Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The distribution of apolipoprotein E (apo E) and apolipoprotein J (apo J) was investigated immunocytochemically in rats at various time intervals after 10 min global cerebral ischemia (GCI) induced by cardiac arrest. Strong apo E and weaker apo J immunoreactivity was found extracellularly in multiple deposits located close to the microvessels. These deposits appeared 3 h after GCI and were present, but not in all the animals, at all time intervals studied post-GCL. In some rats, apo E immunoreactivity was also found in small necrotic foci. Widespread, neuronal apo E immunostaining appeared 6 h post-GCI. However, the strongest neuronal apo E immunoreactivity was found 7 days post-GCI in those neurons, most often observed in the CA1 hippocampal region, exhibiting signs of ischemic cell damage. These ischemically damaged neurons displayed weaker immunoreactivity to apo J, despite its increase in the response to GCI in the various brain regions examined. Our data show that mechanisms operating in ischemia are able to supply large amounts of apo E and apo J to the brain tissue and suggest involvement of both apo E and apo J in a complex series of events occurring in the ischemic brain. Perivascular deposits of apo E/apo J colocalized with amyloid beta protein precursor epitopes that have been disclosed by us previously in this model. Whether this phenomenon is limited to postischemic brain tissue, or can be encountered also in other pathological conditions will require further elaboration.
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PMID:Complete cerebral ischemia with short-term survival in rat induced by cardiac arrest. II. Extracellular and intracellular accumulation of apolipoproteins E and J in the brain. 779 14

The reperfusion of previously ischemic brain is associated with exacerbation of cellular injury. Reperfusion occasionally potentates release of intracellular enzymes, influx of Ca2+, breakdown of membrane phospholipids, accumulation of amyloid precursor protein or amyloid beta-(like) proteins, and apolipoprotein E. In this study, the effect of reperfusion injury on the activity of cerebral cortex enzymes acting on phosphatidyl [3H] inositol (PI) and [14C-arachidonoyl] PI was investigated. Moreover the effect of amyloid beta25-35 on PI degradation by phospholipase(s) of normoxic brain and subjected to ischemia-reperfusion injury was determined. Brain ischemia in gerbils (Meriones unguiculatus) was induced by ligation of both common carotid arteries for 5 min and then brains were perfused for 15 min, 2 h and 7 days. Statistically significant activation of enzyme(s) involved in phosphatidylinositol degradation in gerbils subjected to ischemia-reperfusion injury was observed. Nearly all gerbils showed a higher activity of cytosolic PI phospholipase C (PLC) at 15 min after ischemia. Concomitantly, the significant enhancement of the level of DAG and AA radioactivity at this short reperfusion time confirmed the active PI degradation by phospholipase(s) in cerebral cortex and hippocampus. After a prolonged reperfusion time of 7 days after ischemia, both cytosolic and membrane-bound forms of PI-PLC were activated. The question arises if alteration of membranes by the degradation of phospholipids occurring after an ischemic episode potentiates the effect of Abeta on membrane-bound enzymes. A neurotoxic fragment of amyloid, Abeta 25-35, incubated in the presence of endogenous Ca2+, increased significantly the PI-PLC activity of normoxic brain. In its non-aggregated form, Abeta 25-35 activates PI-PLC but in the aggregated form the enzymatic activity decreased. Thus, Abeta 25-35 exerts a similar effect on the membrane-bound PI-PLC from normoxic brain or subjected to ischemia reperfusion injury. We conclude that the degradation of phosphatidylinositol by cytosolic phosphoinositide-phospholipase C may contribute to the pathophysiology of delayed neuronal death following cerebral ischemia. Thus, a specific inhibitor of this enzyme(s) may offer therapeutic strategies to protect the brain from damage triggered by ischemia. Ischemia-reperfusion injury had no effect on Abeta-evoked alterations of synaptic plasma membrane-bound PI-PLC.
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PMID:Alteration of phosphoinositide degradation by cytosolic and membrane-bound phospholipases after forebrain ischemia-reperfusion in gerbil: effects of amyloid beta peptide. 1049 23

