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)

We have shown that physiological levels of estradiol exert profound protective effects on the cerebral cortex in ischemia induced by permanent middle cerebral artery occlusion. The major goal of this study was to begin to elucidate potential mechanisms of estradiol action in injury. Bcl-2 is a proto-oncogene that promotes cell survival in a variety of tissues including the brain. Because estradiol is known to promote cell survival via Bcl-2 in non-neural tissues, we tested the hypothesis that estradiol decreases cell death by influencing bcl-2 expression in ischemic brain injury. Furthermore, because estradiol may protect the brain through estrogen receptor-mediated mechanisms, we examined expression of both receptor subtypes ERalpha and ERbeta in the normal and injured brain. We analyzed gene expression by RT-PCR in microdissected regions of the cerebral cortex obtained from injured and sham female rats treated with estradiol or oil. We found that estradiol prevented the injury-induced downregulation of bcl-2 expression. This effect was specific to bcl-2, as expression of other members of the bcl-2 family (bax, bcl-x(L), bcl-x(S), and bad) was unaffected by estradiol treatment. We also found that estrogen receptors were differentially modulated in injury, with ERbeta expression paralleling bcl-2 expression. Finally, we provide the first evidence of functional ERbeta protein that is capable of binding ligand within the region of the cortex where estradiol-mediated neuroprotection was observed in cerebral ischemia. These findings indicate that estradiol modulates the expression of bcl-2 in ischemic injury. Furthermore, our data suggest that estrogen receptors may be involved in hormone-mediated neuroprotection.
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PMID:Estradiol modulates bcl-2 in cerebral ischemia: a potential role for estrogen receptors. 1041 67

Epidemiological studies associate post-menopausal estrogen use with a reduction in risk of Alzheimer's disease, a reduction in risk of Parkinson's disease, and death from stroke. The neuroprotective efficacy of estrogens have been well described and may contribute to these clinical effects. Estrogen-mediated neuroprotection has been described in several neuronal culture model systems with toxicities including serum-deprivation, beta-amyloid-induced toxicity, excitotoxicity, and oxidative stress. In animal models, estrogens have been shown to attenuate neuronal death in rodent models of cerebral ischemia, traumatic injury, and Parkinson's disease. Although estrogens are known to exert several direct effects on neurons, the cellular mechanisms behind the neuroprotective efficacy of the steroid are only beginning to be elucidated. In this review, we summarize the data supporting a neuroprotective role for estrogens in both culture and animal models and discuss neuronal effects of estrogens that may contribute to the neuroprotective effects. These effects include activation of the nuclear estrogen receptor, altered expression of bcl-2 and related proteins, activation of the mitogen activated kinase pathway, activation of cAMP signal transduction pathways, modulation of intracellular calcium homeostasis, and direct antioxidant activity.
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PMID:Neuroprotective effects of estrogens: potential mechanisms of action. 1081 19

The protective effects of 17beta-estradiol in cerebral ischemia may be partially due to the blockade of leukocyte adhesion in cerebral endothelial cells, although the molecular mechanisms are not well understood. We report that 17beta-estradiol (E(2)), but not the alpha-enantiomer, inhibited the basal and interleukin-1beta (IL-1beta)-mediated expression of the intercellular adhesion molecule type 1 (ICAM1) and NFkappaB activation, in cultured brain endothelial cells. However, the degradation of IkappaB-alpha, which is an essential requirement for the translocation of NFkappaB to the nucleus, and a common biological target to suppress NFkappaB activation, was not halted by E(2). These findings indicate that decreased expression of adhesion molecules may account for the capacity E(2) to reduce adhesion of leukocytes in cerebral endothelium in vivo, and suggest the existence of brain-specific, estrogen-sensitive pathways, other than IkappaB-alpha_-regulation, to modulate NFkappaB. The stereoselectivity of the E(2) effect is consistent with an estrogen receptor-mediated mechanism.
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PMID:Estrogen inhibits NF kappa B-dependent inflammation in brain endothelium without interfering with I kappa B degradation. 1216 75

