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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Reactive oxygen species (ROS) have been implicated in the pathogenesis of the structural and functional alterations to tissues that are associated with a variety of pathological processes, including: sepsis and septic shock, thermal injury, doxorubicin-induced cardiomyopathy, hemorrhagic shock, and mesenteric ischemia/reperfusion (I/R) injury. Pyruvate (CH3COCOO-), a small molecule that is normally regarded as a key intermediate in the oxidative or anaerobic metabolism of glucose, is also a potent and effective ROS scavenger. Unfortunately, the usefulness of pyruvate as a therapeutic agent is abrogated by its very poor stability in solution. In an effort to take advantage of the ability of pyruvate to scavenge ROS while avoiding the problems associated with the instability of pyruvate in solution, we have developed a novel resuscitation fluid, which consists of a simple derivative of pyruvic acid, ethyl pyruvate, dissolved in a calcium-containing balanced salt solution. We call this solution Ringer's Ethyl Pyruvate Solution (REPS), and have shown in preliminary studies that treatment with REPS can improve outcome in a variety of animal models of critical illness.
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PMID:Ringer's ethyl pyruvate solution: a novel resuscitation fluid. 1137 8

Using 96-well microtiter strip-plates we established in vitro ischemia models with acute, progressive and delayed neuronal death onset. In vitro ischemia was induced by washing neuronal cultures with a balanced salt solution with (acute/delayed models) or without (progressive model) 25 mM 2-deoxy-D-glucose and incubating in an anaerobic chamber. Reperfusion was performed by removing cultures from the anaerobic chamber and washing and/or adding Dulbecco's modified Eagle medium containing N2 supplement. Acute neuronal death resulted in cell swelling during in vitro ischemic incubation with the majority of neurons appearing swollen and necrotic within 3 h post-insult. Progressive neuronal death was characterized by cell shrinkage during and immediately following in vitro ischemia with increasing neuronal degeneration resembling both necrosis and apoptosis over a 24-h period post-in vitro ischemia. Delayed neuronal death was induced by glutamate-receptor blockade during in vitro ischemia. Neurons appeared morphologically normal immediately following and up to 6 h after in vitro ischemia and then started to degenerate over the next 42 h by a process resembling apoptosis. We monitored oxygen consumption during in vitro ischemia and found it to be similar for the three models and have shown that plastic culture wells store oxygen. The establishment of acute, progressive and delayed in vitro models of ischemia using 96-well microtiter strip-plates will provide useful tools to further investigate ischemic neuronal death/survival mechanisms and provide a high-throughput system to evaluate potential neuroprotective agents. Oxygen storage in plastic culture wells is likely to contribute to the extended oxygen- and oxygen-glucose-deprivation times required to induce significant neuronal injury in vitro.
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PMID:Establishment of neuronal in vitro models of ischemia in 96-well microtiter strip-plates that result in acute, progressive and delayed neuronal death. 1173 28

We evaluated the efficacy of cycloheximide, heat stress, NMDA receptor blockade (MK801/AP-5), oxygen--glucose deprivation, hypoxia, hypothermia and TNFalpha preconditioning to protect cortical neurons from in vitro ischemic insults that result in acute necrotic and delayed apoptotic neuronal death. Preconditioning treatments were performed 22--24 h before in vitro ischemia. In vitro ischemia was carried out in 96-well microtitre strip-plates by washing neuronal cultures with a balanced salt solution containing 25 mM 2-deoxy-D-glucose and incubating in an anaerobic chamber. Glutamate receptor blockers were present during in vitro ischemia to induce delayed neuronal death. Cycloheximide, heat stress, MK801 and oxygen--glucose deprivation preconditioning were neuroprotective in both acute and delayed in vitro ischemic neuronal death models. AP-5 preconditioning and a 12 h post-MK801 preconditioning interval protected neurons from acute ischemic neuronal death only. Hypoxia, TNFalpha and hypothermic preconditioning provided no neuronal protection in the in vitro ischemia models. This study has confirmed for the first time that several preconditioning treatments can protect neurons from in vitro ischemia induced acute necrotic and delayed apoptotic neuronal death. In addition, a unique feature of this study is the finding that preconditioning could be induced in near-pure primary cortical neuronal cultures, thus confirming that ischemic tolerance is an intrinsic property of neurons and provides a simplified culture system for identifying neuroprotective proteins.
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PMID:Evaluation of preconditioning treatments to protect near-pure cortical neuronal cultures from in vitro ischemia induced acute and delayed neuronal death. 1184 73

