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

The postischemic time course of amyloid protein precursor (APP), beta-amyloid protein (beta-AP), and apolipoprotein E (APO-E) immunoreactivity were examined in comparison to neuronal necrosis in the selectively vulnerable hippocampal CA1 region of gerbils subjected to 10 min of bilateral carotid occlusion-induced forebrain ischemia. Loss of 90% of the CA neurons occurred between 24 and 72 h after ischemia, after which no further neuronal necrosis was observed. At 24 h postischemia, there was a decrease in APP and beta-AP immunostaining in the CA1 region. However, beginning at 2 days, there was a dramatic increase in the staining for both proteins. This coincided with a progressive increase in the expression of APO-E and glial fibrillary acidic protein (GFAP) staining between Days 2 and 6, indicative of an activation of astrocytic protein synthesis. Each of the immunocytochemical markers also increased in the less vulnerable CA3 region. However, the peak increase in that region was much less than that in CA1 and, by 7 days, only the GFAP staining remained significantly above the sham level. It has been shown that the E4 isoform of APO-E, when oxidized, avidly binds to beta-AP and thus increases the likelihood of co-beta-AP/APO-E deposition. Therefore, it is postulated that the increased levels of amyloid proteins coincident with an increased production of APO-E in response to ischemic neuronal necrosis may provide conditions that are favorable for the postischemic formation of amyloid deposits.
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PMID:Increased amyloid protein precursor and apolipoprotein E immunoreactivity in the selectively vulnerable hippocampus following transient forebrain ischemia in gerbils. 755 50

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

B/A4 is the major component of brain amyloid plaque, one of the hallmarks of Alzheimer's disease (AD). B/A4 is a product of proteolytic processing of its precursor, the Alzheimer amyloid precursor protein (APP). Recently, apolipoprotein E (APO-E) has also been shown to be associated with Alzheimer's disease pathology because it is localized to plaques and tangles, and the gene encoding one of the isoforms of APO-E (E4) is associated with late-onset familial and sporadic AD. In addition, APO-E exhibits high affinity for binding to the B-peptide (B/A4). In this study, we have investigated changes in the steady state levels of APP, APO-E, and the astrocyte-specific marker, glial fibrillary acidic protein (GFAP) mRNA in the gerbil hippocampal CA1 region after a 10-min period of bilateral carotid occlusion-induced forebrain ischemia. Following this insult, we observed a loss of 90% of the CA1 neurons by 72 h post-ischemia. The mRNA levels on day 1 through day 7 post-ischemia were quantitated using an image analyzer. There was an increase in the transcription of APO-E and GFAP mRNAs, with the levels of APO-E mRNA being the highest (3-fold increase on day 7 post-ischemia) (P < 0.005). However, we did not see an increase in APP mRNA. In a parallel study [Hall, E.D. et al., Exp. Neurol., 135(1995) 17-27], we have also seen an increase in levels of APO-E and GFAP protein measured by immunocytochemistry. However, in contrast to the lack of an increase in APP mRNA, immunocytochemical measurement of APP did show an increase, perhaps due to delayed translation of previously formed mRNA. We suggest that neuronal injury or insult results in the induction of certain genes (and, therefore, protein synthesis) in the surrounding reactive astrocytes, and these proteins may contribute to post-injury amyloidogenesis.
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PMID:Induction of apolipoprotein E mRNA in the hippocampus of the gerbil after transient global ischemia. 873 65

The distribution patterns of cystatin C and apolipoprotein E (apo E) were studied immunocytochemically in the gerbil hippocampus before and after 5 min ischemia. In the controls, cystatin C was distributed mainly in astrocytes. In addition, a large number of dots positive for cystatin C were observed around the outlines of neuronal perikarya in the CA1 subfields. One day after ischemia, cystatin C-positive stainings outlining neuronal cell bodies disappeared. On the fourth day, intense stainings for cystatin C appeared in atrophied pyramidal neurons and these stainings in neurons disappeared by the 14th day. A remarkable increase in the number of cystatin C-positive astrocytes occurred on the fourth day and thereafter these spread over the whole of the CA1 subfield. Apo E was also distributed in astrocytes in the control specimens. From the fourth day, extra- and/or intracellular distribution of apo E-immunoreactivities was noted in the stratum pyramidale. Apo E-positive astrocytes disappeared transiently on the fourth day and then reappeared and increased remarkably by the 14th day. These findings indicate that cystatin C and apo E are involved in the degeneration process of brain neuronal cells.
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PMID:Cystatin C and apolipoprotein E immunoreactivities in CA1 neurons in ischemic gerbil hippocampus. 883 51

