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

Transient cerebral ischemia is a pathological process whereby an irreversible suppression of protein synthesis is believed to contribute to the extent of cell death in vulnerable neurons. Endoplasmic reticulum (ER) dysfunction has been identified as being responsible for ischemia-induced shut-down of translation. Recovery from ER dysfunction is facilitated by GADD34, a protein that dephosphorylates eukaryotic initiation factor (eIF)2alpha-P and thus reactivates protein synthesis. We investigated ischemia-induced changes in GADD34 levels in wild-type and Cu2+/Zn2+ SOD (SOD1) over-expressing rats. Transient global cerebral ischemia was induced by common carotid artery occlusion. Tissue samples were taken from the vulnerable hippocampal CA1 subfield and the resistant cerebral cortex of the right and left hemispheres for evaluation of changes in gadd34 mRNA and GADD34 protein levels. In wild-type animals, we found significantly lower GADD34 levels than in SOD1 transgenes but no differences in gadd34 mRNA levels, implying that superoxides regulate gadd34 translation. After ischemia, GADD34 protein levels were significantly increased in the cortex but not in the CA1 subfield, and these changes occurred earlier in SOD1 transgenic than in wild-type animals. The rise in gadd34 mRNA levels did not differ in the cortex and CA1 subfield, implying that gadd34 expression is regulated at the translational level.
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PMID:GADD34 protein levels increase after transient ischemia in the cortex but not in the CA1 subfield: implications for post-ischemic recovery of protein synthesis in ischemia-resistant cells. 1525 48

To assess the role of brain antioxidant capacity in the pathogenesis of neonatal hypoxic-ischemic brain injury, we measured the activity of glutathione peroxidase (GPX) in both human-superoxide dismutase-1 (hSOD1) and human-GPX1 overexpressing transgenic (Tg) mice after neonatal hypoxia-ischemia (HI). We have previously shown that mice that overexpress the hSOD1 gene are more injured than their wild-type (WT) littermates after HI, and that H(2)O(2) accumulates in HI hSOD1-Tg hippocampus. We hypothesized that lower GPX activity is responsible for the accumulation of H(2)O(2). Therefore, increasing the activity of this enzyme through gene manipulation should be protective. We show that brains of hGPX1-Tg mice, in contrast to those of hSOD-Tg, have less injury after HI than WT littermates: hGPX1-Tg, median injury score = 8 (range, 0-24) versus WT, median injury score = 17 (range, 2-24), p < 0.01. GPX activity in hSOD1-Tg mice, 2 h and 24 h after HI, showed a delayed and bilateral decline in the cortex 24 h after HI (36.0 +/- 1.2 U/mg in naive hSOD1-Tg versus 29.1 +/- 1.7 U/mg in HI cortex and 29.2 +/- 2.0 for hypoxic cortex, p < 0.006). On the other hand, GPX activity in hGPX1-Tg after HI showed a significant increase by 24 h in the cortex ipsilateral to the injury (48.5 +/- 5.2 U/mg, compared with 37.2 +/- 1.5 U/mg in naive hGPX1-Tg cortex, p < 0.008). These findings support the hypothesis that the immature brain has limited GPX activity and is more susceptible to oxidative damage and may explain the paradoxical effect seen in ischemic neonatal brain when SOD1 is overexpressed.
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PMID:Manipulation of antioxidant pathways in neonatal murine brain. 1529 91

The effects of the herbal prescription youkongdan (YKD) on memory performance of rodents following cerebral ischemia/reperfusion and scopolamine administration were measured and compared to the age-related changes in mRNA expression induced by dietary supplementation of YKD. Following ischemia, YKD decreased neuronal cell loss in the CA1 region of rat hippocampus by 89% relative to controls. YKD improved the water maze performance of both ischemic and scopolamine-treated animals. Dietary administration of YKD resulted in significant modulation of Egr1, Grp78, Hsp86, SOD1, and alphaB crystallin mRNA expression and a trend toward increased exploratory behavior in older mice.
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PMID:The herbal prescription youkongdan modulates rodent memory, ischemic damage and cortical mRNA gene expression. 1537 Jan 93

The aim of this study was to investigate the role of nitric oxide (NO) in hepatic ischemia-reperfusion (I/R) injury in rats. Immunohistochemistry was used to examine the protein expression of endothelial and inducible nitric oxide synthases (eNOS, iNOS) and nitrotyrosine after I/R challenges to the liver, and blood levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactic dehydrogenase (LDH), hydroxyl radical and NO were measured before ischemia and after reperfusion. Ischemia was induced by occlusion of the common hepatic artery and portal vein for 40 min, followed by reperfusion for 90 min. Reperfusion of the liver induced a significant increase in the blood concentrations of AST, ALT, LDH (n = 8; P < 0.001), hydroxyl radical (n = 8; P < 0.001) and NO (n = 8; P < 0.01). The eNOS, iNOS, nitrotyrosine, SOD1 and SOD2 protein expression was also found to increase significantly after reperfusion (n = 3). Administration of the NOS inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) (n = 8) had a protective effect on the I/R-related injury, but the NO donor L-arginine (L-Arg) (n = 8) potentiated the damage caused by I/R. These results suggest that reperfusion of the liver induces expression of NOS, which is related to the elevation of blood NO. The increase in hydroxyl radical concentration was accompanied by an increase in antioxidant enzyme expression (SOD1 and SOD2), and an increase in nitrotyrosine expression was also observed, reflecting the increased production of NO and oxygen radicals. We concluded from the protective effect of L-NAME and the potentiation by L-Arg that NOS expression and increases in NO and hydroxyl radical production have deleterious effects on the response to I/R in the liver.
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PMID:Ischemia and reperfusion of liver induces eNOS and iNOS expression: effects of a NO donor and NOS inhibitor. 1561 29

