Complete Global Brain Ischemia Research Articles

Weighted gene co-expression network analysis to investigate the key genes implicated in global brain ischemia/reperfusion injury in rats.

Ischemia/reperfusion (I/R) refers to situations where blood is perfused into ischemic or hypoxic tissues, potentially resulting in an inflammatory response and oxidative injury. This study was conducted to explore the pathogenesis of I/R injury. GSE82146 was extracted from the Gene Expression Omnibus, consisting of 15 complete global brain ischemia (CGBI) reperfusion hippocampus samples and 12 non-ischemic control (NIC) hippocampus samples. The differentially expressed genes (DEGs) between the CGBI and NIC samples were selected using LIMMA package, and were then analyzed with weighted gene co-expression network analysis (WGCNA). Using DAVID software, the DEGs in significant modules were run through enrichment analysis. The DEGs in significant modules were merged, and then a protein-protein interaction (PPI) network was built for them using Cytoscape software. After miRNAs and transcription factors (TFs) were predicted for the DEGs using the WebGestalt tool, a TF-miRNA-target regulatory network was built using Cytoscape software. Furthermore, quantitative real-time polymerase chain reaction (qRT-PCR) analysis was conducted to detect the levels of key genes. There were 390 DEGs in the CGBI samples. Based on WGCNA, brown and turquoise modules were screened as CGBI-associated modules. In the PPI network, key nodes HSP90AA1 and HSPA5 were able to interact with each other. In the regulatory network, MYC, HSF1 and miR-22 had higher degree values. Moreover, HSPA5 was targeted by MYC in the regulatory network. In addition, upregulated HSPB1 and HMOX1, as well as downregulated NR4A2, were confirmed with qRT-PCR analysis. HSPB1, HMOX1 and NR4A2 were the key genes correlated with I/R injury. Additionally, HSP90AA1, HSPA5, MYC, HSF1, and miR-22 might be related to the pathogenesis of I/R injury.

Bioinformatic analysis to explore key genes associated with brain ischemia–reperfusion injury in rats

Objectives: Ischemia–reperfusion (I/R) injury can aggravate the dysfunction and structural damage of tissues and organs. This study aimed at investigating the pathogenesis of I/R injury.Methods: GSE82146 was extracted from Gene Expression Omnibus database, which included 12 nonischemic control (NIC) hippocampal tissues and 15 complete global brain ischemia (CGBI)–reperfusion hippocampal tissues. After processing the original data using the affy package, the differentially expressed genes (DEGs) between CGBI and NIC samples were analysed by the limma package. An enrichment analysis for the DEGs was implemented based on the MATHT online tool. Using Cytoscape software, a protein–protein interaction (PPI) network was built and significant network modules were obtained. Finally, miRNA-gene pairs were predicted using the miRWalk2.0 tool, and the miRNA-gene regulatory network was built using the Cytoscape software.Results: Overall, 322 DEGs (279 upregulated and 43 downregulated) were present in the CGBI samples. In PPI network, JUN, STAT3, ATF3, VEGFA and ATF4 had higher degrees. Four significant modules (modules a, b, c and d) were obtained from PPI network. Enrichment analysis suggested that FGF2 in module d was involved in MAPK signalling pathway. In the miRNA-gene regulatory network, rno-miR-125a-5p and rno-miR-125b-5p were among the top 10 miRNAs.Conclusion: JUN, STAT3, ATF3, VEGFA, ATF4, FGF2, rno-miR-125a-5p and rno-miR-125b-5p might affect the development and progression of I/R injury.

Administration of MgSO4 failed to improve the neurological recovery after complete global brain ischemia in dogs.

The cerebral protective effects of MgSO4 after complete global brain ischemia were evaluated with EEG, evoked potentials (EP) and the neurological recovery score (NRS) in the dog. Complete global brain ischemia for 15 min was achieved by occluding the ascending aorta and the caval veins. The MgSO4 group (N=7) were injected with a 10% MgSO4 solution and the control group (N=7) were administered a normal saline intravenously from the beginning of the resuscitation to 48 h after ischemia. The EEG grades (1=normal, 5=flat) in the control group and the MgSO4 group were 3.9±0.1 (mean ±SEM) and 3.7±0.3, and the EEG-EP scores (6=normal, 0=serious deterioration) were 2.6±0.4 and 2.7±0.4 4h after ischemia, respectively. The 7-day survival rates for ischemia were equal in both groups (5/7:71%). The NRSs (0=death, 100=normal) in the control group and the MgSO4 group were 50±3 (n=7) and 43±9 (n=7) on the 3rd day after ischemia, and were 56±5 (n=5) and 42±12 (n=5) on the 7th day. The differences between the two groups were not significant. We conclude that MgSO4 administered after ischemia has no beneficial effects on the recovery of EEG, EP and the NRS after 15 min of complete global brain ischemia in the dog.

