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

Many models of induced ischemic and epileptic tolerance have now been described in the brain. Although detailed mechanisms underlying such protections still remain largely unknown, induction of heat shock proteins is amongst the endogenous responses believed to play an important role in cellular defense mechanisms. This study reveals that the development of epileptic tolerance also coincides with the induction of the 70,000 mol. wt heat shock protein expression within the time window of protection. Adenosine agonists or ATP-sensitive potassium channel openers have also been shown to exert strong neuroprotective effects when injected shortly prior to a severe ischemic or epileptic insult. The present work shows that adenosine receptor activation and ATP-sensitive potassium channel opening induce 70,000 mol. wt heat shock protein expression in the rat hippocampus and are able to mimic neuroprotection driven by preconditioning. R-phenylisopropyladenosine, a purine agonist, or (-)cromakalim, an ATP-sensitive potassium channel opener, was administered three days prior to a lethal ischemic or epileptic episode to mimic preconditioning. Neurodegeneration was assessed using Cresyl Violet staining and cellular DNA fragmentation visualized by the terminal deoxynucleotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick end labeling method. 70, 000 mol. wt heat shock protein expression was analysed by western blotting and immunohistochemistry. The results show a long-lasting neuroprotection induced by activation of adenosine receptors or ATP-sensitive K(+) channels as early as three days prior to induction of a severe ischemic or epileptic challenge. This protective effect is associated with enhanced 70,000 mol. wt heat shock protein expression also occurring three days following administration of R-phenylisopropyladenosine or (-)cromakalim. These findings support the idea that preconditioning doses of R-phenylisopropyladenosine and (-)cromakalim act as mild cellular stresses inducing neuroprotection in a manner similar to a mild kainate treatment prior to a lethal ischemic or severe epileptic insult three days later. They also suggest that a delayed 70,000 mol. wt heat shock protein expression induced by excitatory neuronal stresses such as short ischemia, mild kainic acid treatment or activation of adenosine receptors and ATP-sensitive potassium channels is predictive of neuronal survival against a subsequent lethal injury.
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PMID:K(ATP) channel openers, adenosine agonists and epileptic preconditioning are stress signals inducing hippocampal neuroprotection. 1109 9

Although glial cells in the optic nerve head undergo a reactivation process in glaucoma, the role of glial cells during glaucomatous neurodegeneration of retinal ganglion cells is unknown. Using a coculture system in which retinal ganglion cells and glial cells are grown on different layers but share the same culture medium, we studied the influences of glial cells on survival of retinal ganglion cells after exposure to different stress conditions typified by simulated ischemia and elevated hydrostatic pressure. After the exposure to these stressors, we observed that glial cells secreted tumor necrosis factor-alpha (TNF-alpha) as well as other noxious agents such as nitric oxide into the coculture media and facilitated the apoptotic death of retinal ganglion cells as assessed by morphology, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, and caspase activity. The glial origin of these noxious effects was confirmed by passive transfer experiments. Furthermore, retinal ganglion cell apoptosis was attenuated approximately 66% by a neutralizing antibody against TNF-alpha and 50% by a selective inhibitor of inducible nitric oxide synthase (1400W). Because elevated intraocular pressure and ischemia are two prominent stress factors identified in the eyes of patients with glaucoma, these findings reveal a novel glia-initiated pathogenic mechanism for retinal ganglion cell death in glaucoma. In addition, these findings suggest that the inhibition of TNF-alpha that is released by reactivated glial cells may provide a novel therapeutic target for neuroprotection in the treatment of glaucomatous optic neuropathy.
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PMID:Increased production of tumor necrosis factor-alpha by glial cells exposed to simulated ischemia or elevated hydrostatic pressure induces apoptosis in cocultured retinal ganglion cells. 1110 75

Glial cell line-derived neurotrophic factor (GDNF), a member of the transforming growth factor (TGF)-beta superfamily, is one of the most potent neurotrophic factors and promotes survival of many populations of cells. We examined neuroprotective effect of an adenoviral vector encoding glial cell line-derived neurotrophic factor (AxCAhGDNF) on the transient global ischemia. Gerbils received administration of AxCAhGDNF or an adenoviral vector encoding bacterial beta-galactosidase gene (AxCALacZ) through the lateral ventricle. Two days later, occluding bilateral common carotid arteries for 5 min using aneurysm clips produced the transient global forebrain ischemia. Animals showed intense immunolabeling for GDNF in ependymal cells on 2, 4 and 7 days after the operation. The exogenous gene transducted by adenovirus in the same cells was detected by in situ hybridization. The treatment with AxCAhGDNF significantly prevented the loss of hippocampal CA1 pyramidal neurons 2 to 7 days after the operation, as compared to AxCALacZ treatment. Also terminal deoxynucleotidyl transferase-mediated dUTP-biotin in situ nick end labeling (TUNEL) staining was markedly reduced in the case with AxCAhGDNF treatment at 7 days after the operation. These results indicated that the adenovirus-mediated gene transfer of GDNF might prevent the delayed neuronal death of stroke and other disorders of the cerebral vasculature.
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PMID:Rescue of ischemic brain injury by adenoviral gene transfer of glial cell line-derived neurotrophic factor after transient global ischemia in gerbils. 1110 81

