Cerebral Oxidative Injury Research Articles

Effect of controlled blood pressure increase on cerebral blood flow velocity and oxygenation in patients with subarachnoid haemorrhage.

Patients with aneurysmal subarachnoid haemorrhage (SAH) might have impaired cerebral autoregulation, that is, CBF - and thereby oxygen delivery - passively increase with an increase in CPP. This physiological study aimed to investigate the cerebral haemodynamic effects of controlled blood pressure increase in the early phase after SAH before any signs of delayed cerebral ischaemia (DCI) occurred. The study was carried out within 5 days after ictus. Data were recorded at baseline and after 20 min of noradrenaline infusion to increase mean arterial blood pressure (MAP) by a maximum of 30 mmHg and to an absolute level of no more than 130 mmHg. The primary outcome was the difference in middle cerebral artery blood flow velocity (MCAv) measured by transcranial Doppler (TCD), while differences in intracranial pressure (ICP), brain tissue oxygen tension (PbtO2 ), and microdialysis markers of cerebral oxidative metabolism and cell injury were assessed as exploratory outcomes. Data were analysed using Wilcoxon signed-rank test with correction for multiplicity for the exploratory outcomes using the Benjamini-Hochberg correction. Thirty-six participants underwent the intervention 4 (median, IQR: 3-4.75) days after ictus. MAP was increased from 82 (IQR: 76-85) to 95 (IQR: 88-98) mmHg (p-value: <.001). MCAv remained stable (baseline, median 57, IQR: 46-70 cm/s; controlled blood pressure increase, median: 55, IQR: 48-71 cm/s; p-value: .054), whereas PbtO2 increased significantly (baseline, median: 24, 95%CI: 19-31 mmHg; controlled blood pressure increase, median: 27, 95%CI: 24-33 mmHg; p-value <.001). The remaining exploratory outcomes were unchanged. In this study of patients with SAH, MCAv was not significantly affected by a brief course of controlled blood pressure increase; despite this, PbtO2 increased. This suggests that autoregulation might not be impaired in these patients or other mechanisms could mediate the increase in brain oxygenation. Alternatively, a CBF increase did occur that, in turn, increased cerebral oxygenation, but was not detected by TCD. clinicaltrials.gov (NCT03987139; 14 June 2019).

Forsythiaside B inhibits cerebral ischemia/reperfusion-induced oxidative stress injury in mice via the AMPK/DAF-16/FOXO3 pathway

To study the protective effect of forsythiaside B (FB) against cerebral oxidative stress injury induced by cerebral ischemia/reperfusion (I/R) in mice and explore the underlying mechanism. Ninety C57BL/6 mice were randomized into sham-operated group, middle cerebral artery occlusion (MCAO) model group, and low-, medium and highdose (10, 20, and 40 mg/kg, respectively) FB groups. The expression levels of MDA, ROS, PCO, 8-OHdG, SOD, GSTα4, CAT and GPx in the brain tissue of the mice were detected using commercial kits, and those of AMPK, P-AMPK, DAF-16, FOXO3 and P-FOXO3 were detected with Western blotting. Compound C (CC), an AMPK inhibitor, was used to verify the role of the AMPK pathway in mediating the therapeutic effect of FB. In another 36 C57BL/6 mice randomized into 4 sham-operated group, MCAO model group, FB (40 mg/kg) treatment group, FB+CC (10 mg/kg) treatment group, TTC staining was used to examine the volume of cerebral infarcts, and the levels of ROS and SOD in the brain were detected; the changes in the protein expressions of AMPK, P-AMPK, DAF-16, FOXO3 and P-FOXO3 in the brain tissue were detected using Western blotting. In mice with cerebral IR injury, treatment with FB significantly reduced the levels of ROS, MDA, PCO and 8-OHdG, increased the activities of antioxidant enzymes SOD, GSTα4, CAT and GPx, and enhanced phosphorylation of AMPK and FOXO3 and DAF-16 protein expression in the brain tissue (P < 0.01). Compared with FB treatment alone, the combined treatment with FB and CC significantly reduced phosphorylation of AMPK and FOXO3, lowered expression of DAF-16 and SOD activity, and increased cerebral infarction volume and ROS level in the brain tissue of the mice (P < 0.01). FB inhibits oxidative stress injury caused by cerebral I/R in mice possibly by enhancing AMPK phosphorylation, promoting the downstream DAF-16 protein expression and FOXO3 phosphorylation, increasing the expression of antioxidant enzymes, and reducing ROS level in the brain tissue.

