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 known to stimulate endothelial nitric oxide production and attenuate endothelial dysfunction after ischemia and reperfusion. However, estrogen therapy increases the risk of breast and endometrial cancer. The present study was designed to determine whether idoxifene, a selective estrogen receptor modulator without adverse effects on reproductive organs, may stimulate nitric oxide release and protect endothelial function. In U-46619 precontracted superior mesenteric arterial (SMA) segments isolated from ovariectomized rats, idoxifene and 17 beta-estradiol resulted in a comparable dose-dependent vasorelaxation (maximal relaxation: 75.3 +/- 4.9 and 71 +/- 4.7%, respectively). Treatment of the rings with N(omega)-nitro-L-arginine methyl ester completely blocked idoxifene- and 17 beta-estradiol-induced vasorelaxation. In vitro incubation of SMA rings with TNF alpha significantly reduced vasorelaxation to an endothelium-dependent vasodilator, acetylcholine (maximal relaxation: 73 +/- 3.7 versus 95 +/- 2.9% pre-TNF alpha, P <.01). Idoxifene, but surprisingly not 17 beta-estradiol, prevented TNF alpha-induced endothelial dysfunction (maximal relaxation: 86 +/- 2.6% in idoxifene-treated rings and 77 +/- 5.1% in 17beta-estrogen-treated rings). In vivo ischemia and reperfusion resulted in significant endothelial dysfunction as evidenced by decreased vasorelaxation to acetylcholine (maximal relaxation: 48 +/- 5.5 versus 92 +/- 3.9% in normal SMA rings), but a normal relaxation response to an endothelium-independent vasodilator, acidified NaNO(2) (95 +/- 3.2%). Treatment with idoxifene at either 1 or 2 mg/kg/day, or 17beta-estrogen at 1 mg/kg/day for 4 days significantly preserved endothelial function (P <.01 versus vehicle). Taken together, these results demonstrate that idoxifene is an endothelium-dependent vasodilator and exerts significant endothelial protective effects against TNF alpha- and ischemia-reperfusion-induced endothelial injury. These results suggest that selective estrogen receptor modulators have therapeutic potential in diseases where endothelial dysfunction plays an important role.
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PMID:Nitric oxide stimulatory and endothelial protective effects of idoxifene, a selective estrogen receptor modulator, in the splanchnic artery of the ovariectomized rat. 1104 19

Estrogen-related ischemic neuroprotection has been documented in male and ovariectomized female rats. The precise molecular mechanism underlying estrogen's neuroprotective effect remains obscure. In the present study, we examined whether endogenous estrogen levels affect post-ischemic outcomes in normal cycling female rats. Occlusion of both the common carotid arteries and the right middle cerebral artery (1.5 h) followed by reperfusion (24 h) caused cortical infarction, increased neutrophil accumulation, and elevated antioxidant enzyme and lactate dehydrogenase activities. These post-ischemic changes varied in the female rats and were inversely correlated with circulating estrogen levels. More severe post-ischemic changes and injury accompanied the decline in circulating estrogen levels in normal cycling female rats, indicating that estrogen is probably the major hormonal player in female resistance to ischemia.
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PMID:Association of serum estrogen level and ischemic neuroprotection in female rats. 1113 52

Estrogen has demonstrated great potential as a therapeutic agent in focal ischemic brain injury, as exogenous beta-estradiol has proven beneficial in a variety of focal stroke models. In contrast, the relatively few studies of estrogen's efficacy in transient forebrain ischemia have produced inconsistent results. The present study was therefore designed to clarify estrogen's neuroprotective potential in selective hippocampal neuronal injury resulting from four-vessel occlusion in the rat. Female Wistar rats (normal, ovariectomized, or ovariectomized and estradiol-treated) received 5 or 10 min of ischemia. No differences in hippocampal cell loss were found amongst the groups with 10 min of ischemia. Amongst the groups with 5 min of ischemia, the mildest injury was found in the ovariectomized animals, which lost only 32% of their CA1 pyramidal cells. In comparison, mean cell losses were 54% and 49%, respectively, in intact females and in ovariectomized animals with estradiol replacement. Linear regression analysis demonstrated a highly significant relationship between cell loss and plasma estradiol levels. The mechanism by which exogenous and endogenous estrogen exacerbated the injury is unclear, as estrogen has many neuroprotective effects. On the other hand, many other reported effects of estrogen in hippocampal area CA1 might confer increased sensitivity to ischemia, either by modulating the excitatory effects of glutamate or by modifying the inhibitory effects of GABA. Determining how to modulate the various competing effects of estrogen is of both theoretical and practical importance, as it is now clear that one cannot assume that estrogen administration will always improve outcome in cerebral ischemia.
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PMID:Deleterious effect of beta-estradiol in a rat model of transient forebrain ischemia. 1132 56

