Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estrogen is neuroprotective in adult animals. We wished to determine if estrogen protects against brain injury in the newborn. Four-day-old rat pups were treated with subcutaneously implanted pellets containing 0.05 mg (2.4 microg/day) of 17beta-estradiol or vehicle, designed to release the estrogen over 21 days. At 7 days old the pups had the right carotid artery ligated followed by 2.5 h of 8% oxygen. Brain damage was evaluated by weight deficit of the right hemisphere at 22 days following hypoxia. Estradiol treatments reduced brain weight loss from -17.4+/-2.8% S.E.M. in the vehicle group (n=32) to -9.3+/-2.7% in the treated group (n=32, P<0.05). Brain cortex thiobarbituric acid reacting substances and caspase activities were assessed 24 h after reoxygenation. Estradiol significantly reduced a hypoxia-induced increase in brain thiobarbituric acid reactive substances (P<0.05). Levels of caspase-3, -8 and -9 activity increased due to hypoxia-ischemia. Estradiol had no effect on caspase activity. Estradiol reduced brain injury in the neonatal rat.
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PMID:Estrogen attenuates hypoxic-ischemic brain injury in neonatal rats. 1565 97

17beta-estradiol reduces cell death after global and focal ischemia and subarachnoid hemorrhage in rodents. Presently, we tested whether estrogen improves outcome after intracerebral hemorrhage (ICH) in male rats. Rats were implanted subcutaneously with 0.05, 0.25, or 0.50 mg pellets of estrogen (21-day release) or subjected to a sham procedure. Two weeks after implantation, they were given a striatal ICH via an infusion of collagenase. The three estrogen groups had significantly smaller lesions at a 7-day survival. Some rats had core temperature measured with an implanted telemetry probe, which also measured whole-body movements. Estrogen did not affect temperature nor activity levels after ICH. A second study with 0.25 mg pellets, administered once or twice, showed persistent histologic protection (30 days) and some functional benefit (e.g., elevated beam). A spectrophotometric hemoglobin assay showed that the 0.25 mg dose significantly reduced hemorrhagic blood volume at 12 hours after ICH. Regardless, estrogen did not lessen cerebral edema at 2 days after ICH and functional benefits were not consistently found on all tests (e.g., cylinder task). In summary, estrogen pretreatment reduces injury after ICH, in part by reducing bleeding. Estrogen may thus lessen injury and improve outcome after ICH in humans.
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PMID:17beta-Estradiol pretreatment reduces bleeding and brain injury after intracerebral hemorrhagic stroke in male rats. 1567 26

A distinctive feature of galanin expression is that it is extensively increased by neuronal injury, estrogens, Alzheimer's disease and during development. Since stroke is amongst the clinically most important causes of neuronal injury we studied the tissue concentrations of galanin in a rat stroke model and the possibility of modulating this effect with estrogen. Transient focal middle cerebral artery ischemia was induced in rats that 2 weeks earlier underwent ovariectomy and received 1.5mg 17beta-estradiol slow-release or placebo pellets. The concentrations of galanin and neuropeptide Y were measured after observation periods of 3, 7 and 14 days in extracts of punch biopsies from both the lesioned and the contra lateral control hemisphere. The galanin levels were not changed in any of the brain regions studied except in the hippocampus where they were lower in the ischemic hemisphere in both the estrogen- and placebo-treated animals compared to the corresponding contra lateral intact hemisphere (p=0.015). Estrogen treatment up-regulated galanin concentrations in both the ventral and dorsal hippocampus (p=0.003). The effects on the galanin concentrations were similar after all observation periods: 3, 7 and 14 days (p=0.144). No significant changes were observed in the concentration of neuropeptide Y in response to the lesions. The ischemic lesions were markedly larger in the estrogen-treated animals observed after 3 days compared to the corresponding control group. In the estrogen group the lesion was largest at bregma and the slice 2mm anterior to the bregma, 82% and 435% larger than in the control group (p<0.001). A similar, but much less pronounced (not statistically significant) difference was seen in the groups observed after 7 and 14 days. Earlier studies of lesions in the peripheral and central nervous systems have generally shown an up-regulation of galanin markers in response to but at a distance from the injury. Our results indicate that galanin is not involved in the response of the ischemic penumbra itself to stroke, whereas it may participate in the reactions of the neural stem-cell rich hippocampus to stroke.
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PMID:Estradiol increases brain lesions in the cortex and lateral striatum after transient occlusion of the middle cerebral artery in rats: no effect of ischemia on galanin in the stroke area but decreased levels in the hippocampus. 1591 33