Normothermic ischemia and reperfusion of the liver results in microcirculatory failure followed by necrosis and cell death. Recently, another type of cell death, apoptosis or programmed cell death, was found to be activated during the early phase of reperfusion after liver ischemia. Caspases are cysteine proteinases specifically involved in the initiation and execution phases of apoptosis. The aim of this study was to demonstrate that inhibition of apoptosis by a specific inhibitor of caspases might protect the liver against ischemia/reperfusion injury. Rats were divided into three groups: group 1, control, PBS administration; group 2, Z-Asp-cmk (Z-Asp-2,6-dichlorobenzoyl-oxymethylketone) treatment; group 3, sham-operated control animals. Z-Asp-cmk (0.5 mg Z-Asp-cmk dissolved in 300 microl PBS solution containing 1% DMSO) was injected intravenously, 2 min prior to induction of 120 min ischemia. Survival rates were compared and serum activities of aspartate aminotransferases and alanine aminotransferases were assessed in the blood collected from the suprahepatic vena cava. Histology of the liver was assessed 6 h after the end of ischemia. Apoptosis was detected by the terminal deoxynucleotidyl transferase-mediated dUTP-FITC nick end-labeling method (TUNEL method) and by electrophoresis for analysis of DNA fragmentation. Caspase activity was determined by measuring hydrolysis of the CPP32-like substrate Ac-DEVD-pNA and absorption of paranitroaniline. Z-Asp-cmk treatment significantly increased 7-day survival (95%) compared with that in nontreated rats (30%, P < 0.001). Serum activities of aminotransferases and the extent of liver congestion and necrosis were significantly (P < 0.001) decreased after treatment with Z-Asp-cmk. TUNEL-positive cells were detected 3-6 h after reperfusion in the control group. In Z-Asp-cmk pretreated rats, a dramatic decrease in the number of TUNEL-positive cells was observed. Analysis of DNA fragmentation of freshly isolated hepatocytes confirmed these results. Caspase activity was increased 3-6 h after reperfusion in the control group, but significantly (P < 0.001) decreased after treatment with Z-Asp-cmk. These findings demonstrate that liver injury following ischemia and reperfusion can be prevented by inhibition of caspases. Caspase inhibitors may have important implications for therapy in liver disease and after liver transplantation.
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PMID:Caspase inhibition protects from liver injury following ischemia and reperfusion in rats. 1111 76

Ischemic preconditioning (IP) protects the rat liver. In pigs, in which hepatic tolerance to ischemia is similar to that in humans, information on IP is lacking. Therefore, in enflurane-anesthetized pigs, hepatic vessels were occluded for 120 min (protocol 1) or 200 min (protocol 2) without (control) and with IP (3 times 10 min ischemia-reperfusion each). In protocol 1, cumulative bile flow (CBF) during reperfusion was greater in IP (47.3 +/- 5.2 ml/8 h) than in control (17.1 +/- 7.8 ml/8 h, P < 0.05). ATP content tended to recover toward normal during reperfusion in IP, whereas it remained at ischemic levels in control. Serum enzyme concentrations increased similarly during reperfusion, and <1% hepatocytes were necrotic or stained terminal deosynucleotidyl transferase-mediated dUTP nick-end labeling-positive in control and IP groups. In protocol 2, no differences in CBF, ATP, or serum enzyme concentrations during reperfusion were measured between control and IP groups, except for a somewhat reduced lactate dehydrogenase in IP. The number of necrotic or terminal deosynucleotidyl transferase-mediated dUTP nick-end labeling-positive hepatocytes tended to be greater in the IP than the control group. Thus IP provides some functional protection against reversible ischemia but no protection during prolonged ischemia in pigs.
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PMID:Minimal protection of the liver by ischemic preconditioning in pigs. 1112 34