Estrogen protects the brain from experimental cerebral ischemia, likely through both vascular and neuronal cellular mechanisms. The purpose of this study was to determine whether chronic estrogen treatment in males and repletion in ovariectomized (Ovx) females reverses abnormalities in pial arteriolar reactivity during reperfusion from global forebrain ischemia (4-vessel occlusion, 15 min) and whether the site of protection is vascular endothelium. Male and Ovx female rats were implanted with either placebo or a 25-microg 17 beta-estradiol pellet 10 days before ischemia. With the use of intravital microscopy, pial vessel dilation to ACh (10 microM) and S-nitroso-N-acetyl-penicillamine (SNAP; 1 microM) and vasoconstriction to serotonin (10 microM) was examined in situ at 30--60 min of reperfusion. Postischemic changes in vessel diameter were compared with preischemic values for each agent. Postischemic response to both ACh and SNAP was lost in males and Ovx females, but not in estrogen pellet-implanted males and estrogen-implanted Ovx females, suggesting that estrogen protects both endothelial and smooth muscle-mediated vasodilation. Ischemia blunted vessel constriction to serotonin regardless of treatment. These data demonstrate that estrogen acts as a vasoprotective agent within the cerebral circulation and can improve microvascular function under conditions of an acutely evolving ischemic pathology.
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PMID:Estrogen restores postischemic pial microvascular dilation. 1140 80

Estrogen and progesterone, long considered for their roles as primary hormones in reproductive and maternal behavior, are now being studied as neuroprotective and neuroregenerative agents in stroke and traumatic brain injuries. Collectively, the hormones reduce the consequences of the injury cascade by enhancing anti-oxidant mechanisms, reducing excitotoxicity (altering glutamate receptor activity, reducing immune inflammation, providing neurotrophic support, stimulating axonal remyelinization), and enhancing synaptogenesis and dendritic arborization. Estrogen seems more effective as a prophylactic treatment in females at risk for cardiac and ischemic brain injury, whereas progesterone appears to be more helpful in the post-injury treatment of both male and female subjects with acute traumatic brain damage. However, a recent clinical trial with estradiol replacement therapy in elderly women that have a history of cerebrovascular disease, showed that this hormone was unable to protect against reoccurrence of ischemia or to reduce the incidence of mortality compared to a placebo.
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PMID:Brain damage, sex hormones and recovery: a new role for progesterone and estrogen? 1141 Feb 69

Proinflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) plays an important role in the pathogenesis of neurodegenerative diseases including ischemia. Circulating estrogen is positively associated with neuroprotection against ischemia in female rats. In the present study, we examined whether endogenous estrogen levels affect ischemia-induced TNF-alpha expression in normal cycling female rats. An elevated concentration of TNF-alpha was toxic to neurons. A high level of expression of TNF-alpha accompanied the decline in circulating estrogen levels in normal cycling female rats. Estrogen administration attenuated endotoxin-induced TNF-alpha expression and neuronal injury, indicating that the down-regulation of TNF-alpha expression plays a role in ischemic neuroprotection by estrogen. Therefore, we propose that one mechanism by which estrogen protects females from ischemic damage is through the regulation of TNF-alpha production.
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PMID:Estrogen attenuates tumor necrosis factor-alpha expression to provide ischemic neuroprotection in female rats. 1223 36