Administration of MgSO4 failed to improve the neurological recovery after complete global brain ischemia in dogs

Administration of MgSO4 failed to improve the neurological recovery after complete global brain ischemia in dogs

完全全脳虚血後の脳障害に対する炭酸リチウムの効果に関する研究

完全全脳虚血後の脳障害に対する炭酸リチウムの効果に関する研究

イヌの18分間完全全脳虚血後の血液脳関門の経時的透過性変化に関する実験的研究

イヌの18分間完全全脳虚血後の血液脳関門の経時的透過性変化に関する実験的研究

Hyperbaric oxygen therapy accelerates neurologic recovery after 15-minute complete global cerebral ischemia in dogs.

Although hyperbaric oxygen therapy is clinically used for the treatment of several types of ischemic brain injury, few basic animal studies are available that provide a rationale for this therapy for complete global brain ischemia. Therefore, we investigated the effect of hyperbaric oxygen therapy on neurologic recovery after 15-min complete global cerebral ischemia in a canine model. Complete global ischemia was induced in 19 dogs by occlusion of the ascending aorta and the caval veins. Nine dogs were randomized to treatment with hyperbaric oxygenation (3 atmospheres absolute, 100% oxygen for 1 hr) at 3, 24, and 29 hrs after ischemia under spontaneous respiration, while the other ten dogs served as the control group without hyperbaric oxygen therapy (group C). Neurologic recovery was evaluated based on the electroencephalogram (EEG) activity score (1 = normal; 5 = isoelectric) and the neurologic recovery score (100 = normal; 0 = brain death) over a 14-day postischemic period. The survival rates were 3/10 (30%) in the control group vs. 7/9 (78%) in the group treated with hyperbaric oxygen (p < .05). Over the 14-day postischemic period, the best (lowest) EEG scores of each dog were significantly (1.7 +/- 0.2 vs. 2.9 +/- 0.3; mean +/- SE, p < .01) lower in the hyperbaric oxygen-treated group. The best neurologic recovery scores of each dog were significantly (69 +/- 6 vs. 48 +/- 5; mean +/- SE, p < .05) higher in the treated animals. The number of dogs that recovered to a neurologic recovery score of > 65 (assessed as a slight disability) were 1/10 in the control group and 6/9 in the group treated with hyperbaric oxygen (p < .02). Hyperbaric oxygen therapy performed in the early postischemic period accelerated neurologic recovery and improved the survival rate in dogs after 15-mins of complete global cerebral ischemia.

Uncoupled Cerebral Blood Flow and Metabolism after Severe Global Ischemia in Rats

In a rat model of complete global brain ischemia (neck tourniquet) lasting either 3 min or 20 min, we monitored global CBF (sagittal sinus H2 clearance) and CMRO2 for 6 h to test the hypothesis that delayed postischemic hyperemia and uncoupling of CBF and CMRO2 occur depending on the severity of the insult. Early postischemic hyperemia occurred in both the 3-min and 20-min groups (p less than 0.05 vs. baseline values) and resolved by 15 min. Hypoperfusion occurred in the 3-min group between 15 and 60 min postischemia (approximately 23% reduction), and in the 20-min group from 15 to 120 min postischemia (approximately 50% reduction) (p less than 0.05), and then resolved. CMRO2 was not significantly different from baseline at any time after ischemia in the 3-min group. After 20 min of ischemia, however, CMRO2 was decreased (approximately 60%) throughout the postischemic period (p less than 0.05). At 5 min after ischemia, CBF/CMRO2 was increased in both groups but returned to baseline from 60 to 120 min postischemia. In the 3-min group, CBF/CMRO2 remained at baseline throughout the rest of the experiment. However, in the 20-min group, CBF/CMRO2 once again increased (approximately 100%), reaching a significant level at 180 min and remaining so for the rest of the 6-h period (p less than 0.05). These data demonstrate biphasic uncoupling of CBF and CMRO2 after severe (20 min) global ischemia in rats. This relatively early reemergence of CBF/CMRO2 uncoupling after 180 min of reperfusion is similar to that observed after prolonged cardiac arrest and resuscitation in humans.