Following a complete disruption of blood flow to the brain, cerebral ischemia, a specific neuronal population, namely the CA1 pyramidal neurons in the hippocampus, will die a delayed type of cell death. This is often referred to as "delayed neuronal death" (DND). It is not known why it takes around 48 hours for these cells to die. It is very often speculated that events, intrinsic to the CA1 neurons, regulate their demise, whereas it is less often considered that extrinsic mechanisms also could play an important role for the development of DND. We discovered that in addition to the CA1 pyramidal neurons, cells in the choroid plexus were TUNEL (terminaldeoxynucleotidyl-mediated biotin-dUTP nick-end labeling)-positive following transient forebrain global ischemia. The time course and the number of TUNEL-positive cells were determined. A dramatic increase in the number of TUNEL-positive cells in the choroid plexus was seen at 18, 24, and at 36 hours of recovery, but not at 48 hours of recovery following 15 minutes of transient forebrain global ischemia. No TUNEL-positive cells were seen at 24 hours of recovery in the CA1 region. The cell death in the choroid plexus thus preceded the occurrence of cell death in the CA1 region. Massive cell death in the choroid plexus will inevitably lead to a leaky blood-CSF barrier, which in turn will allow substances to enter the ventricular system and from there reach the brain parenchyma. We, therefore, conclude that choroid plexus cell death may adversely affect the outcome of CA1 pyramidal neurons following transient forebrain global ischemia, through, e.g., a disruption of the blood-cerebro spinal fluid barrier. Alternatively, the choroid plexus may produce factors, which can affect the outcome of neurons.
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PMID:Cell death in the choroid plexus following transient forebrain global ischemia in the rat. 1113 55

The temporospatial expression pattern of the nuclear DNA repair enzyme redox factor-1 (ref-1), the p53-activated gene (pag) 608 and the effector caspase-3 was examined by in situ hybridization histochemistry in gerbils subjected to two 10-min episodes of unilateral common carotid artery occlusion, separated by 5h. Gene responses were correlated with the metabolic state, as revealed by regional adenosine 5'-triphosphate bioluminescent imaging, and with the degree of histological damage, as assessed by haematoxylin-eosin staining and terminal deoxynucleotidyl transferase-mediated-dUTP nick end labeling (TUNEL), in order to evaluate the role of these genes in the maturation of injury. Focal infarcts developed in the dorsolateral cerebral cortex at the bregma level and the nucleus caudate-putamen within four days after repeated unilateral ischemia, as indicated by a secondary adenosine 5'-triphosphate loss after initial adenosine 5'-triphosphate recovery and by histomorphological signs of pannecrosis. The more caudal cortex at hippocampal levels and the hippocampus (CA1>CA3 area), however, exhibited selective neuronal injury without adenosine 5'-triphosphate depletion. TUNEL+ cells appeared starting 5h after repeated unilateral ischemia. TUNEL+ cells reached maximum levels in the caudate-putamen at 12-24h, but much later in the cortex and hippocampus at two days after ischemia. Remarkably few TUNEL+ cells were noticed in the thalamus, where adenosine 5'-triphosphate state did not recover after reperfusion. Following repeated unilateral ischemia, a transient elevation of ref-1 mRNA was detected after 5h in the cerebral cortex and hippocampal CA1 area. Ref-1 mRNA levels decreased within 12-24h, before the onset of tissue damage. Subsequently, pag608 and caspase-3 mRNA levels increased, closely in parallel with the appearance of DNA fragmented cells, but slightly prior to the deterioration of adenosine 5'-triphosphate state. In the caudate-putamen, pag608 and caspase-3 mRNAs reached maximum levels already 12-24h after repeated common carotid artery occlusion, when DNA fragmentation was most prominent, and declined thereafter. In the cortex and hippocampal CA1-3 areas, where DNA damage appeared more slowly, pag608 and caspase-3 mRNAs were induced starting 24h after ischemia, and remained elevated even after two to four days. The levels of pag608 and caspase-3 mRNAs were similar at rostral and caudal levels of the cortex, as well as in the hippocampal CA1 and CA3 area, although the degree of injury differed considerably between these structures. Notably, pag608 and caspase-3 mRNAs were not elevated in the thalamus after repeated unilateral ischemia. The present report shows a close temporal association between the induction of ref-1, pag608 and caspase-3 mRNAs, the manifestation of cell injury and the secondary adenosine 5'-triphosphate depletion in infarcting brain areas, suggesting (i) that de novo responses of these genes may be involved in the maturation of cell injury and (ii) that apoptotic programs and the secondary deterioration of cerebral energy state may interfere with each other after ischemia.
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PMID:Expression of redox factor-1, p53-activated gene 608 and caspase-3 messenger RNAs following repeated unilateral common carotid artery occlusion in gerbils--relationship to delayed cell injury and secondary failure of energy state. 1118 42