Transient global ischemia induces selective, delayed neuronal death in the hippocampal CA1 and delayed cognitive deficits. Estrogen treatment ameliorates hippocampal injury associated with global ischemia. Although much is known about the impact of estrogen on neuronal survival, relatively little is known about its impact on functional outcome assessed behaviorally. We investigated whether long-term estradiol (21-day pellets implanted 14 days prior to ischemia) or acute estradiol (50 microg infused into the lateral ventricles immediately after ischemia) attenuates ischemia-induced cell loss and improves visual and spatial working memory in ovariectomized female rats. Global ischemia significantly impaired visual and spatial memory, assessed by object recognition and object placement tests at 6-9 days. Global ischemia did not affect locomotion, exploration, or anxiety-related behaviors, assessed by an open-field test at 6 days. Long-term estradiol prevented the ischemia-induced deficit in visual working memory, maintaining normal performance in tests with retention intervals of up to 1 h. Long-term estradiol also prevented ischemia-induced deficits in spatial memory tests with short (1 and 7 min), but not longer (15 min), retention intervals. Acute estradiol significantly improved visual memory assessed with short retention intervals, but did not prevent deficits in spatial memory. Acute estradiol significantly increased the number of surviving CA1 neurons, assessed either at 7 days after ischemia or after the completion of behavioral testing 9 days after ischemia. In contrast, chronic estradiol did not reduce CA1 cell death 9 days after ischemia. Thus, long-term estradiol at near physiological levels and acute estradiol administered after ischemic insult improve functional recovery after global ischemia. These findings have important implications for intervention in the neurological sequellae associated with global ischemia.
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PMID:Acute and chronic estradiol treatments reduce memory deficits induced by transient global ischemia in female rats. 1612 3

This study examined the effects of estrogen supplementation on markers of neutrophil infiltration and damage in skeletal muscle of rats following ischemia. Male and female gonad-intact rats, with or without 14 days of estrogen supplementation were subjected to two hours of hind-limb ischemia and sacrificed at 24, 48 or 72 hours post-ischemia. Control animals were sacrificed without ischemia. Plantaris and red and white gastrocneimus muscles were removed and assayed for myeloperoxidase (MPO), a marker of neutrophil infiltration, and glucose-6-phosphate dehydrogenase (G6PD) and beta-glucuronidase (betaGLU), as markers of muscle damage. Significant elevations of MPO, G6PD and betaGLU activities were observed at various time points post-ischemia. No systematic differences between genders were noted in any of the measures. Estrogen supplementation in both male and female animals failed to significantly attenuate post-ischemia increases in MPO, G6PD and betaGLU activities in any of the muscles studied and in some cases accentuated activities of some of these measures. Unlike previous findings following exercise in skeletal muscle, this study failed to demonstrate estrogen-induced attenuation of indices of neutrophil infiltration or damage in skeletal muscles of rats up to 72 hours following ischemia. This demonstrates that estrogen may not consistently attenuate neutrophil infiltration and that a number of variables including damage modality, tissue or estrogen level may influence this.
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PMID:Estrogen supplementation failed to attenuate biochemical indices of neutrophil infiltration or damage in rat skeletal muscles following ischemia. 1623