Recent evidence suggests that apolipoprotein E (ApoE) plays a role in neurologic disease. This experiment compared the neurologic and histologic outcome of ApoE-deficient mutant and wild-type mice subjected to a 60- or 90-minute episode of middle cerebral artery filament occlusion and a recovery interval of 24 hours. With 60 minutes of ischemia, there was no mortality. Apolipoprotein E-deficient mice had larger infarcts (cortex: ApoE deficient = 20 mm3 +/- 12, wild-type = 9 +/- 7 mm3, P = 0.03; subcortex: ApoE deficient = 22 +/- 7 mm3, wild-type = 16 +/- 7 mm3, P = 0.07). Hemiparesis was less severe in wild-type animals (P = 0.02). After 90 minutes of ischemia, mortality in ApoE-deficient mice (n = 10) was 40% versus 0% in wild-type mice (n = 10; P = 0.09). Intraparenchymal hemorrhage was found in 3 of the 4 dead mice. No difference in cortical (ApoE deficient = 37 +/- 8 mm3; wild-type = 31 +/- 18 mm3; P = 0.49) or subcortical (ApoE deficient = 30 +/- 11 mm3; wild-type = 32 +/- 18 mm3; P = 0.78) infarct volumes was present among survivors. ApoE-deficient mice had a prolonged activated partial thromboplastin time and increased fibrinogen concentration. This data supports the hypothesis that apolipoprotein E plays a role in the pathophysiology of ischemic brain damage.
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PMID:Apolipoprotein E-deficient mice have increased susceptibility to focal cerebral ischemia. 927 Apr 92

A brief period of bilateral carotid occlusion (BCO)-induced forebrain ischemia in gerbils triggers neuronal degeneration and the subsequent expression of amyloid precursor protein (APP), b-amyloid protein (b-AP), and apolipoprotein E (APO-E) in the selectively vulnerable CA1 region of the hippocampus. The increase in immunoreactivity is secondary to the postischemic degeneration of the CA1 neurons and is largely astrocyte-derived as evidenced by a simultaneous increase in glial fibrillary acidic protein (GFAP) staining. Oxygen radical-induced lipid peroxidation has been strongly suggested to play a role in postischemic neuronal damage and Alzheimer's disease. Recent literature suggests a possible link between early oxidative stress and APP overexpression. Therefore, the present investigation examined the effect of two novel brain-penetrating pyrrolopyrimidine lipid peroxidation inhibitors (PNU-101033E and PNU-104067F) on CA1 neurodegeneration and the subsequent increase in APP, b-AP, APO-E, and GFAP immunostaining at 4 days after a 5-minute episode of forebrain ischemia. Using an antibody for lipid peroxidation-derived malondialdehyde (MDA)-modified proteins, the authors also examined the effects of PNU-104067F on MDA immunostaining 2 days after ischemia, before completion of the neuronal loss. At 2 days, the authors also evaluated microglial activation using an antibody to surface major histocompatibility complex class II antigen expressed by activated microglia. Gerbils were treated at 30 mg/kg orally 30 minutes before the BCO and 2 hours after ischemia, followed by daily dosing for the next day (microglia and MDA) and the successive 3 days for APP, b-AP, APO-E, and GFAP immunostaining. APP and APO-E staining was significantly suppressed by 50% and 66%, respectively, with either compound. b-AP immunoreactivity was decreased 56% with both compounds, and GFAP expression was significantly decreased 53% (PNU-101033E) and 60.5% (PNU-104067F). There was a concomitant partial sparing of the CA1 hippocampal neurons by both PNU-101033E and PNU-104067F (P < .01) as determined by cresyl violet histochemistry. PNU-104067F significantly inhibited lipid peroxidation-derived MDA immunostaining and microglia activation (P < .05) at 48 hours after ischemia. Brain-penetrable lipid peroxidation inhibitors may provide attenuation of various glial response proteins after ischemic injury, probably secondary to neuronal protection.
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PMID:Neuroprotective efficacy and mechanisms of novel pyrrolopyrimidine lipid peroxidation inhibitors in the gerbil forebrain ischemia model. 959 46

Myocardial infarction is linked to atherosclerosis, yet the sequence leading from silent coronary atherosclerosis to acute myocardial infarction has remained unclear. Here we show that hypercholesterolemic apolipoprotein E-/- low density lipoprotein receptor-/- mice develop not only coronary atherosclerosis but also myocardial infarction. Exposure of mice to mental stress or hypoxia led to acute ischemia, which, in a large proportion of the mice, was followed by electrocardiographic changes, leakage of troponin T, and loss of dehydrogenase from the myocardium, all indicative of acute myocardial infarction. Apoptotic death of cardiomyocytes was followed by inflammation and fibrosis in the heart. All these pathological changes could be prevented by a blocker of the endothelin type A receptor. Thus, stress elicits myocardial infarction through endothelin receptor signaling in coronary atherosclerosis caused by hypercholesterolemia.
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PMID:Myocardial infarction mediated by endothelin receptor signaling in hypercholesterolemic mice. 1035 14

In the present study, we have examined the expression of both presenilins in the rat hippocampus, cortex, striatum, and cerebellum after middle cerebral artery occlusion (MCA-O), an animal model of ischemia. The cortex showed the greatest increase in PS mRNA levels (7-10-fold) at 4 and 8 days posttreatment. Presenilin-1 (PS-1) levels in the contralateral cortex were significantly increased 1 day after MCA-O. In comparison, PS mRNA content was only modestly elevated in the hippocampus and striatum at 4 and 8 days after MCA-O (30-100% changes). Other Alzheimer's disease (AD)-related genes, amyloid precursor protein and apolipoprotein E, are induced in brain injury suggesting that these AD-related genes may well be components of a brain-injury response. Thus, a breakdown in this response via cerebrovascular disease and/or genetic mutation may contribute to AD pathology.
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PMID:Induction of presenilins in the rat brain after middle cerebral arterial occlusion. 1037 15

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


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