Regional differences in rat brain lipids during global ischemia.

Membrane lipid degradation plays an important role in the pathogenesis of ischemic brain damage, but there is little information on changes in cerebrosides, sulfatides, and sphingomyelin. We studied regional changes in the quantities of these lipids during complete global brain ischemia in rats. Nitrous oxide-anesthetized rats were subjected to ischemia by a high-pressure neck cuff and arterial hypotension for 0 (control), 3, 10, or 30 minutes (n = 5 at each time). Brain temperature was allowed to fall spontaneously during ischemia, and the brain was frozen in situ with liquid N2 without recirculation. The frontal cortex, hippocampus, and basal ganglia were dissected at -15 degrees C. The lipids were separated by column and high-performance thin-layer chromatography and quantified by charring and densitometry. Total lipid content was higher (p less than 0.01) in the hippocampus (72.6 +/- 2.8 mg/g wet wt, mean +/- SD) than in the frontal cortex and basal ganglia (57.7 +/- 2.1 and 62.6 +/- 1.5 mg/g wet wt, respectively). Ischemic changes occurred only in the frontal cortex, where total lipid content fell (p less than 0.01) by 11% after 30 minutes of ischemia because sulfatide and cerebroside contents fell by 44% and 38%, respectively. Despite a marked accumulation of free fatty acids during complete global brain ischemia in rats, the only detectable changes in brain lipids were in the amounts of cerebrosides and sulfatides in the frontal cortex.

The effects of calcium antagonists on EEG, evoked potentials and neurologic recovery after complete global brain ischemia for 15 minutes in dogs.

The effects of three calcium antagonists on the recovery from neurologic damages after complete global brain ischemia were examined by evaluating the change of a electroencephalogram (EEG), evoked potentials (EP) and a neurologic recovery score (NRS) in dogs. Fifteen minutes global brain ischemia was achieved by occluding the ascending aorta and the caval veins. Nicardipine (NC), flunarizine (FL) and diltiazem (DL) were administered with continuous infusions for three days after the ischemia. The EEG-EP scores (0 : no response - 6 : normal) 3 hr after the ischemia were 1.4 +/- 0.4 (mean +/- SE) in the control, 2.2 +/- 0.3 in the NC, 2.2 +/- 0.4 in the FL and 2.1 +/- 0.2 in the DL. There were no significant differences between the 4 groups. The survival rates on the 7th day after the ischemia were 67% (6/9) in the control, 78% (7/9) in the NC, 56% (5/9) in the FL and 89% (8/9) in the DL. No significant differences were presented between the 4 groups. The NRSs (0 : death - 100 : normal) on the 7th day were 40.3 +/- 7.3 in the control, 59.0 +/- 8.5 in the NC, 63.2 +/- 9.7 in the FL and 55.7 +/- 3.3 in the DL. Each treated group showed a tendency to have a higher NRS than that in the untreated control group. The NRS in all dogs treated by the Ca(++) antagonists on the 7th day was 58.7 +/- 4.1, which was significantly higher than that in the control group ( P < 0.05). We conclude that the continuous administration of calcium antagonists for three days after the global brain ischemia would be beneficial for the neurologic recovery.

完全全脳虚血後の脳障害に及ぼすニモジピンの効果に関する実験的研究

The effects of the calcium channel entry blocker nimodipine on the brain injury induced by complete global brain ischemia (CGBI) in dogs were studied. Dogs were kept under 18 minutes of CGBI by a method of clamping the ascending aorta combined with a bypass formation between the aorta to the right atrium and the aorta to the femoral vein, and then divided into two groups, control group and nimodipine-treated group (group N). In this study, 10μg/kg of nimodipine was initially administered 15 minutes after CGBI followed by a maintenance doze of 1.0μg/kg/min for 6 hours. In both groups, hemodynamic changes, such as cerebral blood flow (CBF), mean arterial pressure (MAP), and heart rate (HR) were measured for seven hours after CGBI, the neurologic data were recorded for seven days after CGBI and the histological changes were evaluated on the 7 th day after CGBI.The reduced CBF in group N was significantly improved compared to the control group, MAP and HR in group N were lower than in the control group, and the increase in CI in group N was greater than in the control group. Neurologic data also showed no significant difference between the two groups, and the histological examination showed that damage of cerebral cortex and CA3 region of hippocampus in group N was severer than in the control group.In conclusion, nimodipine had no beneficial effects on brain injury induced by 18 minutes of CGBI and the delayed post-ischemic hypoperfusion itself might not necessarily play an important role in brain injury.