Overexpression of copper/zinc superoxide dismutase (SOD1) in transgenic mice protects from transient focal cerebral ischemia in adult animals, but increases oxidative injury in perinatal mice. The effect of SOD1 overexpression on astrocytes subjected to ischemia-like insults has not yet been determined. Overexpression of human SOD1 in astrocytes resulted in a 3-fold increase in SOD1 activity without coupled up-regulation of catalase or glutathione peroxidase activities. Cells subjected to oxygen-glucose deprivation (OGD) or glucose deprivation to mimic ischemic injury were protected by SOD1 overexpression. OGD injury was reduced 47.6+/-9.3%, assessed by release of lactate dehydrogenase. OGD also caused a significant increase in catalase activity which was moderated by SOD1 overexpression. The level of glutathione in astrocytes overexpressing SOD1 was maintained at higher levels following 5 h OGD compared to control cultures under the same conditions. Reduction of glutathione prior to OGD significantly increased cell death of SOD1-overexpressing astrocytes as well as controls, but SOD1 still provided significant protection, suggesting that both GSH-dependent scavenging and GSH-independent scavenging are relevant to SOD1 protection in astrocytes.
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PMID:Overexpression of copper/zinc superoxide dismutase decreases ischemia-like astrocyte injury. 1578 Jul 69

While superoxide dismutase (SOD) may be useful in treating inflammation, the problems of getting it into the blood in the right concentration, for long enough periods, and to the intended organ, have limited its translation into human clinical medicine. None of the three naturally occurring forms of human SOD is well suited for use as a therapeutic agent. SOD1 and SOD2 are normally intracellular enzymes and are rapidly cleared by the kidney. SOD3 occurs outside cells, but binds so tightly to cell surfaces or to collagen fibrils in the intracellular matrix that it remains largely in the few organs that secrete it. The "stickiness" of SOD3 results from a positively charged region in the hydrophilic C-terminus of each subunit. We have genetically engineered a hybrid chimeric SOD called SOD2/3 with greatly improved pharmacological properties. It has the sequence encoding the mature human SOD2 fused to the C-terminus of human SOD3. This hybrid SOD2/3 is highly expressed and easily purified. The molecule binds to endothelial cells, but less tightly than SOD3, and circulates well enough to become widely attached to extracellular surfaces, presumably in many tissues. The loose binding appears to produce a buffering effect on enzyme concentration, effectively eliminating bell-shaped dose-response curves. Single IV injections of SOD2/3 have protected experimental animals against a variety of models involving inflammation or ischemia/reperfusion.
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PMID:Anti-inflammatory properties of a chimeric recombinant superoxide dismutase: SOD2/3. 1586 16

In the present study, we investigated the chronological alterations in SOD1 and its copper chaperone (chaperone for superoxide dismutase, CCS) immunoreactivities and their neuroprotective effects against neuronal damage in the gerbil hippocampus after 5 min of transient forebrain ischemia. SOD1 and CCS immunoreactivities were significantly increased in the stratum pyramidale of the CA1 region at 24 and 12 h after ischemic insult, respectively. At 24 h after ischemic insult, the SOD1 and CCS immunoreactivities were colocalized in the CA1 pyramidal cells of the stratum pyramidale. Thereafter, their immunoreactivities were significantly decreased in the CA1 region. To elucidate the effects of CCS or CCS/SOD1, we constructed the expression vectors PEP-1-SOD and PEP-1-CCS. In the CCS-treated group and the CCS/SOD1-treated group, 43.9 and 78.9% pyramidal cells, respectively, compared to the sham-operated group, were stained with cresyl violet 5 or 7 days after ischemic insult. The distribution pattern of active astrocytes and microglia in the PEP-CCS/SOD1-treated group 5 days after ischemic insult was similar to that of the sham-operated group. In addition, the SOD activity in the PEP-CCS- or PEP-CCS/SOD1-treated group was maintained by 10 days after ischemic insult. The SOD activity was higher in the PEP-CCS/SOD1-treated group vs the CCS-treated group. These results suggest that the enhanced expression of SOD1 and CCS may be related to compensatory mechanisms against ischemic damage and that cotreatment with CCS and SOD1 has a greater neuroprotective effect than treatment with CCS or SOD1 in isolation.
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PMID:Copper chaperone for Cu,Zn-SOD supplement potentiates the Cu,Zn-SOD function of neuroprotective effects against ischemic neuronal damage in the gerbil hippocampus. 1769 34