There are 750,000 new cases of stroke each year in the United States, and brain damage from stroke leads to high health care costs and disabilities. Needed, but currently not available, are therapies that can be administered prior to, during, or after cerebral ischemia that reduce or eliminate neuronal damage from stroke. To address this issue, we began to assess the neuroprotective effects of estrogens and related compounds in stroke neuroprotection to determine whether these compounds had potential for clinical application. First, we demonstrated that 17 beta-estradiol (E2) pretreatment exerted potent neuroprotection of the cerebral cortex over a wide dose range and pretreatment interval. Thereafter, we assessed the ability of a variety of non-feminizing estrogens to protect brain tissue from stroke. We observed that pretreatment with 17 alpha-estradiol, the complete enantiomer of E2 (ENT-E2), 2-adamantylestrone, and the enantiomer of 17-desoxyestradiol, were as effective as E2 in pretreatment protection from stroke damage. These data suggest that non-estrogen receptor mechanisms are involved in brain neuroprotection under our treatment conditions. We then determined whether the observed E2 protection could be extended to times after the onset of the cerebral ischemic event. Using a formulation of E2 that rapidly delivers the steroid, a necessary condition for acute therapy of an ongoing stroke, we demonstrated that 100 mg E2/kg could protect brain tissue for up to 3 h after the onset of the stroke. To determine whether this therapeutic window could be extended with higher doses of the steroid, we conducted a dose-response assessment of E2 when administered at 6 h after the onset of the ischemic event. While the effectiveness of the 100 micro g E2/kg was reduced at this time interval, higher doses of E2 were effective. E2, at doses of 500 and 1000 micro g/kg, reduced infarct volume by more than 50%, even with this 6-h delay in treatment. Collectively, these data indicate that estrogens could prove to be useful therapies in preventing brain damage from strokes.
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PMID:The use of estrogens and related compounds in the treatment of damage from cerebral ischemia. 1499 44

The present study employs selective estrogen receptor (ER) agonists to determine whether 17beta-estradiol-induced neuroprotection in global ischemia is receptor mediated and, if so, which subtype of receptor (ERalpha or ERbeta) is predominantly responsible. Halothane-anesthetized female C57Bl/6J mice were ovariectomized, and osmotic minipumps containing ERbeta agonist diarylpropiolnitrile (DPN) (8 mg.kg(-1).day(-1), n = 12) or vehicle (50% DMSO in 0.9% saline) (n = 9) or ERalpha agonist propyl pyrazole triol (PPT) (2 mg.kg(-1).day(-1), n = 13) or vehicle (50% DMSO in 0.9% saline) (n = 10) were implanted subcutaneously. One week later transient global ischemia was induced by bilateral carotid artery occlusion under halothane anesthesia, and the mice were perfusion fixed 72 h later. ERbeta agonist DPN significantly reduced ischemic damage by 70% in the caudate nucleus and 55% in the CA1 region compared with vehicle controls (P < 0.05, Mann-Whitney U-statistic). In contrast, pretreatment with the ERalpha agonist PPT had no effect on the extent of neuronal damage compared with controls. The data indicate a significant estrogen receptor-mediated neuroprotection in a global cerebral ischemia model involving ERbeta.
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PMID:Neuroprotection by a selective estrogen receptor beta agonist in a mouse model of global ischemia. 1515 57

We have synthesized a library of estrogen analogues, including enantiomers of estradiol and A-ring substituted estrogens. These compounds have reduced or no binding to either estrogen receptor-alpha or estrogen receptor-beta, exhibit enhanced neuroprotective activity in in vitro models, and are potent in protecting brain tissue from cerebral ischemia/reperfusion injury. These potent, nonfeminizing estrogen analogues are prime candidates for use in stroke neuroprotection.
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PMID:Estrogen-like compounds for ischemic neuroprotection. 1547 7

The objectives of the study were to (1) characterize the dose-response relationship to the TXA2 analog, U46619 (0.01, 0.1, and 1 micromol/L) after global cerebral ischemia, (2) determine whether chronic 17beta-estradiol (E2) replacement alters this relationship, and (3) determine if E2's mechanisms are transduced through cognate estrogen receptors. Rats were assigned to five groups (n=6): placebo-implanted ovariectomized (OVX) females, OVX plus chronic E2 (CE), OVX plus acute E2 (AE), OVX plus chronic E2 plus the estrogen receptor inhibitor ICI 182,780 (CEI), and OVX plus acute E2 plus ICI 182,780 (AEI). Rats were anesthetized, intubated, cannulated (femoral artery and vein), fitted with a closed cranial window, and subjected to 15-min reversible forebrain ischemia (4-vessel occlusion, 4-VO) and 60 mins of reperfusion. Arterial blood gases, intrawindow pressure, and temperature were controlled. Vessel diameter was measured before and 5 mins after superfusion of each concentration of U46619. Compared with preischemic responses, contractile response to U46619 was depressed at all concentrations after ischemia in the OVX group. In the chronic E2 and acute E2 groups, contractile response to 1 micromol/L of U46619 was normalized to near baseline values. However, in the CEI and the AEI groups, postischemic vasoconstriction was similar to that observed in the OVX rats. We conclude that E2 targets the cerebral microvasculature to preserve postischemic pial artery reactivity and that the effect is receptor mediated. Restoration of normal constriction to vascular agonists may be an important mechanism by which E2 protects the vasculature and diminishes tissue damage after ischemia.
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PMID:Estrogen restores postischemic sensitivity to the thromboxane mimetic U46619 in rat pial artery. 1575 45