Estrogen's prothrombotic effects are of increasing concern, particularly in stroke risk and recovery. Using an ischemic rodent model, the authors sought to determine (a) if estrogen replacement increases postischemic platelet reactivity, (b) if changes in estrogen status alter intraplatelet endothelial nitric oxide synthase (eNOS) synthesis, and (c) if estrogen-mediated effects on platelets alter cerebral blood flow during reperfusion. Intact (I), ovariectomized (OVX), and OVX + 17 beta-estradiol (E50) rats were subjected to 30 min of forebrain ischemia and 60 min of reperfusion. Using the platelet activation marker P-selectin, postischemic platelet reactivity was quantified by flow cytometry. In a separate cohort (I, OVX, E50), the authors quantified platelet eNOS by Western blot. Another cohort (OVX, E50) was subjected to ischemia/reperfusion, and cerebral blood flow was determined using the iodoantipyrine technique. Collagen-stimulated platelet P-selectin expression was increased in the OVX rats at 60 min of reperfusion, and this effect was reversed by estrogen treatment. No differences in platelet eNOS expression were detected among groups. Cerebral blood flow at 60 min reperfusion was comparable between the OVX and the E50 rats. The authors conclude that during reper-fusion, estrogen deficiency increases postischemic platelet sensitivity to stimuli in estrogen-deficient rats. Estrogen treatment mitigates effects of estrogen loss on platelets, but this early effect is apparently not caused by intraplatelet eNOS depression. Neither estrogen deficiency nor estrogen treatment changes early postischemic regional brain blood flow. In this rodent global cerebral ischemic model, physiologic doses of estrogen are not deleterious to platelet reactivity and may initially reduce postischemic platelet reactivity.
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PMID:Effects of estrogen on platelet reactivity after transient forebrain ischemia in rats. 1626 75

Sex differences in myocardial recovery have been reported after acute ischemia and reperfusion injury. Estrogen and the estrogen receptor are critical determinants of cardiovascular sex differences. However, the mechanistic pathways responsible for these differences remain unknown. We hypothesized that estrogen receptor-alpha is an important modulator of 1) myocardial functional recovery after ischemia and 2) inflammatory signaling via MAPK. To study this, adult male and female wild-type (WT) and estrogen receptor-alpha knockout (ER1KO) mouse hearts were isolated, perfused via Langendorff model, and subjected to 20 min of ischemia and 60 min of reperfusion. Myocardial contractile function (left ventricular developed pressure and positive and negative first derivative of pressure) was continuously recorded. After ischemia-reperfusion, hearts were assessed for expression of inflammatory cytokines (ELISA) and activation of MAPK and caspase-3 (Western blot analysis). Data were analyzed with two-way ANOVA or Student's t-test, and P < 0.05 was statistically significant. ER1KO females exhibited significantly less functional recovery than WT females and were similar to WT males. Activated ERK was increased in female WT hearts compared with female ER1KO. Activated JNK was decreased in female WT hearts compared with female ER1KO. No significant differences were found between male WT, female WT, male ER1KO, and female ER1KO in activated p38 MAPK, proinflammatory cytokine expression, and proapoptotic signaling. Estrogen receptor-alpha plays a role in the protection observed in the female heart. Differential activation of MAPK may mediate this protection. Further studies are necessary to delineate these mechanistic pathways.
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PMID:Estrogen receptor-alpha mediates acute myocardial protection in females. 1641 70

Estrogen is neuroprotective against ischemia in both in vivo and in vitro injury models. Because of the promising preclinical data on neuroprotection, the Women's Estrogen for Stroke Trial was initiated. The outcomes from this trial were, however, unsuccessful and questions emerged about the safety of chronic estrogen treatment in women. In contrast to the chronic estrogen treatment strategy, the present study aims to investigate: (1) the neuroprotective efficacy of single estrogen pretreatment/preconditioning; and (2) the existence of a similarity between estrogen- and ischemic preconditioning-induced neuroprotection against cerebral ischemia. The efficacy of estrogen was tested in an in vitro model of cerebral ischemia using hippocampal organotypic slice culture system. The hippocampal organotypic slice cultures were generated from female neonatal (9-11 days old) Sprague-Dawley rats. The slices were exposed to estradiol-17beta (0.5, 1, 5 nM) for various durations (1, 2 or 4 h) 48 h prior to ischemia (40 min of oxygen-glucose deprivation). For ischemic preconditioning, slices were exposed to sublethal oxygen-glucose deprivation (15 min), 48 h prior to lethal oxygen-glucose deprivation. Quantification of cell death in hippocampal CA1 region was conducted by using propidium iodide fluorescence staining technique. Results demonstrated that estrogen preconditioning significantly protects the hippocampal CA1 region against ischemia (P<0.001) and mimicked ischemic preconditioning-induced neuroprotection. The propidium iodide fluorescence values of estrogen preconditioning, ischemic preconditioning and ischemia groups were 21+/-2 (mean+/-S.E.M.) (1 nM; 2 h; n=15), 18+/-2 (5 nM; 4 h; n=12), 32+/-3 (n=8), 65+/-3 (n=27), respectively. Further, estrogen preconditioning initiated a calcium-mediated signaling pathway leading to protection of CA1 neurons against ischemia. Future investigations in estrogen preconditioning may suggest new estrogen regimens that avoid potential side effects of chronic estrogen treatment for stroke patients.
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PMID:Estrogen preconditioning protects the hippocampal CA1 against ischemia. 1677 51