The ability of intraventricular infusion of apolipoprotein E (apoE) to reduce neuronal damage after global cerebral ischemia was investigated in apoE-deficient and wild-type mice. ApoE (5 microg/mL lipid-conjugated derived from human plasma; 1 microL/h, continuous infusion) significantly reduced neuronal damage in the caudate nucleus and CA2 pyramidal cell layer by approximately 50% in apoE-deficient mice after global ischemia compared to vehicle infusion. In wild-type mice infused with apoE, there was a trend for ischemic neuronal damage to be reduced. ApoE-infused mice had a marked reduction in 4-hydroxynonenal immunoreactivity, as a marker of lipid peroxidation. The results show that the presence of apoE at or after the time of injury can be neuroprotective, possibly via an anti-oxidant mechanism.
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PMID:Intraventricular infusion of apolipoprotein E ameliorates acute neuronal damage after global cerebral ischemia in mice. 1072 9

Transient brain ischemia in the rat produces a stereotyped pattern of selective neuronal degeneration which simulates early Alzheimer's disease (AD) pathology. The aim of the present study was to determine if apolipoprotein E (ApoE) variables are related to alterations in other proteins which play a central role in the pathogenesis of AD; amyloid precursor protein (APP) and beta-amyloid peptide (A beta). The postischemic time course of ApoE and APP and A beta immunoreactivity in brain was examined at survival time from 2 days to 1 year in rats subjected to 10 min cardiac arrest. These data indicate that there are long lasting alterations of ApoE and A beta after brain ischemia. The most likely stimulus for promoting increase of both ApoE and A beta expression are ischemic-reperfusion processes. Our data suggest that ApoE modulates the outcome following cerebral ischemia via molecular events in common with AD pathogenesis. We propose that ischemic-reperfusion processes in brain are the fountain-head of a cycle of molecular and cellular events that have neurodegenerative consequences which finally lead to AD.
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PMID:The role of apolipoprotein E in the deposition of beta-amyloid peptide during ischemia-reperfusion brain injury. A model of early Alzheimer's disease. 1081 22

Oxidative stress and lipid peroxidation may contribute to the pathology of neurodegenerative disorders such as Alzheimer's disease (AD) and cerebral ischemia. 4-Hydroxynonenal (4-HNE) is a toxic by-product of lipid peroxidation, and immunoreactivity to 4-HNE has been used to examine lipid peroxidation in the pathogenesis of AD and ischemia. This study sought to determine 1) if there are cellular alterations in 4-HNE immunoreactivity in the human hippocampus after global ischemia, and 2) whether possession of an apolipoprotein E (APOE) epsilon4 allele influenced the extent of 4-HNE immunoreactivity. 4-HNE immunoreactivity was assessed semi-quantitatively in the temporal lobe of a group of controls (n = 44) and in a group of patients who had an episode of global ischemia as a result of a cardiorespiratory arrest and subsequently died (n = 56, survival ranged from 1hr to 42 days). There was minimal cellular 4-HNE immunoreactivity in the control group. However, compared to controls, 4-HNE immunoreactivity was significantly increased in neurons (p < 0.0002) and glia (p < 0.0001) in the hippocampal formation after global ischemia. Possession of an APOE epsilon4 allele did not influence the extent of neuronal or glial 4-HNE immunostaining in the control or global ischemia group. There was a significant negative correlation between the extent of neuronal 4-HNE immunoreactivity with survival period after global ischemia (r2 = 0.0801; p < 0.036) and a significant positive correlation between the extent of glial 4-HNE immunoreactivity and survival after global ischemia (r2 = 0.2958; p < 0.0001). The data indicate a marked increase in neuronal and glial 4-HNE. This substantiates a role for lipid peroxidation in the pathogenesis of cerebral ischemia. There was no indication that APOE genotype influenced the extent of 4-HNE immunoreactivity.
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PMID:4-Hydroxynonenal immunoreactivity is increased in human hippocampus after global ischemia. 1155 86