The relative rarity of stroke in oral contraceptive (OC) users, estimated at 14/100,000 women per year, does not mean that the risk is not significant; it is 4 to 9 times as high for OC users as for controls. 86 well-documented cases of stroke in OC users treated at a neurologic clinic in Paris between 1974 and 1984 are analyzed. There were 5 groups of patients: 1) 66 cases of cerebrovascular accidents, 64 of which were ischemic 2) 6 cases of intracranial venous thrombosis 3) 6 cases of benign and reversible intracranial hypertension or cerebral pseudotumor without demonstrated venous thrombosis 4) 5 cases of vascular complications in the retina or optic nerve, and 5) a miscellaneous group of 5 cases. The patients were aged from 16-49 years and the mean age was 30.5 years. The duration of use of OCs varied from a few days to 15 years, with an average of 39 months. 42 to 56% had family histories of cerebrovascular problems and 40 to 50% had personal or familial histories of migraine. Among 79 OC users with strokes, 41% used moderate dosed and 59% used microdose pills. No patients used microdose progestin only pills. There were 2 peak age groups of patients, those 25-29 and 38-42 years old. Young women aged 25-29 had intracranial venous thrombosis, intracranial hypertension or pseudotumor, and acute ischemia of the optic nerve. The average age of the 64 patients with ischemic cerebral vascular accidents was 31 years. Of the 30 infarcts, 1/3 left significant sequelae and 3 were fatal. There were 21 transitory ischemic accidents and 13 prolonged reversible ischemic accidents usually without sequelae. There were warning signals in 52% of infarct cases. 45% of patients with cerebrovascular accidents had family histories of cerebrovascular accidents or cardiac infarct and 40 to 50% had personal or family histories of migraine. Fewer than 25% had hyperlipidemia, 20% smoked, and 8% had diabetes or a problem of glycoregulation. Coagulation changes were found in 6 of 64 patients, but 22 of 26 had immune complexes and anti-ethinyl estradiol or antiprogesterone antibodies. Among the 6 cases of intracranial venous thrombolic accidents there were 2 deaths and 2 cases of very serious sequelae. The average age of these patients was about 27. The role of OCs is difficult to confirm because there are too few cases for statistical analysis. Antihormone antibodies were found in 3 such cases studied, but coagulation problems were not observed. Patients in the study who had laboratoratory or angiographic evidence of atheromatous disorders mostly were in the older peak age groups. The younger patients with cerebral ischemic accidents were largely without atheromatous lesions, but were very likely to have antiestrogen or antiprogesterone antibodies.
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PMID:[Stroke and combined oral contraceptives]. 1228 Feb

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

Estrogen increases nitric oxide (NO) production by inducing the activity of endothelial NO synthase (eNOS) (Simoncini et al. Nature 407: 538, 2000). Ischemia (30 min) and reperfusion (I/R) increased the number of adherent leukocytes and decreased their rolling velocities in mouse cremaster muscle venules with a strong dependence on wall shear rate. Minimum rolling velocity at approximately 5 min after the onset of reperfusion was accompanied by increased P-selectin expression. This preceded the peak in leukocyte adhesion (at 10-15 min). In untreated wild-type mice, I/R caused a decrease of leukocyte rolling velocity from 37 to 26 microm/s and a 2.0-fold increase in leukocyte adhesion. Both were completely abolished by 0.25 mg ip estrogen 1 h before surgery. In eNOS(-/-) mice, the decrease of leukocyte rolling velocity and increase in adhesion were similar but were only marginally improved by estrogen. We conclude that the protective effect of estrogen, as measured by leukocyte rolling and adhesion, is significantly reduced in eNOS(-/-) mice, suggesting that induction of eNOS activity is the major mechanism of vasoprotection by estrogen in this model.
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PMID:Vascular protection by estrogen in ischemia-reperfusion injury requires endothelial nitric oxide synthase. 1238 53

Estrogen replacement therapy is thought to attenuate the incidence of Alzheimer's disease in women and enhance cognitive functions. In rodents, estrogen protects cerebral cortical neurons from ischemic injury and cultured neurons from a variety of perturbations. Because few nuclear estrogen receptors have been detected in the dorsal hippocampus, the present studies used a global ischemia model to evaluate the neuroprotective actions of estrogen in this region. Ovariectomized gerbils were treated with placebo, 0.5 mg or 1 mg pellets of estradiol for 13 days. On day 7, the common carotid arteries were occluded for 5 min and on day 13 the animals were killed. Analysis of neurogranin mRNA, a marker of hippocampal neurons, with in situ hybridization revealed a dramatic and selective loss of CA1 neurons in the placebo-treated ovariectomized gerbils, whereas both 0.5 mg and 1 mg pellets of 17beta-estradiol prevented cell loss. Subsequent studies showed that a variety of estrogens, including diethylstilbestrol, estrone and 17alpha-estradiol as well as vitamin E, also protected CA1 neurons from ischemic injury in ovariectomized gerbils, whereas treatment with the estrogen antagonist tamoxifen was ineffective. The results of in vivo binding studies with 17alpha-iodovinyl-11beta-methoxyestradiol revealed a concentration of nuclear estrogen binding sites in the CA1 region of the ovariectomized gerbil brain, whereas binding in other hippocampal regions was limited. Moreover, the binding studies revealed that the regional pattern of binding was not altered after ischemic injury, with the exception of the hippocampus, where the binding sites were attenuated in ovariectomized animals with time after ischemic injury. Together, these data demonstrate that a variety of steroidal and non-steroidal estrogens are potent neuroprotective agents in an animal model of global ischemia, agents that protect neurons critical for learning and memory and susceptible to neurodegenerative diseases.
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PMID:Estrogen prevents the loss of CA1 hippocampal neurons in gerbils after ischemic injury. 1257 24


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