Ovarian hormones can protect against brain injury, neurodegeneration, and cognitive decline. Most attention has focused on estrogens and accumulating data demonstrate that estrogen seems to specifically protect cortical and hippocampal neurons from ischemic injury and from damage due to severe seizures. Although multiple studies demonstrate protection by estrogen, in only a few instances is the issue of how the steroid confers protection known. Here, we first review data evaluating the neuroprotective effects of estrogens, a selective estrogen receptor modulator (SERM), and estrogen receptor alpha- and beta-selective ligands in animal models of focal and global ischemia. Using focal ischemia in ovariectomized ERalphaKO, ERbetaKO, and wild-type mice, we clearly established that the ERalpha subtype is the critical ER mediating neuroprotection in mouse focal ischemia. In rats and mice, the middle cerebral artery occlusion (MCAO) model was used to represent cerebrovascular stroke, while in gerbils the two-vessel occlusion model, representing global ischemia, was used. The gerbil global ischemia model was used to evaluate the neuroprotective effects of estrogen, SERMs, and ERalpha- and ERbeta-selective compounds in the hippocampus. Analysis of neurogranin mRNA, a marker of viability of hippocampal neurons, with in situ hybridization, revealed that estrogen treatment protected the dorsal CA1 regions not only when administered before, but also when given 1 h after occlusion. Estrogen rarely is secreted alone and studies of neuroprotection have been less extensive for a second key ovarian hormone progesterone. In the second half of this review, we present data on neuroprotection by estrogen and progesterone in animal model of epilepsy followed by exploration into ovarian steroid effects on neuronal damage in models of multiple sclerosis and traumatic brain injury.
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PMID:Neuroprotection by ovarian hormones in animal models of neurological disease. 1678 98

Estrogen exerts complex biological effects through the two isoforms of estrogen receptors (ERs): ERalpha and ERbeta. Whether through alteration of gene expression or rapid, plasma membrane-localized signaling to non-transcriptional actions, estrogen-activated ERs have significant implications in cardiovascular physiology. 17-beta-estradiol (E2) generally has a protective property on the vasculature. Estrogen treatment is anti-atherogenic, protecting injured endothelial surfaces and lowering LDL oxidation in animal models. Increased NO production stimulated by E2 results in vasodilation of the coronary vascular bed, and involves rapid activation of phosphotidylinositol-3 kinase (PI3K)/Akt signaling to eNOS in carotid and femoral arteries. Both isoforms of ERs impact various vascular functions, modulating ion channel integrity, mitigating the response to arterial injury, inducing vasodilation, and preventing development of hypertension in animal models. In addition to reducing afterload by vasodilation, ERs have a direct antihypertrophic effect on the myocardium. E2-activated ERs (E2/ER) antagonize the hypertrophic pathway induced by vasoactive peptides such as angiotensin II by activating PI3K, subsequent MICIP gene expression, leading to the inhibition of calcineurin activity and the induction of hypertrophic genes. In models of ischemia-reperfusion, E2/ER is antiapoptotic for cardiomyocytes, exerting the protective actions via PI3K and p38 MAP kinases and suppressing the generation of reactive oxygen species. In sum, E2-activated ERs consistently and positively modulate multiple aspects of the cardiovascular system.
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PMID:Estrogen signaling in the cardiovascular system. 1686 19


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