Acetyl-L-carnitine and/or liposomal co-enzyme Q10 prevent propionic acid-induced neurotoxicity by modulating oxidative tissue injury, inflammation, and ALDH1A1-RA-RARα signaling in rats

Propionic acid (PPA) is a short-chain fatty acid produced endogenously by gut microbiota and found in foodstuffs and pharmaceutical products as an additive. Exposure to PPA has been associated with the development of autism spectrum disorder (ASD). The purpose of this study was to investigate the protective effect of acetyl‐L‐carnitine (ALCAR) and liposomal Co-enzyme Q10 (CoQ10) against cerebral and cerebellar oxidative injury, inflammation, and cell death, and alterations in ALDH1A1-RA-RARα signaling in an autism-like rat model induced by PPA. The rats were treated with PPA and concurrently received ALCAR and/or CoQ10 for 5 days. The animals were sacrificed, and the cerebral cortex and cerebellum were collected for analysis. PPA caused histopathological alterations along with increased malondialdehyde (MDA), NF-κB p65, TNF-α, and IL-6 in the cerebrum and cerebellum of rats. Reduced glutathione (GSH) and antioxidant enzymes were declined in the brain of rats that received PPA. Concurrent treatment with ALCAR and/or CoQ10 prevented tissue injury, decreased MDA, NF-κB p65, and pro-inflammatory cytokines, and enhanced cellular antioxidants in PPA-administered rats. ALCAR and/or CoQ10 upregulated Bcl-2 and decreased Bax and caspase-3 in the brain of rats. In addition, ALCAR and/or CoQ10 upregulated cerebral and cerebellar ALDH1A1 and RARα in PPA-treated rats. The combination of ALCAR and CoQ10 showed more potent effects when compared with the individual treatments. In conclusion, ALCAR and/or CoQ10 prevented tissue injury, ameliorated oxidative stress, inflammatory response, and apoptosis, and upregulated ALDH1A1-RA-RARα signaling in the brain of autistic rats.

Salidroside attenuates high altitude hypobaric hypoxia-induced brain injury in mice via inhibiting NF-κB/NLRP3 pathway

Salidroside (Sal), an active ingredient from Rhodiola crenulate, has been reported to exert neuroprotection in cerebral injury from hypobaric hypoxia (HH) at high altitude. However, it remains to be understood whether its protective effects are related to inflammation suppression. In the present work, we aimed to reveal the mechanism of Sal attenuating HH-induced brain injury in mice caused by an animal hypobaric and hypoxic chamber. Our results provided that Sal could attenuate HH-evoked pathological injury and oxidative stress response by decreasing the content of ROS and MDA, and elevating the activities of SOD and GSH-Px. Sal treatment could partly enhance the energy metabolism, evidenced by increasing the activities of Na+-K+-ATPase, Ca2+-Mg2+-ATPase, ATP, SDH, HK and PK, while decreasing the release of LDH and LD. Meanwhile, Sal administration reversed the degradation of tight junction proteins ZO-1, Occludin and Claudin-5. Further, the increased levels of TNF-α, IL-1β and IL-6 were confined with Sal administration under the HH condition. Importantly, Sal could downregulate the proteins expression of p–NF–κB-p65, NLRP3, cleaved-Caspase-1 and ASC. Sal also decreased the protein expression of iNOS and COX2 with the increased CD206 and Arg1 expression. Taken together, these data provided that the inhibited NF-κB/NLRP3 pathway by Sal could attenuate HH-induced cerebral oxidative stress injury, inflammatory responses and the blood brain barrier (BBB) damage, attributing to the improved energy metabolism and the microglial phenotype of anti-inflammatory M2. The findings suggested that Sal was expected to be a promising anti-inflammatory agent for high altitude HH-induced brain injury.

Mild hypothermia protects against cerebral oxidative stress injury by regulating endoplasmic reticulum stress in rats after cardiopulmonary resuscitation

Mild hypothermia protects against cerebral oxidative stress injury by regulating endoplasmic reticulum stress in rats after cardiopulmonary resuscitation

Correction to: Oxygen Exposure During Cardiopulmonary Resuscitation Is Associated With Cerebral Oxidative Injury in a Randomized, Blinded, Controlled, Preclinical Trial.

Correction to: Oxygen Exposure During Cardiopulmonary Resuscitation Is Associated With Cerebral Oxidative Injury in a Randomized, Blinded, Controlled, Preclinical Trial.