イヌの完全全脳虚血後の血液脳関門の透過性に関する研究

イヌの完全全脳虚血後の血液脳関門の透過性に関する研究

完全全脳虚血後の脳障害に対するヘパリン・ウロキナーゼ併用療法の効果に関する実験的研究

完全全脳虚血後の脳障害に対するヘパリン・ウロキナーゼ併用療法の効果に関する実験的研究

イヌの完全全脳虚血後の脳障害に及ぼすSMA-SODの効果に関する実験的研究

イヌの完全全脳虚血後の脳障害に及ぼすSMA-SODの効果に関する実験的研究

イヌを用いた18分間完全全脳虚血モデルにおける,神経細胞の経時的組織学的変化に関する研究

イヌを用いた18分間完全全脳虚血モデルにおける,神経細胞の経時的組織学的変化に関する研究

The effects of a thromboxane A2 receptor antagonist on neurologic recovery after 15 min complete global brain ischemia in dogs.

The effects of a thromboxane A(2) receptor antagonist (anti-TXA(2); ONO-3708) on the neurologic recovery after 15 min complete cerebral ischemia were investigated in dogs. Complete cerebral ischemia was achieved by occlusion of the trunk of the aorta, the superior and the inferior caval vein. Seventeen dogs were divided into 2 groups; 1) control group (no drug, n = 9), 2) Anti-TXA(2) group (anti-TXA(2) 200 mcg.kg(-1) in iv bolus soon after recirculation followed by continuous infusion at a rate of 10 mcg.kg(-1).min(-1) for 3 days, n = 8). EEG, auditory brainstem response (ABR), middle latency response (MLR), and somatosensory evoked potential (SEP) recordings were obtained before ischemia, 120 min after re-circulation and on the 7th day after ischemia. The neurologic recovery score (NRS) were determined on the 3rd and the 7th day. Impaired EEG score was significantly higher in the anti-TXA(2) group on 7th day after ischemia ( P < 0.05). Anti-TXA(2) increased the reappearance rates of the ABR-Vth ( P < 0.05) and the SEP-N(3) waves ( P < 0.01) at 120 min after ischemia. The survival rate tended to be higher in the anti-TXA(2) group. However, NRS did not significantly differ in the groups.

Histological changes of neuronal damage in vegetative dogs induced by 18 minutes of complete global brain ischemia: two-phase damage of Purkinje cells and hippocampal CA1 pyramidal cells

We have developed a functional vegetative model by an 18-min clamping of the ascending aorta combined with a bypass formation between the aorta to right atrium and the aorta to femoral vein. Complete global brain ischemia (CGBI) induced for 18 min with this model provided the following distinct advantages: cardiopulmonary functions were well preserved during postischemic recirculation, and all dogs survived without serious extracerebral complications. Neuronal damage in vegetative dog induced by an 18-min CGBI was studied by light and electron microscopy. The Purkinje cells and the hippocampal CA1 pyramidal cells showing clumping of nuclear chromatin and slightly increased stainability were observed after CGBI without recirculation. All these neurons showed transient increased stainability with microvacuolation 15 min after recirculation. Over 50% of these neurons showed virtually normal features 1 h after recirculation. Damage to these neurons progressed again slowly up to 6 h after recirculation. However, all these neurons had disintegrated 2-3 days after recirculation. A decrease in synaptic vesicles was observed in many presynaptic terminals in the molecular layers of the cerebellum after CGBI without recirculation. These changes in the presynaptic terminals progressed 15 min after recirculation. These results indicated that the damage to the Purkinje cells and the CA1 pyramidal cells induced by CGBI consisted of two phases, and that the change in the early phase was reversible. We speculate that the damage to the Purkinje cells in the early stage is related to the decrease of the synaptic vesicles in the presynaptic terminals.

Multifaceted therapy after global brain ischemia in monkeys.

