI patients were recruited. The correlations of plasma 8-iso-PGF2α concentration with 1-year mortality and unfavorable outcome (Glasgow Outcome Scale score of 1-3) were analyzed.. Thirty-one patients (29.2%) died and 48 patients (45.3%) had an unfavorable outcome at 1 year after TBI. Patients had significantly higher plasma 8-iso-PGF2α levels compared to healthy controls (572.1±157.5 pg/ml vs. 84.3±18.9 pg/ml, P<0.001). A multivariate analysis selected plasma 8-iso-PGF2α level as an independent predictor for 1-year unfavorable outcome [odds ratio (OR) 1.401, 95% confidence interval (CI) 1.107-2.371, P=0.005] and mortality (OR 1.609, 95% CI 1.113-3.142, P=0.003). A receiver operating characteristic curve analysis showed plasma 8-iso-PGF2α level predicted 1-year unfavorable outcome [area under curve (AUC), 0.871; 95% CI, 0.792-0.928] and mortality (AUC, 0.881; 95% CI, 0.804-0.936) as statistically significantly. The prognostic value of 8-iso-PGF2α was similar to that of Glasgow Coma Scale score for 1-year clinical outcomes (both P>0.05). However, 8-iso-PGF2α did not improve the prognostic value of Glasgow Coma Scale score for 1-year clinical outcomes (both P>0.05).. Plasma 8-iso-PGF2α level is highly associated with 1-year clinical outcomes of TBI.

Topics: Adolescent; Adult; Aged; Area Under Curve; Brain Injuries; Case-Control Studies; Dinoprost; Female; Glasgow Coma Scale; Glasgow Outcome Scale; Humans; Male; Middle Aged; Multivariate Analysis; Prognosis; ROC Curve; Survival Analysis

Oxidative stress is a major contributor to the secondary injury process after experimental traumatic brain injury (TBI). The importance of oxidative stress in the pathobiology of human TBI is largely unknown. The F(2)-isoprostane 8-iso-prostaglandin F(2α) (8-iso-PGF(2α)), synthesized in vivo through non-enzymatic free radical catalyzed peroxidation of arachidonic acid, is a widely used biomarker of oxidative stress in multiple disease states, including TBI and cerebral ischemia/reperfusion. Our hypothesis is that harvesting of biomarkers directly in the injured brain by cerebral microdialysis (MD) is advantageous because of its high spatial and temporal resolution compared to blood or cerebrospinal fluid sampling. The aim of this study was to test the feasibility of measuring 8-iso-PGF(2α) in MD, ventricular cerebrospinal fluid (vCSF), and plasma samples collected from patients with severe TBI, and to compare the MD signals with MD-glycerol, implicated as a biomarker of oxidative stress, as well as MD-glutamate, a biomarker of excitotoxicity. Six patients (4 men, 2 women) were included in the study, three of whom had a focal/mixed TBI, and three a diffuse axonal injury (DAI). Following the bedside analysis of routine MD biomarkers (glucose, lactate:pyruvate ratio, glycerol, and glutamate), two 12-h MD samples per day were used to analyze 8-iso-PGF(2α) from 24 h up to 8 days post-injury. The interstitial levels of 8-iso-PGF(2α) were markedly higher than the levels obtained from plasma and vCSF (p<0.05), supporting our hypothesis. The MD-8-iso-PGF(2α) levels correlated strongly (p<0.05) with MD-glycerol and MD-glutamate, which are widely used biomarkers of membrane phospholipid degradation/oxidative stress and excitotoxicity, respectively. This study demonstrates the feasibility of analyzing 8-iso-PGF(2α) in MD samples from the human brain. Our results support a close relationship between oxidative stress and excitotoxicity following human TBI. MD-8-iso-PGF(2α) in combination with MD-glycerol may be useful biomarkers of oxidative stress in the neurointensive care setting.

Topics: Adolescent; Adult; Aged; Biomarkers; Brain Injuries; Cerebral Cortex; Dinoprost; Female; Humans; Male; Microdialysis; Middle Aged; Oxidative Stress; Young Adult

Recovery of neurological function in patients following cardiac arrest and cardiopulmonary resuscitation (CPR) is a complex event. Free radical induced oxidative stress is supposed to be involved in this process. We studied levels of 8-iso-PGF2alpha (indicating oxidative injury) and 15-keto-dihydro-PGF2alpha (indicating inflammatory response) in venous plasma obtained from the jugular bulb in a porcine model of experimental cardiopulmonary resuscitation (CPR) where 2, 5, 8, 10 or 12 min of ventricular fibrillation (VF) was followed by 5 or 8 min of closed-chest CPR. A significant increase of 8-iso-PGF2alpha was observed immediately following restoration of spontaneous circulation in all experiments of various duration of VF and CPR. No such increase was seen in a control group. When compared between the groups there was a duration-dependent maximum increase of 8-iso-PGF2alpha which was greatest in animals subjected to the longest period (VF12 min + CPR8 min) of no or low blood flow. In contrast, the greatest increase of 15-keto-dihydro-PGF2alpha was observed in the 13 min group (VF8 min + CPR5 min). Thus, a time-dependent cerebral oxidative injury occurs in conjunction which cardiac arrest and CPR.