Oxygen Exposure During Cardiopulmonary Resuscitation Is Associated With Cerebral Oxidative Injury in a Randomized, Blinded, Controlled, Preclinical Trial.

BackgroundHyperoxia during cardiopulmonary resuscitation (CPR) may lead to oxidative injury from mitochondrial‐derived reactive oxygen species, despite guidelines recommending 1.0 inspired oxygen during CPR. We hypothesized exposure to 1.0 inspired oxygen during CPR would result in cerebral hyperoxia, higher mitochondrial‐derived reactive oxygen species, increased oxidative injury, and similar survival compared with those exposed to 21% oxygen.Methods and ResultsFour‐week‐old piglets (n=25) underwent asphyxial cardiac arrest followed by randomization and blinding to CPR with 0.21 (n=10) or 1.0 inspired oxygen (n=10) through 10 minutes post return of spontaneous circulation. Sham was n=5. Survivors received 4 hours of protocolized postarrest care, whereupon brain was obtained for mitochondrial analysis and neuropathology. Groups were compared using Kruskal‐Wallis test, Wilcoxon rank‐sum test, and generalized estimating equations regression models. Both 1.0 and 0.21 groups were similar in systemic hemodynamics and cerebral blood flow, as well as survival (8/10). The 1.0 animals had relative cerebral hyperoxia during CPR and immediately following return of spontaneous circulation (brain tissue oxygen tension, 85% [interquartile range, 72%–120%] baseline in 0.21 animals versus 697% [interquartile range, 515%–721%] baseline in 1.0 animals; P=0.001 at 10 minutes postarrest). Cerebral mitochondrial reactive oxygen species production was higher in animals treated with 1.0 compared with 0.21 (P<0.03). Exposure to 1.0 oxygen led to increased cerebral oxidative injury to proteins and lipids, as evidenced by significantly higher protein carbonyls and 4‐hydroxynoneals compared with 0.21 (P<0.05) and sham (P<0.001).ConclusionsExposure to 1.0 inspired oxygen during CPR caused cerebral hyperoxia during resuscitation, and resultant increased mitochondrial‐derived reactive oxygen species and oxidative injury following cardiac arrest.

Carvacryl acetate, a semisynthetic monoterpenic ester obtained from essential oils, provides neuroprotection against cerebral ischemia reperfusion-induced oxidative stress injury via the Nrf2 signalling pathway.

Carvacryl acetate (CA) is a semisynthetic monoterpenic ester obtained from essential oils, and it exerts an antioxidation effect. The purpose of our study was to investigate whether CA could provide neuroprotection against oxidative stress caused by cerebral ischemia-reperfusion injury (CIRI) and elucidate the underlying mechanism. Middle cerebral artery occlusion (MCAO)-induced damage was established in Sprague Dawley (SD) rats and PC12 cells were exposed to hydrogen peroxide (H2O2) to imitate oxidative stress damage. TTC, HE and Nissl staining were used to observe the pathological morphology of lesions. The contents of ROS and MDA, and the activity of SOD were measured to reflect the level of oxidative stress. In addition, the TUNEL method was used to assess injuries in vitro, and the expression of Nrf2 was determined by immunohistochemical staining and western blot analysis. Importantly, we constructed and validated Nrf2 knockdown PC12 cells to confirm the key role of Nrf2 in the neuroprotective effect of CA against oxidative stress injuries. CA alleviated CIRI in rats with MCAO, as shown by brain tissue pathophysiology. The contents of ROS and MDA were reduced, and the SOD activity was augmented by the simultaneous promotion of Nrf2 expression. In addition, the H2O2-induced injury in Nrf2-knockdown PC12 cells was more serious than it was in control cells, and CA-mediated neuroprotection was exclusively inhibited by the knock down of Nrf2 in PC12 cells. In conclusion, it is shown here that CA has the effect of relieving cerebral ischemia reperfusion-induced oxidative stress injury via the Nrf2 signalling pathway.