We previously showed that pretreatment with a solution of ethyl pyruvate in a calcium-containing balanced salt solution, Ringer's ethyl pyruvate solution (REPS), ameliorates gut mucosal damage in rats subjected to mesenteric ischemia/reperfusion. Herein, we sought to test the hypothesis that REPS would be beneficial as a post-treatment (i.e., resuscitation fluid) for hemorrhagic shock. Anesthetized Sprague-Dawley rats were bled to a mean arterial pressure (MAP) of 40 mmHg until 40% of shed blood was returned. The animals then were resuscitated over 60 min with the remaining shed blood plus twice the shed blood volume as either Ringer's lactate solution (RLS) or REPS. In Experiment 1, RLS or REPS was then infused for 3 h more (or until death) at 3 mL/kg/h. Read-outs were post-resuscitation ileal mucosal permeability to fluorescein-labeled Dextran with an average molecular mass of 4000 Da (FD4) and survival. Permeability, determined just before death (MAP < 40 mmHg) or after 4 h of resuscitation, was assessed using an ex vivo everted gut sac technique and is expressed as a clearance (nL/cm/min). In Experiment 2, the read-outs were ileal FD4 permeability measured at 60 min after starting resuscitation and gut and liver malondialdehyde (MDA) formation. FD4 clearance data were logarithmically transformed prior to performing statistical analyses. In Experiment 1, 4/8 (50%) of RLS-treated rats survived 4 h after resuscitation whereas 7/7 (100%) of REPS-treated rats survived (P< 0.05). Ileal FD4 clearances were 105 +/- 30*, 85 +/- 34*, and 38 +/- 7 for all rats treated with RLS, surviving rats treated with RLS, and rats treated with REPS, respectively (the asterisk indicates P < 0.05 vs. REPS). In Experiment 2, ileal FD4 clearances were 71 +/- 13* and 34 +/- 8 for rats treated with RLS and REPS (n = 5 each), respectively. Post-resuscitation levels of MDA in the ileum and liver were significantly lower in rats treated with REPS as compared with RLS. Resuscitation with REPS, a stable and nontoxic antioxidant solution, improves survival and ameliorates ileal mucosal permeability in a rat model of severe hemorrhagic shock.
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PMID:Resuscitation from hemorrhagic shock with Ringer's ethyl pyruvate solution improves survival and ameliorates intestinal mucosal hyperpermeability in rats. 1206 83

The glycolytic intermediate, pyruvate, is capable of scavenging reactive oxygen species (ROS). However, this compound is relatively unstable and hence is not useful as a therapeutic agent. Ethyl pyruvate, a simple derivative of pyruvate, appears to be more stable, and when formulated in a calcium-containing Ringer's-type balanced salt solution (REPS), has been shown to be salutary in rat models of two pathophysiological conditions--mesenteric ischemia/reperfusion and hemorrhagic shock/resuscitation--that are thought to be mediated, at least in part, by ROS. Because ROS also have been implicated in the pathogenesis of lipopolysaccharide (LPS)-induced shock, we carried out a series of experiments to determine if REPS is beneficial in this condition. Anesthetized rats were challenged with intravenous LPS (20 mg/kg). When mean arterial pressure (MAP) decreased to 60 mmHg, 3- to 5-mL boluses of either REPS (n = 10) or Ringer's lactate solution (RLS; n = 10) were infused as needed to prevent MAP from decreasing further. By design, the maximal volume of fluid infused was 7 mL/kg. Resuscitation with REPS as compared with RLS prolonged survival time (498 +/- 48 min vs. 362 +/- 30 min; P = 0.0014). Resuscitation with REPS as compared with RLS also was associated with significantly lower circulating concentrations of nitrite/nitrate and interleukin (IL)-6 and higher plasma levels of IL-10. These data support the view that delayed treatment with REPS modulates the inflammatory response to LPS, and prolongs survival time in a lethal model of endotoxic shock.
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PMID:Resuscitation with Ringer's ethyl pyruvate solution prolongs survival and modulates plasma cytokine and nitrite/nitrate concentrations in a rat model of lipopolysaccharide-induced shock. 1246 57