Recent studies have demonstrated that apolipoprotein E (APOE) deficiency worsened neuronal injuries after transient focal and global cerebral ischemia. However, the molecular mechanism underlying the protective effect of APOE remains uncertain, even though several mechanisms, including excitotoxicty, free radicals, and apoptosis, have been cited as causes of selective neuronal vulnerability in cerebral ischemia. In the present study, we first compared the vulnerability of cultured neurons prepared from APOE-knockout mice upon exposure to glutamate, hydrogen peroxide, and staurosporine. No significant difference in cell viability was observed after exposure to glutamate or staurosporine between APOE-deficient and wild-type mice. However, exposure to hydrogen peroxide significantly increased the level of cell death in APOE-deficient mice compared with that in wild-type mice. After transient forebrain ischemia for 12 min, APOE-deficient mice showed more neuronal death than wild-type mice. Pretreatment of APOE-deficient mice with vitamin E for 2 months markedly reduced neuronal death caused by ischemia. The results suggest that APOE exerted its neuroprotective effect against ischemia through its antioxidant action but not through mitigation of glutamate toxicity or blocking of apoptosis.
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PMID:Protective effect of apolipoprotein E against ischemic neuronal injury is mediated through antioxidant action. 1194 67

The emerging evidence of ethnic variations in apolipoprotein polymorphism and Alzheimer disease risk shows that one cannot generalize findings based on a single cultural group too broadly ( Tang et al., 2001). Presence of one apolipoprotein E epsilon 4 allele is a stronger risk factor for Alzheimer disease in whites and Asians than in blacks ( Farrer et al., 1997). Environmental or genetic cofactors may modulate the effects of epsilon 4 on beta-amyloid metabolism differently in different subpopulations ( Shadlen, 1998). Recognizing this, the Alzheimer's Association has extended its goals to strengthen the scientific information base on the interactions of population diversity and Alzheimer disease heterogeneity ( NIA, 1998). This new focus is timely since minority elderly are the most rapidly increasing segment of the elderly population ( Lilienfeld and Perl, 1994, Brookmeyer et al., 1998). In this article, the authors highlight recent progress in research on Alzheimer disease among culturally diverse populations with a special emphasis on gaps in the knowledge base. The authors recommend four priorities for future Alzheimer disease research: (1) determine whether genetic causative factors interact differently in different populations; (2) reexamine the nature and role of cerebral ischemia and infarction and variations in symptom severity of Alzheimer disease; (3) explore the interaction of genes and environmental influences that are protective against Alzheimer disease; and (4) recruit and enroll ethnically diverse subjects in Alzheimer disease clinical trials.
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PMID:Research agenda for understanding Alzheimer disease in diverse populations: work group on cultural diversity, Alzheimer's association. 1235 23

Estrogen can ameliorate brain damage in experimental models of focal cerebral ischemia., estrogen increases levels of apolipoprotein E (apoE), which also has neuroprotective effects in brain injury. The authors tested the hypotheses that physiologically relevant levels of 17beta-estradiol are neuroprotective in global cerebral ischemia and that neuroprotection is mediated via apoE. In the first study, subcutaneous implants of 17beta-estradiol were tested in female C57Bl/6J mice (ovariectomized and nonovariectomized) and plasma levels measured by radioimmunoassay to validate that physiologically relevant levels could be achieved. In the second study, female C57Bl/6J and apoE-deficient mice were ovariectomized and implanted with 17beta-estradiol or placebo pellet. Two weeks later, transient global ischemia was induced by bilateral carotid artery occlusion and the mice killed after 72 hours. Ischemic and normal neurons were counted in the caudate nucleus and CA1 pyramidal cell layer and the percentage of neuronal damage was compared between the treated groups. In C57Bl/6J mice, there was less neuronal damage in the 17beta-estradiol-treated group compared with placebo group in the caudate nucleus (15 +/- 20% versus 39 +/- 27%, = 0.02) and in the CA1 pyramidal cell layer (1.8 +/- 2% versus 10 +/- 14%, = 0.08). In contrast, neuronal damage was not significantly different between the 17beta-estradiol and placebo groups in apoE-deficient mice in the caudate nucleus (47 +/- 35% versus 53 +/- 29%, = 0.7) or in the CA1 pyramidal cell layer (24 +/- 19% versus 24 +/- 19%, = 1.0). The data indicate a neuroprotective role for estrogen in global ischemia, the mechanism of which is apoE-dependent.
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PMID:Estrogen is neuroprotective via an apolipoprotein E-dependent mechanism in a mouse model of global ischemia. 1236 57

