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

Arterial dysfunction and disease affect a majority of women during their life time. Ovarian hormones inhibit the development of atherosclerosis and play an integral role in the maintenance of normal arterial function. Estrogens act in the liver to improve and maintain lipid profiles and also act in the walls of arteries and in cardiac myocytes to maintain function and prevent disease. Death from cardiovascular disease is reduced in women receiving estrogen replacement therapy (ERT). Ten-year follow-up studies of women with advanced coronary artery disease (CAD) show a marked reduction in fatalities among the women receiving estrogens compared with untreated women. Sublingual estradiol-17 beta compared with placebo results in improved exercise tolerance and reduced ischemia during exercise in women with CAD. Estradiol-17 beta infused into the coronary arteries in women with CAD leads to improved arterial function. Estrogen deficiency has been reported in women with angina pectoris who have normal coronary arteries, and these women respond to estrogen treatment. HRT implies the use of ERT with the addition of a progestin. Progestins oppose the actions of estrogens. Counter-effects of lipid metabolism appear to be minimal with progestins currently in use. Oppositional effects of progestins on hemodynamic actions of estrogens may be significant, as progestins appear to induce vasoconstriction of estrogenized vessels.
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PMID:Cardiovascular disease in women: implications of hormone replacement therapy. 882 4

A growing body of evidence supports the hypothesis that estrogens may be beneficial in Alzheimer's disease and other neurodegenerative processes. Less is known of their therapeutic potential in acute CNS insults. In this study, we assessed the effect of estrogens in three injury paradigms that may be relevant to CNS hemorrhage, trauma, and ischemia. Supraphysiologic concentrations of 17beta-estradiol, estrone, or equilin attenuated neuronal loss due to prolonged exposure to the pro-oxidant hemoglobin, with complete protection at 10 microM. Most of this effect persisted despite concomitant treatment with the antiestrogen ICI 182,780 or the protein synthesis inhibitor cycloheximide. In contrast, the non-estrogenic steroid methylprednisolone, which is currently in clinical use in spinal cord injury, reduced neuronal loss by only about 30%. High concentrations of equilin or estrone also attenuated the submaximal neuronal injury induced by 3.5-4.5 h exposure to the cytochrome oxidase inhibitor sodium azide, with near complete protection at 30 microM. Estrogens had a weaker and somewhat variable effect on pure excitotoxic injury, reducing neuronal loss due to 24 h kainate exposure by about half, and due to 24 h NMDA exposure by 15-65%; similar neuroprotection was provided by the antioxidant 21-aminosteroid U74500A. These results suggest that estrogens may be beneficial in acute CNS injuries associated with oxidative and excitotoxic stress. Investigation of high dose estrogen therapy in in vivo models of CNS hemorrhage, trauma, and ischemia is warranted.
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PMID:Estrogens attenuate neuronal injury due to hemoglobin, chemical hypoxia, and excitatory amino acids in murine cortical cultures. 929 2

Estrogens are potent neuroprotective compounds in a variety of animal and cell culture models, and data indicate that estrogen receptor (ER)-mediated gene transcription is not required for some of these effects. To further address the requirement for an ER in estrogen enhancement of neuronal survival, we assessed the enantiomer of 17beta-estradiol (ENT-E(2)), which has identical chemical properties but interacts only weakly with known ERs, for neuroprotective efficacy. ENT-E(2) was both as potent and efficacious as 17beta-estradiol in attenuating oxidative stress-induced death in HT-22 cells, a murine hippocampal cell line. Further, ENT-E(2) completely attenuated H(2)O(2) toxicity in human SK-N-SH neuroblastoma cells at a 10 nM concentration. In a rodent model of focal ischemia, 17beta-estradiol (100 microgram/kg) or ENT-E(2) (100 microgram/kg), injected 2 h before middle cerebral artery occlusion, resulted in a 60 and 61% reduction in lesion volume, respectively. ENT-E(2), at the doses effective in this study, did not stimulate uterine growth or vaginal opening in juvenile female rats when administered daily for 3 days. These data indicate that the neuroprotective effects of estrogens, both in vitro and in vivo, can be disassociated from the peripheral estrogenic actions.
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PMID:The nonfeminizing enantiomer of 17beta-estradiol exerts protective effects in neuronal cultures and a rat model of cerebral ischemia. 1114 3