Topics: Animals; Brain; Brain Injuries; Cardiopulmonary Resuscitation; Dinoprost; Eicosanoids; F2-Isoprostanes; Female; Free Radicals; Heart Arrest; Inflammation; Male; Oxidative Stress; Radioimmunoassay; Swine; Time Factors; Ventricular Fibrillation

Previous studies have shown that oxygen radical scavengers prevent the reduced cerebral blood flow that occurs following experimental traumatic brain injury. The exact chemical species responsible for the posttraumatic reduction in flow is unknown. We tested whether isoprostanes, which are formed by non-cyclooxygenase-dependent free radical attack of arachidonic acid and are vasoconstrictors of the cerebral circulation, are increased in astrocytes following stretch-induced trauma or injury with a free radical generating system. Isoprostane (8-epi-prostaglandin F2alpha) was analyzed in cells and in media by immunoassay. Confluent rat cortical astrocytes in culture were injured by a hydroxyl radical generating system consisting of hydrogen peroxide and ferrous sulfate or by rapid stretch of astrocytes grown on a deformable silastic membrane. Some cells were treated with the iron chelator deferoxamine for 1 h before injury. The hydroxyl generating system caused free and cell-bound isoprostanes to increase to more than 400% of control. After trauma, free and membrane bound isoprostanes increased to 321 +/- 34% and 229 +/- 23% of control, respectively, and posttraumatic increases were prevented by deferoxamine. Since astrocytes are in close proximity to cerebral vessels, posttraumatic free radical formation may increase the formation of isoprostanes, which in turn produce vasoconstriction and decrease cerebral blood flow.

Topics: Animals; Astrocytes; Brain; Brain Injuries; Cells, Cultured; Cerebral Arteries; Cerebrovascular Circulation; Chelating Agents; Deferoxamine; Dinoprost; F2-Isoprostanes; Rats; Reactive Oxygen Species; Vasoconstriction

Oxidative stress may contribute to many pathophysiologic changes that occur after traumatic brain injury. In the current study, contemporary methods of detecting oxidative stress were used in a rodent model of traumatic brain injury. The level of the stable product derived from peroxidation of arachidonyl residues in phospholipids, 8-epi-prostaglandin F(2alpha), was increased at 6 and 24 h after traumatic brain injury. Furthermore, relative amounts of fluorescent end products of lipid peroxidation in brain extracts were increased at 6 and 24 h after trauma compared with sham-operated controls. The total antioxidant reserves of brain homogenates and water-soluble antioxidant reserves as well as tissue concentrations of ascorbate, GSH, and protein sulfhydryls were reduced after traumatic brain injury. A selective inhibitor of cyclooxygenase-2, SC 58125, prevented depletion of ascorbate and thiols, the two major water-soluble antioxidants in traumatized brain. Electron paramagnetic resonance (EPR) spectroscopy of rat cortex homogenates failed to detect any radical adducts with a spin trap, 5,5-dimethyl-1-pyrroline N:-oxide, but did detect ascorbate radical signals. The ascorbate radical EPR signals increased in brain homogenates derived from traumatized brain samples compared with sham-operated controls. These results along with detailed model experiments in vitro indicate that ascorbate is a major antioxidant in brain and that the EPR assay of ascorbate radicals may be used to monitor production of free radicals in brain tissue after traumatic brain injury.

Topics: Animals; Antioxidants; Ascorbic Acid; Biomarkers; Brain Chemistry; Brain Injuries; Cerebral Cortex; Chromatography, High Pressure Liquid; Cyclooxygenase 2; Dinoprost; Disease Models, Animal; Electron Spin Resonance Spectroscopy; F2-Isoprostanes; Free Radicals; Hippocampus; Isoenzymes; Male; Oxidation-Reduction; Oxidative Stress; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Sprague-Dawley; Wounds, Nonpenetrating

The gonadal hormone, progesterone, has been shown to have neuroprotective effects in injured nervous system, including the severity of postinjury cerebral edema. Progesterone's attenuation of edema is accompanied by a sparing of neurons from secondary neuronal death and with improvements in cognitive outcome. In addition, we recently reported that postinjury blood-brain barrier (BBB) leakage, as measured by albumin immunostaining, was significantly lower in progesterone treated than in nontreated rats, supporting a possible protective action of progesterone on the BBB. Because lipid membrane peroxidation is a major contributor to BBB breakdown, we hypothesized that progesterone limits this free radical-induced damage. An antioxidant action, neuroprotective in itself, would also account for progesterone's effects on the BBB, edema, and cell survival after traumatic brain injury. To test progesterone's possible antiperoxidation effect, we compared brain levels of 8-isoprostaglandin F2 alpha (8-isoPGF2 alpha), a marker of lipid peroxidation, 24, 48, and 72 h after cortical contusion in male rats treated with either progesterone or the oil vehicle. The brains of progesterone treated rats contained approximately one-third of the 8-isoPGF2 alpha found in oil-treated rats. These data suggest progesterone has antioxidant effects and support its potential as a treatment for brain injury.

Topics: Animals; Brain; Brain Injuries; Dinoprost; F2-Isoprostanes; Immunoenzyme Techniques; Lipid Peroxidation; Male; Oxidation-Reduction; Progesterone; Rats; Rats, Sprague-Dawley