In the present study, we investigated chronological changes in Cu,Zn-superoxide dismutase (SOD1) immunoreactivity and its protein levels in the hippocampal CA1 region of adult and aged gerbils after transient forebrain ischemia to compare ischemia-related changes in SOD1 in adult and aged gerbils. Delayed neuronal death in the CA1 region at 4 days after ischemic insult was prominent in adult gerbils compared to that in aged gerbils. In sham-operated gerbils, SOD1 immunoreactivity and protein level in the aged group were significantly higher than that in the adult group. At 12 h after ischemia-reperfusion, SOD1 immunoreactivity and protein level were increased in both the groups. At 1 day after ischemia, SOD1 immunoreactivity and protein level in the adult group were significantly increased: the SOD1 immunoreactivity was increased in non-pyramidal cells as well as pyramidal cells. At this time after ischemia, SOD1 immunoreactivity and protein level in the aged group were decreased: the immunoreactivity was decreased significantly in pyramidal cells. At 4 days after ischemia, SOD1 immunoreactivity was detected only in non-pyramidal cells of the CA1 region in both the groups. These results suggest that SOD1 in the gerbil hippocampal CA1 region is higher in sham-aged group than that in sham adult one, and that different changes in SOD1 in CA1 pyramidal cells after ischemia in adult and aged gerbils may indicate different processes in delayed neuronal death with time after ischemic insult.
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PMID:Comparative study on Cu,Zn-SOD immunoreactivity and protein levels in the adult and aged hippocampal CA1 region after ischemia-reperfusion. 1667 1

In this study, we examined changes in the level and immunoreactivity of alpha-synuclein in the hippocampal CA1 region of adult (6 months old) and aged (24 months old) gerbils after 5 min of transient forebrain ischemia. The delayed neuronal death of CA1 pyramidal cells in adult gerbils was severer than that in aged gerbils 4 days after ischemia/reperfusion. Alpha-synuclein immunoreactivity in the CA1 region of adult and aged gerbils significantly changed after ischemia. In control animals, alpha-synuclein immunoreactivity and level in the aged-gerbil CA1 region were higher than those in the adult-gerbil CA1 region. In both adult and aged gerbils, alpha-synuclein immunoreactivity and level started to increase 3h after ischemia, and they were highest 1 day after ischemia. Thereafter, alpha-synuclein immunoreactivity and level decreased with time after ischemia. We also observed the effects of Cu,Zn-superoxide dismutase (SOD1) on ischemic damage using the Pep-1 transduction domain. Alpha-synuclein level in the CA1 region was lower in Pep-1-SOD1-treated adult and aged gerbils than in vehicle-treated adult and aged gerbils. We conclude that neuronal loss in the hippocampal CA1 region of adult gerbils was more prominent than that in aged gerbils 4 days after ischemia/reperfusion. The higher level of alpha-synuclein in the aged-gerbil CA1 region than that in the adult-gerbil CA1 region may be associated with the earlier induction of reactive oxygen species, and Pep-1-SOD1 potentially and reversibly inhibits the accumulation of alpha-synuclein in the CA1 region after transient ischemia.
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PMID:Comparison of alpha-synuclein immunoreactivity and protein levels in ischemic hippocampal CA1 region between adult and aged gerbils and correlation with Cu,Zn-superoxide dismutase. 1675 29

Nuclear factor-kappa B (NF-kappaB) is activated by oxidative stress such as that induced by transient focal cerebral ischemia (tFCI). Whether NF-kappaB has a role in cell survival or death in stroke is a matter of debate. We proposed that the status of oxidative stress may determine its role in cell death or survival after focal ischemia. To characterize the coordinated expression of genes in NF-kappaB signaling after mild cerebral ischemia, we investigated the temporal profile of a NF-kappaB-pathway-focused DNA array after 30 mins of tFCI in wild-type (WT) mice and human copper/zinc-superoxide dismutase transgenic (SOD1 Tg) mice that had a significantly reduced level of superoxide. Differentially expressed genes among 96 NF-kappaB-related genes were further confirmed and compared in the WT and SOD1 Tg mice using quantitative polymerase chain reaction, Western blotting, and immunohistochemistry. Persistent upregulation of NF-kappaB seen at 7 days in the WT mice was decreased in the SOD1 Tg mice. Lymphocytotrophic cytokine genes such as interleukin-2, interleukin-12, and interferon-alpha1 were increased in the SOD1 Tg mice compared with the WT mice after tFCI. In addition, antiapoptosis factors bcl-2 and tumor necrosis factor receptor-associated factor 1 rapidly increased in the SOD1 Tg mice compared with the WT mice. This study indicates that reduced oxidative stress by SOD1 overexpression increased NF-kappaB-related rapid defenses, such as immune response and antiapoptosis factors, and prevented brain damage after tFCI-induced oxidative stress.
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PMID:Reduced oxidative stress promotes NF-kappaB-mediated neuroprotective gene expression after transient focal cerebral ischemia: lymphocytotrophic cytokines and antiapoptotic factors. 1686 54


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