Pyruvate plays a central role in intermediary metabolism. Pyruvate, however, is also a potent antioxidant and free radical scavenger, and numerous studies have shown that treatment with this compound can be salutary in numerous pathologic conditions that are thought to be mediated, at least in part, by redox-dependent phenomena. Unfortunately, aqueous solutions of pyruvate rapidly undergo an aldol-like condensation reaction to form 2-hydroxy-2-methyl-4-ketoglutarate (parapyruvate), a compound that is a potent inhibitor of a critical step in the mitochondrial tricarboxylic acid cycle. To circumvent this issue, our laboratory formulated a derivative of pyruvic acid, ethyl pyruvate, in a calcium- and potassium-containing balanced salt solution. We showed that treatment with this fluid could ameliorate much of the structural and functional damage to the intestinal mucosa caused by mesenteric ischemia and reperfusion in rats. In subsequent studies, we showed that treatment with ethyl pyruvate solution could improve survival in rodent models of hemorrhagic shock and resuscitation and also down-regulate a number of proinflammatory genes. Recently, ethyl pyruvate was also shown to improve survival in murine models of acute endotoxemia and bacterial peritonitis. Although the biochemical basis for the anti-inflammatory actions of pyruvate remain to be elucidated, this simple compound warrants further evaluation as a treatment for a number of conditions commonly encountered in the practice of critical care medicine.
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PMID:Ethyl pyruvate: a novel anti-inflammatory agent. 1254 77

Brain ischemia can be studied in vitro by depriving primary neurons of oxygen and glucose by replacing oxygen with argon and glucose with its antimetabolite 2-deoxy-D-glucose. In this contribution, we explain how to construct a reliably functioning ischemia chamber and use it to study neuronal cell death in neuron-enriched fetal primary cortical cultures grown under serum-free conditions. We observed that these cultures exhibited a significant cell death even during exposure to oxygenated balanced salt solution used as control for oxygen-glucose deprivation. We show that addition of only 2% fetal calf serum 24 h prior, during, and after treatment almost abolished this undesirable cell loss and proportionally increased cell death induced by oxygen-glucose deprivation. Western blots and immunocytochemistry showed that these effects were mainly due to an increase in neuronal viability under control conditions accompanied by a limited glial proliferation independent of the treatment condition. Under these modified conditions, the cultures could also still be effectively preconditioned by a short-term oxygen-glucose deprivation. In summary, this modified protocol combines the advantages of serum-free neuronal culture, where potentially toxic antimitotic substances can be omitted, with a serum-mediated protection of neurons against unspecific factors and concomitant sensitization for oxygen-glucose deprivation.
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PMID:Short-term serum supplementation improves glucose-oxygen deprivation in primary cortical cultures grown under serum-free conditions. 1580 Nov 69