A novel biscoumarin compound ameliorates cerebral ischemia reperfusion-induced mitochondrial oxidative injury via Nrf2/Keap1/ARE signaling

Some phytochemical-derived synthetic compounds have been shown to improve neurological disorders, especially in ischemic stroke. In this study, we identified a novel biscoumarin compound, known as COM 3, which had substantial antioxidant effects in neurons. Next, we found that COM 3 occupies a critical binding site between the Nrf2 and Keap1 dipolymer, impairing the inhibitory effects of Keap1 on Nrf2, both of which play central roles in increasing endogenous antioxidant activity. We verified that COM 3 could increase the survival of neurons experiencing oxygen and glucose deprivation (OGD) from 51.1% to 77.2% when exposure to 2.5 and 10 μg/mL of COM 3, respectively. In addition, the same concentrations of COM 3 could reduce brain infarct volumes by 33.8%to13.7%, respectively, while also reducing the neurobehavioral score from 3.3 to 1.4 on average in mice with a middle cerebral artery occlusion (MCAO). COM 3 reduced neuronal death from 36.5% to 13.9% and apoptosis from 35.1% to 18.2%. In addition, COM 3 could improve the neuronal mitochondrial energy metabolism after experiencing oxidative stress caused by OGD or MCAO. The present study suggests that COM 3 protects against OGD in neurons and MCAO in mice by interfering with the structure of Keap1 to activate the nuclear transcription of Nrf2, which balances endogenous redox activity and restores mitochondrial function. Hence, COM 3 might be a potential therapeutic agent for ischemic stroke in the clinic.

Upregulated microRNA-31 inhibits oxidative stress-induced neuronal injury through the JAK/STAT3 pathway by binding to PKD1 in mice with ischemic stroke.

Ischemic stroke (IS), which is characterized by high morbidity, disability, and mortality, is recognized as a major cerebrovascular disease. MicroRNA-31 (miR-31) was reported to participate in the progression of brain disease. The present study was conducted in order to investigate the effect of miR-31 on oxidative stress-induced neuronal injury in IS mice with the involvement of protein kinase D1 (PKD1) and the JAK/STAT3 pathway. C57BL/6J mice were used to establish the middle cerebral artery occlusion (MCAO) model. Astrocytes were transfected with miR-31 mimic, miR-31 inhibitor, si-PKD1, or JAK-STAT3 pathway inhibitor. Following the establishment of an oxygen-glucose deprivation (OGD) model, the astrocytes were cocultured with neuronal OGD. Lower miR-31, higher PKD1 expressions, and activated JAK/STAT3 pathway were found in both the MCAO and OGD models. miR-31 could negatively target PKD1. In an MCAO model, overexpressing miR-31 and silencing PKD1 reduced neuronal injury, cerebral infarct volume, neuron loss, and oxidative stress injury, inhibited the activation of JAK/STAT3 pathway and the expressions of PKD1, interleukin (IL)-1β, IL-6, tumor necrosis factor-α, malondialdehyde, 4-HNE, 8-HOdG, caspase-3, and Bax, but increased the superoxide dismutase content. In the OGD model, overexpression of miR-31 and silencing of PKD1 attenuated oxidative stress-induced neuronal injury, and diminished the lactate dehydrogenase leakage and reactive oxygen species level, accompanied by elevated neuronal viability. These results indicate that miR-31 alleviates inflammatory response as well as an oxidative stress-induced neuronal injury in IS mice by downregulating PKD1 and JAK/STAT3 pathway.

Integrated network pharmacology and antioxidant activity-guided screen system to exploring antioxidants and quality markers of Shunaoxin pills against chronic cerebral ischemia

Objective: The main objective of the study is to screen the quality markers (Q-markers) for relieving oxidative stress damage and against chronic cerebral ischemia in Shunaoxin pills (SNX). Methods: The benefit effect of SNX was evaluated by a rat chronic cerebral ischemia model. The main ingredients of SNX were identified by ultra-performance liquid chromatography-quadrupole time-of-flight, whereas its core targets and pathways around antioxidative stress were predicted by PharmMapper and kyoto encyclopedia of genes and genomes (KEGG) analysis. Moreover, the antioxidants were screened by high-performance liquid chromatography with postcolumn derivatization system and then representative ingredients were verified by cell experiments. Results: SNX could increase expression of catalase and superoxide dismutase (SOD) as well as antagonize oxidative damage in the brain. The effects may be related to three types of antioxidant pathways, including nitrogen metabolism, arachidonic acid metabolism, and the cyclic guanosine monophosphate-dependent protein kinase (cGMP-PKG) signaling pathway by multiple active components regulate targets. Among them, ferulic acid and ligustilide were shown the key scavenging ability for reactive oxygen free radicals and significantly increased the contents of nitric oxide (NO), NO synthase, and SOD as well as decreased malonaldehyde. Conclusion: The oxidation resistances of biological and chemical processes in SNX to protect against cerebral oxidative stress injury were preliminary revealed by an integrated network pharmacology and antioxidant activity-guided screen system. Ferulic acid and ligustilide played a major antioxidant role that could be used as Q-markers to control the quality of SNX.