Mitochondria are recognized as modulators of neuronal viability during ischemia, hypoxia and toxic chemical exposure, wherein mitochondria dysfunction leading to ATP depletion may be a common pathway of cell death. Estrogens have been reported to be neuroprotective and proposed to play a role in the modulation of cerebral energy/glucose metabolism. To address the involvement of 17beta-estradiol preservation of mitochondrial function, we examined various markers of mitochondrial activity in human SK-N-SH neuroblastoma cells exposed to 3-nitroproprionic acid (3-NPA), a succinate dehydrogenase inhibitor which uncouples oxidative phosphorylation. 3-NPA (10 mM) significantly increased ATP levels at 2 h then caused a 40% and a 50% decrease in ATP levels from baseline when treated for 12 h and 24 h, respectively. 3-NPA also induced significant increases in levels of cellular hydrogen peroxide and peroxynitrite at 2 h and a 60% decrease in mitochondrial membrane potential (MMP) at 12 h exposure. 17beta-Estradiol (17beta-E(2)) pretreatment restored the ATP level back to 80% at 12 h of that in control cells treated with 3-NPA but without E(2), blunted the effect of 3-NPA on MMP and reactive oxygen species levels. The present study indicates that 17beta-E(2) can preserve mitochondrial function in the face of inhibition of oxidative phosphorylation.
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PMID:Estradiol protects against ATP depletion, mitochondrial membrane potential decline and the generation of reactive oxygen species induced by 3-nitroproprionic acid in SK-N-SH human neuroblastoma cells. 1133 9

This review highlights some recent research addressing sarcolemmal K(ATP) channels in ageing. These channels are abundant in cardiac myocytes where they are essential in coupling the cellular metabolic state with membrane excitability. The opening of sarcolemmal ATP-sensitive K+ (K(ATP)) channels occurs during ischaemia and protect the heart against injury. Age-dependent changes in the myocardial susceptibility to ischemia have been observed in different species, including humans. Recent research has demonstrated that ageing is associated with decrease in numbers of sarcolemmal K(ATP) in hearts from females, but not males. This phenomenon seems to be associated with age-dependent decrease in concentration of circulating estrogens. In the heart, SUR2A, a regulatory subunit of K(ATP) channels, is present in excess over Kir6.2, a pore-forming K(ATP) channel subunit. The consequence of this is that SUR2A is a subunit that controls the number of sarcolemmal K(ATP) channels. Estrogens specifically up-regulate SUR2A and, thereby, control the number of sarcolemmal K(ATP) channels. Age-dependent loss of sarcolemmal K(ATP) channels creates a cardiac phenotype more sensitive to ischaemia, which may explain, at least in part, an ageing-associated decrease of myocardial tolerance to stress that occurs in elderly women.
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PMID:Sarcolemmal K(ATP) channels in ageing. 1517 55

Estrogens are now recognized as potent neuroprotectants in a variety of in vitro and in vivo model for cerebral ischemia. These protective effects of estrogens are seen in neurons, astrocytes, microglia and vascular endothelial cells and result in a profound protection of the brain during stroke. Herein, we provide a thesis that indicates that the protective effects of estrogens during stroke may be a combined effect on multiple targets of the neurovascular unit (NVU) through a fundamental protective effect of estrogens on the subcellular organelle that defines the fate of cells during insults, the mitochondria. By protecting mitochondria during insult, estrogens are able to reduce or eliminate the signal for cellular necrosis or apoptosis and thereby protect the NVU from ischemia/reperfusion. In this context, estrogens may be unique in their ability to target the cellular site of initiation of damage during stroke and could be a central compound in a multi-drug approach to the prevention and treatment of brain damage from stroke.
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PMID:Estrogens as protectants of the neurovascular unit against ischemic stroke. 1585 2

Estrogens have antiinflammatory actions and protect the brain from ischemic injury. Cerebral ischemia is accompanied by an inflammatory reaction that contributes to the tissue damage, an effect mediated in part by toxic amounts of nitric oxide (NO) produced by the inducible isoform of NO synthase (iNOS). Therefore, estrogens may protect the female brain by modulating postischemic iNOS expression. To test this hypothesis, we studied whether iNOS plays a role in the mechanisms of the reduced susceptibility to ischemic injury observed in female mice. The middle cerebral artery was occluded for 20 mins using an intraluminal filament in C57Bl/6 mice, and infarct volume was assessed 3 days later in cresyl violet-stained sections. Infarcts were 53% smaller in female mice than in males (P < 0.05), a reduction abolished by ovariectomy (OVX) and reinstated by estrogen replacement. In normal female mice, postischemic iNOS mRNA was lower than in males (P < 0.05). Ovariectomy increased iNOS mRNA after ischemia and estrogen replacement blocked this effect. Furthermore, the iNOS inhibitor aminoguanidine reduced infarct volume in male, but not in female, mice. Similarly, male iNOS-null mice had smaller infarcts than wild-type mice, but female iNOS nulls were not protected. Ovariectomy and OVX with estrogen replacement did not affect infarct volume in iNOS-null female mice. The findings suggest that the neuroprotection conferred by estrogens is, in part, related to attenuation of iNOS expression. Such attenuation could result from the potent antiinflammatory effects of estrogens that downregulate iNOS expression via transcriptional or posttranscriptional mechanisms.
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PMID:Inducible nitric oxide synthase contributes to gender differences in ischemic brain injury. 1604 26