Ethyl pyruvate is a simple derivative in Ca(+2)- and K(+)-containing balanced salt solution of pyruvate to avoid the problems associated with the instability of pyruvate in solution. It has been shown to ameliorate the effects of ischemia-reperfusion (I/R) injury in many organs. It has also been shown that I/R injury delays the healing of colonic anastomosis. In this study, the effect of ethyl pyruvate on the healing of colon anastomosis and anastomotic strength after I/R injury was investigated. Anastomosis of the colon was performed in 32 adult male Wistar albino rats divided into 4 groups of 8 individuals: (1) sham-operated control group (group 1); (2) 30 minutes of intestinal I/R by superior mesenteric artery occlusion (group 2); (3) I/R+ ethyl pyruvate (group 3), ethyl pyruvate was administered as a 50-mg/kg/d single dose; and (4) I/R+ ethyl pyruvate (group 4), ethyl pyruvate administration was repeatedly (every 6 hours) at the same dose (50 mg/kg). On the fifth postoperative day, animals were killed. Perianastomotic tissue hydroxyproline contents and anastomotic bursting pressures were measured in all groups. When the anastomotic bursting pressures and tissue hydroxyproline contents were compared, it was found that they were decreased in group 2 when compared with groups 1, 3, and 4 (P < .05). Both anastomotic bursting pressure (P = .005) and hydroxyproline content (P < .001) levels were found to be significantly increased with ethyl pyruvate administration when compared with group 2. When ethyl pyruvate administration doses were compared, a significant difference was not observed (P > .05). Ethyl pyruvate significantly prevents the delaying effect of I/R injury on anastomotic strength and healing independent from doses of administration.
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PMID:Ethyl pyruvate protects colonic anastomosis from ischemia-reperfusion injury. 1906 91

Stimulation of the Na(+)-H(+) exchanger plays an important role in the pathway of myocardial dysfunction and injury following hemorrhagic shock. Inhibition of the Na(+)-H(+) exchanger appears to be a new pharmacological tool for myocardial protection. Despite the extensive research that has been done on the role of the Na(+)-H(+) exchanger in ischemia reperfusion, little is known about the role of the exchanger following hemorrhagic shock. The purpose of this study was to examine the protective effects of blocking the cardiac Na(+)-H(+) exchanger, using 20 microM dimethyl amiloride (DMA), a specific Na(+)-H(+) exchanger blocker, on myocardial contractile function after ex vivo perfusion of isolated rat heart following 1 h of hemorrhagic shock. Sprague-Dawley rats were assigned to hemorrhage + DMA, hemorrhage, sham hemorrhage + DMA and sham hemorrhage groups (n = 6 per group). Hearts were perfused with a balanced salt solution for 60 min. In the DMA treated group, 20 microM DMA was added for the first 5 min of the 60-min ex vivo heart resuscitation. The results showed that inhibition of the Na(+)-H(+) exchanger for 5 min on ex vivo perfusion of the isolated hearts following hemorrhagic shock using 20 microM DMA improved myocardial contractile function. Blocking the Na(+)-H(+) exchanger on ex vivo perfusion of isolated hearts using 20 muM DMA has protective effects on myocardial contractile function.
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PMID:Dimethyl amiloride, a Na+-H+ exchange inhibitor, and its cardioprotective effects in hemorrhagic shock in in vivo resuscitated rats. 1934 May 41

The cysteine proteases caspase-3 and cathepsins are involved in both neuronal plasticity and neuropathology. Using primary neuroglial and glial cerebellar cultures, the pH dependence of cleavage of a synthetic caspase-3 substrate, Ac-DEVD-AMC, was studied. At acidic pH, cathepsin B cleaved Ac-DEVD, this activity being significantly higher than that of caspase-3 at pH 7.4. This activity is blocked by peptide inhibitors of both caspase-3 and cathepsin B. Substitution of culture medium for balanced salt solution stimulated cathepsin B secretion in both types of cultures. Ischemia (oxygen-glucose deprivation) significantly decreased secretion of cathepsin B activities into the culture medium.
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PMID:A secreted caspase-3-substrate-cleaving activity at low pH belongs to cathepsin B: a study on primary brain cell cultures. 1936 22


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