Omi/HtrA2 Regulates a Mitochondria-Dependent Apoptotic Pathway in a Murine Model of Septic Encephalopathy

Background/Aims: the pathogenesis of sepsis-associated encephalopathy (SAE) is multifactorial, involving neurotransmitter alterations, inflammatory cytokines, oxidative damage, mitochondrial dysfunction, apoptosis, and other factors. Mitochondria are major producers of reactive oxygen species, resulting in cellular injury. Omi/HtrA2 is a proapoptotic mitochondrial serine protease involved in caspase-dependent cell death; it is translocated from mitochondria to the cytosol after an apoptotic insult. We previously found that UCF-101, a specific inhibitor of Omi/HtrA2, has neuroprotective effects on cerebral oxidative injury and cognitive impairment in septic rats. In this study, the mechanisms and molecular pathways underlying these effects were investigated. Methods: Male Sprague–Dawley rats were subjected to cecal ligation and puncture (CLP) or sham-operated laparotomy and were administered vehicle or UCF-101 (10 µmol/kg). The hippocampus was isolated for subsequent analysis. Omi/HtrA2 expression in the mitochondria or cytosol was evaluated by immunofluorescence or western blotting. Terminal deoxynucleotidyl transferase dUTP nick end labeling staining was utilized to evaluate levels of apoptosis, and western blotting was used to evaluate apoptosis-related proteins, such as cleaved caspase-3, caspase-9, and poly (ADP-ribose) polymerase (PARP). Tight junction expression was assessed by immunofluorescence and western blotting. Mitochondrial function, inflammatory cytokines, and oxidative stress were also assayed. In addition, a wet/dry method was used to evaluate brain edema and Evans blue extravasation was used to evaluate blood–brain barrier (BBB) integrity. Results: After CLP treatment, the hippocampus exhibited a mild increase in Omi/HtrA2 expression; cytosolic Omi/HtrA2 expression increased significantly, whereas mitochondrial Omi/HtrA2 expression was reduced, indicating that CLP-induced oxidative stress resulted in the translocation of Omi/HtrA2 from mitochondria to the cytosol. Hippocampal cleaved caspase-3, caspase-9, and PARP levels were significantly higher in animals treated with CLP than in sham-operated animals, while XIAP expression was lower. Treatment with UCF-101 prevented the mobilization of Omi/HtrA2 from mitochondria to the cytosol, attenuated XIAP degradation, and decreased cleaved caspase-3, caspase-9, and PARP expression as well as apoptosis. UCF-101 also reversed the decreased mitochondrial complex I, II, and III respiration and the reduced ATP caused by CLP. In addition, UCF-101 treatment resulted in a significant improvement in BBB integrity, as demonstrated by increased occludin, claudin-5, and zonula occludens 1 levels and reduced Evans blue extravasation. No significant effects of UCF-101 on brain edema were found. Inflammatory cytokines and oxidative stress were significantly higher in the CLP-treated group than in the sham-operated group. However, the inhibition of Omi/HtrA2 by UCF-101 significantly alleviated these responses. Conclusion: Our data indicated that Omi/ HtrA2 regulates a mitochondria-dependent apoptotic pathway in a murine model of septic encephalopathy. Inhibition of Omi/HtrA2 by UCF-101 leads to neuroprotection by inhibiting the cytosolic translocation of Omi/HtrA2 and antagonizing the caspase-dependent apoptosis pathway. Therapeutic interventions that inhibit Omi/HtrA2 translocation or protease activity may provide a novel method to treat SAE.

Cerebral Tissue Oxidative Ischemia-Reperfusion Injury in Connection with Experimental Cardiac Arrest and Cardiopulmonary Resuscitation: Effect of Mild Hypothermia and Methylene Blue