Estrogens are believed to provide females with endogenous protection against cerebrovascular events although clinical trials studying long-term hormone replacement have yielded disappointing results. In contrast, estrogens might be neuroprotective after experimental ischemia. We performed a systematic review of controlled experimental studies that administered estrogens before, or after, cerebral ischemia and measured lesion volume. Relevant studies were found from searching PubMed, Embase and Web of Science. From 161 identified publications, 27 studies using 1,304 experimental subjects were analyzed using the Cochrane Review Manager software. Estrogens reduced lesion volume in a dose-dependent manner, after either transient (P<0.001) or permanent (P<0.001) ischemia and whether administered before or up to 4 h after ischemia onset; no studies assessed efficacy for later time periods. The effect size for estrogens decreased with increasing quality scores for studies of transient ischemia. Estrogens reduced lesion volume when administered to ovariectomized females and young adult males, but had no effect in intact females. Limited data were present for aged animals and the full dose-response relationship was not available in all experimental groups. On the basis of these data, estrogens are a candidate treatment for ischemic stroke, although further preclinical studies are also warranted.
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PMID:Estrogens and experimental ischemic stroke: a systematic review. 1643 60

Neuroprotection exerted by 17beta-estradiol (17beta-E(2)) has been widely investigated in animal models of acute cerebral ischemia. Estrogens interact with intracellular receptors (ERalpha and ERbeta) to modulate the transcription of target genes, including those implicated in neuronal survival. Neuroprotection may also occur via interaction with ER-like membrane receptors mediating rapid, non-genomic, actions or via receptor-independent mechanisms. There is also evidence that blockade of inflammatory factors may represent an important mechanism involved in estrogenic neuroprotection. Here we investigate whether reduced brain damage by acute pharmacological treatment with 17beta-E(2) in male rats subjected to transient (2h) middle cerebral artery occlusion (tMCAo) involves modulation of interleukin-1beta (IL-1beta), a proinflammatory cytokine strongly implicated in the pathophysiology of ischemic stroke. Administration of 17beta-E(2) (0.2mg/kg, i.p., 1h before tMCAo) results in significant reduction of brain infarct volume, and this is reverted by the ER antagonist ICI 182,780 (0.25mg/kg, i.p.) administered 1h before 17beta-E(2). Two hours MCAo followed by 2-h reperfusion results in a significant, threefold increase of IL-1beta levels in the cortical tissue ipsilateral to the ischemic damage. Interestingly, a pretreatment with a neuroprotective dose of 17beta-E(2) attenuates the cytokine elevation and this appears to occur through ER activation. In addition, neuroprotection by 17beta-E(2) is accompanied by reduced cytochrome c translocation both in the striatum and in the cortex as revealed by Western blotting 3h after reperfusion. In conclusion, we report the original observation that neuroprotection exerted by 17beta-E(2) in a rat model of transient focal brain ischemia is accompanied by reduced cytochrome c translocation to the cytosol and involves early modulation of IL-1beta production.
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PMID:Evidence to implicate early modulation of interleukin-1beta expression in the neuroprotection afforded by 17beta-estradiol in male rats undergone transient middle cerebral artery occlusion. 1767 71

Estrogens attenuate renal injury induced by ischemia/reperfusion (I/R), an effect that is related to nitric oxide production in the post-ischemic kidney. The compound 17beta-estradiol (E(2)-beta) acting via estrogen receptors (ERs) is known to activate endothelial nitric oxide synthase (eNOS) through the phosphatidylinositol-3 kinase (PI3K)/Akt pathway. We determined if this pathway contributes to the renoprotective effect of E(2)-beta in the uninephrectomized ischemia reperfusion rat model of acute renal injury. Treatment with E(2)-beta suppressed the I/R-induced increases in blood urea nitrogen, plasma creatinine, urine flow, and fractional excretion of sodium while augmenting creatinine clearance, renal blood flow, and urine osmolality, indicating attenuation of renal injury. Phosphorylation of Akt and eNOS protein was significantly increased 30-60 min after reperfusion in estradiol-treated compared to vehicle-treated rats. The protective effects of E(2)-beta and protein phosphorylation were reversed by the PI3K inhibitor wortmannin or the ER antagonist tamoxifen. Furthermore, the E(2)-beta-induced renoprotective effects were not seen in eNOS knockout mice with renal injury. We conclude that the E(2)-beta-induced renoprotective effect is due to activation of the PI3K/Akt pathway followed by increased eNOS phosphorylation in the post-ischemic kidney.
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PMID:Protective effect of 17beta-estradiol on ischemic acute renal failure through the PI3K/Akt/eNOS pathway. 1800 95


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