To determine whether apoptotic process is involved in the delayed neuronal death in hippocampal CA1 region following forebrain ischemia in gerbils, time dependent activation of caspase and DNA fragmentation were evaluated by immuno-staining and terminal dUTP nick-end-labeling staining, respectively. After transient forebrain ischemia in gerbils, activation of apoptosis related caspase, including caspase-3, was apparent, and it preceded DNA fragmentation in CA1 region. These observations suggest that apoptotic process is involved in hippocampal delayed neuronal death.
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PMID:Caspase activation as an apoptotic evidence in the gerbil hippocampal CA1 pyramidal cells following transient forebrain ischemia. 1120 85

Inhibition of the renin-angiotensin system (RAS) has been shown to be beneficial in providing cardioprotective effects in humans, but the mechanism of these effects is not well understood. In this study, we examined the effects and mechanism of RAS inhibitors on ischemia/reperfusion (IR)-induced myocardial injury in rats. Rats were randomly divided into five groups and treated with vehicle (C), angiotensin converting enzyme inhibitor (ACE-I), angiotensin II type 1 receptor antagonist (AT1-A), angiotensin II type 2 receptor antagonist (AT2-A) or ACE-I plus bradykinin B2 antagonist. Ten minutes after administration, the left main coronary artery was ligated for 45 min, and then reperfused for 120 min. IR-induced cardiomyocyte apoptosis was assessed by terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) assay and confirmed by typical DNA laddering. Mitogen-activated protein kinase, extracellular signal-regulated protein kinase (ERK) and c-Jun NH2-terminal protein kinase (JNK) activity in the ischemic zone were measured by an in vitro kinase assay. The duration of ventricular tachycardia (VT) during ischemia was reduced by AT2-A and ACE-I, and increased by AT1-A and ACE-I+icatibant. ACE-I and AT2-A reduced apoptosis (by 54% and 53%) and infarct size (by 42% and 41%), while AT1-A increased apoptosis (by 86%) and infarct size (by 45%). These changes were negatively correlated with the change in ERK activity. The effects of ACE-I on apoptosis and infarct size were abolished by the coadministration of icatibant. Apoptosis was correlated with the occurrence of VT (r=0.837, p<0.001). These results suggest that both the accumulation of bradykinin and inhibition of AT2 receptor are cardioprotective against IR injury through the activation of ERK, but not JNK.
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PMID:Mechanism of the cardioprotective effect of inhibition of the renin-angiotensin system on ischemia/reperfusion-induced myocardial injury. 1132 78

In a rat forebrain ischemia model, the authors examined whether loss of cytochrome c from mitochondria correlates with ischemic hippocampal CA1 neuronal death and how cytochrome c release may shape neuronal death. Forebrain ischemia was induced by bilateral common carotid artery occlusion with simultaneous hypotension for 10 minutes. After reperfusion, an early rapid depletion of mitochondrial cytochrome c and a late phase of diffuse redistribution of cytochrome c occurred in the hippocampal CA1 region, but not in the dentate gyrus and CA3 regions. Intracerebroventricular administration of Z-DEVD-FMK, a relatively selective caspase-3 inhibitor, provided limited but significant protection against ischemic neuronal damage on day 7 after reperfusion. Treatment with 3 minutes of ischemia (ischemic preconditioning) 48 hours before the 10-minute ischemia attenuated both the early and late phases of cytochrome c redistribution. In another subset of animals treated with cycloheximide, a general protein synthesis inhibitor, the late phase of cytochrome c redistribution was inhibited, whereas most hippocampal CA1 neurons never regained mitochondrial cytochrome c. Examination of neuronal survival revealed that ischemic preconditioning prevents, whereas cycloheximide only delays, ischemic hippocampal CA1 neuronal death. DNA fragmentation detected by terminal deoxytransferase-mediated dUTP-nick end labeling (TUNEL) in situ was largely attenuated by ischemic preconditioning and moderately reduced by cycloheximide. These results indicate that the loss of cytochrome c from mitochondria correlates with hippocampal CA1 neuronal death after transient cerebral ischemia in relation to both caspase-dependent and -independent pathways. The amount of mitochondrial cytochrome c regained may determine whether ischemic hippocampal CA1 neurons survive or succumb to late-phase death.
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PMID:Both caspase-dependent and caspase-independent pathways may be involved in hippocampal CA1 neuronal death because of loss of cytochrome c From mitochondria in a rat forebrain ischemia model. 1133 63


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