The present investigation is an expansion of previous studies which all share a basic experimental protocol of a porcine-induced cardiac arrest (CA) of 12 min followed by 8 min of cardiopulmonary resuscitation (CPR), different experimental treatments (immediate as well as postponed induced mild hypothermia and administration of much or less cool intravenous fluids), and a follow-up period of 3 h after which the animals were sacrificed. Another group of animals was studied according to the same protocol after 12-min CA and “standard CPR.” After death (within 1 min), the brains were harvested and frozen in liquid nitrogen awaiting analysis. Control brains of animals were collected in the same way after short periods of untreated CA (0 min, 5 min, and 15–30 min). Previous studies concerning chiefly neuropathological changes were now expanded with analyses of different tissue indicators (glutathione, luminol, leucigenin, malonialdehyde, and myeloperoxidase) of cerebral oxidative injury. The results indicate that a great part of oxidative injury occurs within the first 5 min after CA. Immediate cooling by administration of much intravenous fluid results in less cerebral oxidative injury compared to less intravenous fluid administration. A 30-min postponement of induction of hypothermia results in a cerebral oxidative injury comparable to that of “standard CPR” or the oxidative injury found after 5 min of untreated CA. Intravenous administration of methylene blue (MB) during and immediately after CPR in combination with postponed cooling resulted in no statistical difference in any of the indicators of oxidative injury, except myeloperoxidase, and glutathione, when this treatment was compared with the negative controls, i.e., animals subjected to anesthesia alone.

Neuroprotective effects of sulfiredoxin-1 during cerebral ischemia/reperfusion oxidative stress injury in rats

As an endogenous antioxidant protein, Sulfiredoxin1 (Srxn1) can prevent cell oxidative stress damage. However, its role in cerebral ischemia/reperfusion (I/R) injury and the underlying signaling mechanisms remain largely unknown. Here, we explored effects of Srxn1 knockdown on oxidative stress using in vitro and in vivo I/R models and investigated related neuroprotective mechanisms. For in vitro studies, primary cortical neuronal cultures were transfected with an interfering lentivirus targeting Srxn1. Oxygen-glucose deprivation (OGD) was conducted after Srxn1 knockdown. MTS and lactate dehydrogenase assays indicated that knockdown of Srxn1 increased cell death and reduced cell viability. Similarly, superoxide dismutase (SOD) and reduced glutathionekits assays showed that knockdown of Srxn1 worsened oxidative stress injury. For in vivo studies, siRNA for Srxn1 or negative control siRNA was injected intracerebroventricularly 24h before middle cerebral artery occlusion (MCAO). Data shows silencing Srxn1 resulted in a significant increase in cerebral infarction, neurological deficits, histological injury, and oxidative stress injury 24h after ischemic stroke. Moreover, immunoblot analysis assessed the relationship between Srxn1 levels and Prdx1–4 as well as Prdx-SO3 activity both in vitro and in vivo models. We found that decreased Srxn1 reduced Prdx1–4 and enhanced Prdx-SO3 protein levels. In addition, knockdown of Nrf2 was performed; immunoblot analysis was used to measure Srxn1 and NQO1 protein levels. We further found that interference of Nrf2 reduced Srxn1 and NQO1 protein levels. In summary, Srxn1 can protect neurons from I/R oxidative stress injury and the mechanism involves Prdx activity. Srxn1, which might be downstream of Nrf2, can prevent cerebral ischemia reperfusion by reversing overoxidized Prdx and restoring antioxidant activity of Prdx.

Intraoperative cerebral oxygenation, oxidative injury, and delirium following cardiac surgery

BackgroundDelirium affects 20–30% of patients after cardiac surgery and is associated with increased mortality and persistent cognitive decline. Hyperoxic reperfusion of ischemic tissues increases oxidative injury, but oxygen administration remains high during cardiac surgery. We tested the hypothesis that intraoperative hyperoxic cerebral reperfusion is associated with increased postoperative delirium and that oxidative injury mediates this association. MethodsWe prospectively measured cerebral oxygenation with bilateral oximetry monitors in 310 cardiac surgery patients, quantified intraoperative hyperoxic cerebral reperfusion by measuring the magnitude of cerebral oxygenation above baseline after any ischemic event, and assessed patients for delirium twice daily in the ICU following surgery using the confusion assessment method for ICU (CAM-ICU). We examined the association between hyperoxic cerebral reperfusion and postoperative delirium, adjusted for the extent of cerebral hypoxia, the extent of cerebral hyperoxia prior to any ischemia, and additional potential confounders and risk factors for delirium. To assess oxidative injury mediation, we examined the association between hyperoxic cerebral reperfusion and delirium after further adjusting for plasma levels of F2-isoprostanes and isofurans at baseline and ICU admission, the association between hyperoxic cerebral reperfusion and these markers of oxidative injury, and the association between these markers and delirium. ResultsNinety of the 310 patients developed delirium following surgery. Every 10%·hour of intraoperative hyperoxic cerebral reperfusion was independently associated with a 65% increase in the odds of delirium (OR, 1.65 [95% CI, 1.12–2.44]; P=0.01). Hyperoxia prior to ischemia was also independently associated with delirium (1.10 [1.01–1.19]; P=0.02), but hypoxia was not (1.12 [0.97–1.29]; P=0.11). Increased hyperoxic cerebral reperfusion was associated with increased concentrations of F2-isoprostanes and isofurans at ICU admission, increased concentrations of these markers were associated with increased delirium, and the association between hyperoxic cerebral reperfusion and delirium was weaker after adjusting for these markers of oxidative injury. ConclusionsIntraoperative hyperoxic cerebral reperfusion was associated with increased postoperative delirium, and increased oxidative injury following hyperoxic cerebral reperfusion may partially mediate this association. Further research is needed to assess the potential deleterious role of cerebral hyper-oxygenation during surgery.