The pathophysiology of postischemic encephalopathy is complex, and includes tissue acidosis, edema, hypoperfusion, membrane dysfunction, impaired energy production, and possibly hypermetabolism. We tested the hypothesis that this multifactorial clinical problem must be approached with multifaceted therapy, with specific treatment aimed at each of the above postischemic changes. Eighteen minutes of complete global brain ischemia was produced with a higher pressure neck cuff in pigtailed monkeys. Control treatment postischemia (n = 9): 1) Normotension (MAP greater than or equal to 80 mmHg) restored within 2 min postischemia, 2) controlled ventilation for 24 hours with PaCO2 = 25 mmHg, 3) normothermia, and 4) phenytoin seizure prophylaxis from 20 hours postischemia. Experimental treatment (n = 10): Control treatment plus the following modifications: 1) Hemodilution to hematocrit 25% at 1-4 min postischemia, 2) brief hypertension (MAP 130 mmHg for 5 min) after accomplished hemodilution, 3) hypothermia for 6 hours, 4) pentobarbital 30 mg/kg i.v., 5) dexamethasone 4 mg/kg i.v. Outcome was evaluated at 96 hours postischemia by overall performance categories (OPC) (OPC I = normal, OPC V = brain death), neurologic deficit (ND) scores (100% ND = brain death, 0% ND = normal), and histologic damage scores of the brains. Brain death developed in 1/9 control and 0/10 treated animals. The number of awake monkeys (OPC I and II) at 96 hours postischemia was significantly higher in the treated group (7/10) than in the control group (2/9) (p = 0.05). The median ND scores for the two groups were 16 and 35% respectively (p greater than 0.05). The results strongly suggest that postischemic treatment may be beneficial and that a multifaceted therapeutic approach is worth pursuing.

Thiopental treatment after global brain ischemia in pigtailed monkeys.

The authors investigated the value of high-dose thiopental (TH) therapy after 16-min complete global brain ischemia (GBI) in three groups of pigtailed monkeys, using a neck cuff model of GBI with 96 h intensive care postischemia (PI). Control group (n18): Normotension was restored within 2 min PI; paralysis/controlled ventilation was maintained for 48 h PI with 50% N2O/O2. Thiopental loading group (n13): Control treatment plus TH-loading with 90 mg/kg iv given from 5 to 65 min PI (mean peak TH plasma level 130 micrograms/ml). Thiopental anesthesia group (n14): Control treatment plus TH anesthesia with 90 mg/kg iv given over 12 h PI (sustained TH plasma levels of 25-35 micrograms/ml and EEG burst suppression). Norepinephrine requirement for blood pressure control PI was greater in the TH groups than in the control group (P less than 0.05). Lidocaine was needed for control of arrhythmias in the TH loading group. There was no significant difference in mortality or neurologic outcome between the groups. At 96 h PI seven of 11 animals were awake in the control group, compared with seven of 12 and six of 12 in the two TH groups. Neurologic deficit scores (NDS) for the survivors at 96 h PI were 23 +/- 6% (mean +/- SD) (n10) in the control group, compared with 25 +/- 9% (n11) and 26 +/- 12% (n10) in the two TH groups (NDS 100% = brain death, 0% = normal). Seizures PI (in 1-2 of each group) were associated with worse neurologic deficits.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of nizofenone on pyramidal response, electrocorticogram and regional cerebral blood flow following recirculation after complete global brain ischemia in cats

Effect of nizofenone on pyramidal response (PR), electrocorticogram (ECoG) and regional cerebral blood flow (rCBF) following recirculation after complete global brain ischemia was compared with that of pentobarbital in gallamine-immobilized cats. The basilar artery and the branches of both carotid arteries (superior thyroid artery, dorsal muscular branch, internal carotid artery, occipital artery and ascending pharyngeal artery) were all ligated. The cats were subjected to complete brain ischemia by occluding both common carotid arteries for 45 min, followed by 180 min recirculation. rCBF of the cortex (suprasylvian gyrus) and the internal capsule was monitored by the hydrogen clearance method. Blood gases were regulated within a range determined previously in freely-moving cats throughout the experiment. Nizofenone (1 mg/kg, i.v.) facilitated the recovery of PR and ECoG, and it inhibited the phenomenon of secondary suppression evidenced by interruption and reversion of the recovery process. rCBF showed good recovery throughout the recirculation period. Pentobarbital (20 mg/kg, i.v.) facilitated the recovery of PR during the early period of recirculation, but secondary suppression of PR, associated with the decline of rCBF, was evident. These results suggest that the ameliorative effect of nizofenone on the recovery of neuronal functions is due to its ability to protect neurons against ischemic anoxia and to prevent interruption of postischemic circulation, and also the good recovery of rCBF is due to its ability to protect vasculature against ischemic anoxia.