Accumulating evidence suggests that among the 3 human apolipoprotein E (apoE) isoforms encoded by the human APOE gene, the e4 allele may act to exacerbate brain damage in humans and animals. This study aimed to compare the isoform-specific vulnerability conferred by human apoE to ischemic brain damage, using mice expressing human apoE isoforms (apoE2, apoE3, or apoE4) in place of mouse apoE, produced by the gene-targeting technique in embryonic stem cells (knock-in, KI). Homozygous human apoE2 (2/2), apoE3 (3/3), or apoE4 (4/4) KI mice were subjected to permanent focal cerebral ischemia by a modified intraluminal suture method. Twenty-four h thereafter, brain damage, (as estimated by infarct volume and neurologic deficit) was significantly worse in 4/4 KI mice versus 2/2 or 3/3 KI mice (p < 0.001 for each comparison), with no significant differences between 2/2 and 3/3 KI mice. Immunohistochemistry for human apoE expression revealed similar apoE distribution with no significant difference in the immunostaining intensity among the 3 lines of KI mice. Notably. increased expression of human apoE was detected in neurons and astrocytes in the peri-infarct area, and a punctate expression pattern was evident in the border between the infarct and peri-infarct areas in all KI mice subjected to ischemia. Taken together, our results show that apoE affects the outcome of acute brain damage in an isoform-specific fashion (apoE4 > apoE3 = apoE2) in genetically engineered mice.
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PMID:Increased vulnerability to focal ischemic brain injury in human apolipoprotein E4 knock-in mice. 1263 32

The treatment of ischemic strokes is limited to the prevention of cerebrovascular risk factors and to the modulation of the coagulation cascade during the acute phase. A new therapeutic strategy could be to preventively protect the brain against noxious biological reactions induced by cerebral ischemia such as oxidative stress and inflammation to minimize their neurological consequences. Here, we show that a peroxisome proliferator-activated receptor (PPAR-alpha) activator, fenofibrate, protects against cerebral injury by anti-oxidant and anti-inflammatory mechanisms. A 14 d preventive treatment with fenofibrate reduces susceptibility to stroke in apolipoprotein E-deficient mice as well as decreases cerebral infarct volume in C57BL/6 wild-type mice. The neuroprotective effect of fenofibrate is completely absent in PPAR-alpha-deficient mice, suggesting that PPAR-alpha activation is involved as a mechanism of the protection against cerebral injury. Furthermore, this neuroprotective effect appears independently of any improvement in plasma lipids or glycemia and is associated with (1) an improvement in middle cerebral artery sensitivity to endothelium-dependent relaxation unrelated to an increase in nitric oxide synthase (NOS) type III expression, (2) a decrease in cerebral oxidative stress depending on the increase in numerous antioxidant enzyme activities, and (3) the prevention of ischemia-induced expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in cerebral vessels without any change in NOS II expression. These data demonstrate that PPAR-alpha could be a new pharmacological target to preventively reduce the deleterious neurological consequences of stroke in mice and suggest that PPAR-alpha activators could preventively decrease the severity of stroke in humans.
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PMID:Peroxisome proliferator-activated receptor-alpha activation as a mechanism of preventive neuroprotection induced by chronic fenofibrate treatment. 1286 11


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