Brown propolis attenuates cerebral ischemia-induced oxidative damage via affecting antioxidant enzyme system in mice

Oxidative stress plays a critical role in ischemic brain injury. Superoxide dismutase (SOD) and glutathione peroxidase (GPx) are the enzymes underlying the endogenous antioxidant mechanisms affected by stroke and are considered as oxidative stress biomarkers. Brown propolis (BP) is a bioactive natural product with a set of biological activities that in turn may differ depending on the area from which the substance is originated. The aim of this study was to investigate the effect of water-extracted brown propolis (WEBPs), from two regions of Iran, against cerebral ischemia-induced oxidative injury in a mouse model of stroke. Experimentally, the chemical characterization and total polyphenol content were determined using GC/MS and Folin–Ciocalteu assay respectively. Seventy-two adult male mice were randomly divided into the surgical sham group, control group (treated with vehicle), and four groups of WEBPs-treated animals. The WEBPs were administered at the doses of 100 and 200mg/kg IP, during four different time points. Oxidative stress biomarkers (SOD and GPx activity, SOD/GPx ratio), lipid peroxidation (LPO) index (malondialdehyde content) and infarct volume were measured 48h post stroke. Behavioral tests were evaluated 24 and 48h after stroke. WEBPs treatment resulted in significant restoration of antioxidant enzymes activity and a subsequent decrease in LPO as well as the infarct volume compared to the control group. Sensory-motor impairment and neurological deficits were improved significantly as well. These results indicate that Iranian BP confers neuroprotection on the stroke-induced neuronal damage via an antioxidant mechanism which seems to be mediated by the endogenous antioxidant system.

Thymoquinone: An edible redox-active quinone for the pharmacotherapy of neurodegenerative conditions and glial brain tumors. A short review.

There exist few efficient agents in the neurological and neurosurgical armamentarium for treatment of neurotrauma, refractory seizures and high grade glial tumors. Pathophysiological conditions of diverse neural injuries have converging common pathways including oxidative stress and apoptosis. Targeted therapies have been throughly investigated, but limited success has been achieved until now. Phytochemical drugs may provide easily achievable and cheap adjunctive sources. Thymoquinone is an edible quinone obtained from Nigella sativa seed oil and exerts powerful antiinflammatory, antioxidant and antitumor activities in experimental models. Recently emerging studies conducted with animal models suggest that thymoquinone - bearing a very simple molecular structure - significantly crosses the blood brain barrier and exerts neuromodulatory activities. Indeed, in animal studies, the following actions of thymoquinone were demonstrated: 1-Protection against ischemic brain damage. 2-Reduction of epileptic seizures and associated cerebral oxidative injury. 3-Reduction of morphine tolerance and associated oxidative brain damage. 4-Anxiolytic effects and reduction of immobility stress-associated cerebral oxidative injury. 5-Reduction of diabetes-induced cerebral oxidative stress, 6-Reduction of cerebral oxidative injuries induced by noxious exposures including toluene, lead and ionizing radiation. Substantial in vitro data suggest that thymoquinone may be beneficial in treatment of glial tumors. However, there is no clinical study investigating its antitumor effects. In fact, thymoquinone suppresses growth and invasion, and induces apoptosis of glial tumor cells via degrading tubulins and inhibiting 20S proteasome, telomerase, autophagy, FAK and metalloproteinases. A simple and easily available agent may be a promising adjunctive treatment option in neurological and neurosurgical practice.

Neuroprotective Effect of Punicalagin against Cerebral Ischemia Reperfusion-induced Oxidative Brain Injury in Rats

Punicalagin (PG) is a hydrolyzable polyphenol in Punica granatum. It has been previously reported that it has a protective effect against hypoxia-induced ischemia brain injury. It is a potent antioxidant. The present study is aimed to evaluate the antioxidant potential of PG against focal cerebral ischemia-reperfusion injury in rats subjected to middle cerebral artery occlusion (MCAO). Rats were randomly divided into sham, MCAO, PG-treated groups. PG (15 and 30 mg/kg) vehicle was administered orally for 7 days before MCAO. Rats were anesthetized with ketamine (100 mg/kg), xylazine (10 mg/kg), and subjected to 2 hours occlusion, and 22 hours reperfusion. Neurologic deficit, brain water content (BWC), histopathology changes, and oxidative stress markers were evaluated after 22 hours of reperfusion. In comparison with MCAO model group, treatment with PG significantly reduced the neurologic deficit scores and BWC. PG-attenuated neuronal damage occurred by downregulating the levels of malondialdehyde, sodium-potassium adenosine triphosphatase activity, nitric oxide, protein carbonyl content, and mitochondria-generated reactive oxygen species and upregulating the superoxide dismutase, catalase, glutathione peroxidase, reduced glutathione, glutathione reductase activities. Taken together, these results suggested that supplementation of PG treatment effectively ameliorates the cerebral ischemia/reperfusion induced oxidative damage by virtue of its antioxidant potential.

Ucf-101 protects against cerebral oxidative injury and cognitive impairment in septic rat

Omi/HtrA2 is a proapoptotic mitochondrial serine protease involved in caspase-dependent and caspase-independent cell apoptosis. It has been verified that Omi/HtrA2 is related to apoptosis due to oxidative stress, which may play an important role in the integrity of mitochondria. Ucf-101 is a specific inhibitor of Omi/HtrA2 and it has been demonstrated that Ucf-101 has organ protective effects in a variety of in vitro and in vivo studies. The aim of our study was to examine the neuroprotective effects of Ucf-101 on cerebral oxidative injury and cognitive impairment in septic rats. Male Sprague Dawley rats are subjected to cecal ligation and puncture (CLP) or sham-operated laparotomy. Rats were divided into 4 groups: (1) a sham group plus normal saline (10 mL/kg); (2) a sham group plus Ucf-101 (10 umol/kg); (3) CLP plus normal saline (10 mL/kg); and (4) CLP plus Ucf-101 (10 umol/kg). Brain tumor necrosis factor (TNF)-α level, caspase-3 and caspase-9 activities, malondialdehyde (MDA) content and catalase (CAT) activities were examined. TUNEL staining was utilized to evaluate the amount of apoptosis and the cognitive function was evaluated by the MWM test. The study also assessed the clinical scores of animals and the survival time for the 7-day period. CLP resulted in a poor survival rate, evidence of hippocampal oxidative injury, cell apoptosis and cognitive dysfunction as well as elevated TNF-α level and caspases activities, increased weight loss and clinical scores. Ucf-101 pre-treatment could significantly inhibit caspases activities and cell apoptosis, reduce TNF-α and MDA levels, slightly reverse CAT activities in the brain and attenuate this CLP effect on cognitive dysfunction. In addition, the survival rate and survival time was significantly improved by pre-treatment with Ucf-101. The present results demonstrated that ucf-101 has the neuroprotective effects on cerebral oxidative injury and cognitive impairment in septic rats.

Effect of Sevoflurane postconditioning on gene expression in brain tissue of the middle cerebral artery occlusion rat model

Ischemic postconditioning has been described in both heart and brain. The first aim of this study was to evaluate the effects of Sevoflurane postconditioning (SP) on brain biochemical parameters, Bcl-2, Bax, c-Fos and Caspase-3 protein levels and Bcl-2, Bax, TNF-α and Caspase-3 mRNA expression in the middle cerebral artery occlusion model. Results showed that SP markedly decreased cerebral oxidative injury and improved immunity activity. In addition, SP significantly enhanced cerebral Bcl-2, c-Fos and decreased Bax, Caspase-3 proteins positive expression. Reverse transcription polymerase chain reaction analysis showed that SP markedly enhanced Bcl-2, and decreased Bax, TNF-α and Caspase-3 mRNA expression. Our results confirm that SP can play the protective action against cerebral ischemia reperfusion-induced brain injury by regulating cerebral antioxidant enzymes activities, Bcl-2, Bax, c-Fos and Caspase-3 protein positive expression levels and Bcl-2, Bax, TNF-α and Caspase-3 mRNA expression.