Estrogen is a powerful neuroprotective agent in rodent models of ischemic stroke. However, in humans, estrogen treatment can increase risk of stroke. Health risks associated with hormone replacement have led many women to consider alternative therapies including high-soy diets or supplements containing soy isoflavones, which act as estrogen receptor ligands to selectively mimic some of estrogen's actions. We hypothesized that a high-soy diet would share the neuroprotective actions of estrogen in focal cerebral ischemia. Female Sprague-Dawley rats were ovariectomized and divided into three groups: isoflavone-free diet + placebo (IF-P), isoflavone-free diet + estradiol (IF-E), or high-soy diet + placebo (S-P). Two weeks after being placed on diets, rats underwent left permanent middle cerebral artery occlusion (MCAO). Reductions in ipsilateral cerebral blood flow were equivalent across groups ( approximately 50%). Twenty-four hours later neurological deficit was determined, and brains were collected for assay of cerebral infarct by TTC staining. In the IF-P rats MCAO produced a 50 +/- 4% cerebral infarct. Estrogen and high-soy diet both significantly reduced the size of the infarcts to 26 +/- 5% in IF-E rats and to 37 +/- 5% in S-P rats. Analysis at five rostro-caudal levels revealed that estrogen treatment was slightly more effective at reducing infarct size than high soy diet. Overall neurological deficit scores at 24 h correlated with infarct size; however, there were no statistically significant differences among the treatment groups. These data show that 2 wk of a high-soy diet is an effective prophylactic strategy for reducing stroke size in a rat model of focal cerebral ischemia.
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PMID:High-soy diet decreases infarct size after permanent middle cerebral artery occlusion in female rats. 1595 59

Recent studies have highlighted that female sex hormones represent potential neuroprotective agents against damage produced by acute and chronic injuries in the adult brain. Clinical reports have documented the effectiveness of estrogens to attenuate symptoms associated with Parkinson's disease, and to reduce the risk of Alzheimer's disease and cerebrovascular stroke. This evidence is corroborated by numerous experimental studies documenting the protective role of female sex hormones both in vitro and in vivo. Accordingly, estrogens have been shown to promote survival and differentiation of several neuronal populations maintained in culture, and to reduce cell death associated with excitotoxicity, oxidative stress, serum deprivation or exposure to beta-amyloid. The neuroprotective effects of estrogens have been widely documented in animal models of neurological disorders, such as Alzheimer's and Parkinson's diseases, as well as cerebral ischemia. Although estrogens are known to exert several direct effects on neurones, the cellular and molecular mechanisms implicated in their protective actions on the brain are not completely understood. Thus, on the basis of clinical and experimental evidence, in this review, we discuss recent findings concerning the neuronal effects of estrogens that may contribute to their neuroprotective actions. Both estrogen receptor-dependent and -independent mechanisms will be described. These include modulation of cell death regulators, such as Bcl-2, Akt and calpain, as well as interaction with growth factors, such as BDNF, NGF, IGF-I and their receptors. The anti-inflammatory effects of estrogens will also be described, namely their ability to reduce brain levels of inflammatory mediators, cytokines and chemokines. Finally, a brief overview about receptor-independent mechanisms of neuroprotection will aim at describing the antioxidant effects of estrogens, as well as their ability to modulate neurotransmission.
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PMID:From clinical evidence to molecular mechanisms underlying neuroprotection afforded by estrogens. 1596 77

Estrogens are potent and efficacious neuroprotectants both in vitro and in vivo in a variety of models of neurotoxicity. We determined the structural requirements for neuroprotection in in vitro assays using a library of more than 70 novel estratrienes, synthesized to reduce or eliminate estrogen receptor (ER) binding. We observed that neuroprotection could be enhanced by as much as 200-fold through modifications that positioned a large, bulky group at the C2 and/or C4 position of the phenolic A ring of the estratriene. Further, substitutions on the B, C, or D rings either reduced or did not markedly change neuroprotection. For this library of compounds, there was a negative correlation between ER binding and neuroprotection, as the more potent compounds showed weaker or no ER binding. In an in vivo model for neuroprotection, transient cerebral ischemia, efficacious compounds were active in protection of brain tissue from this pro-oxidant insult. Finally, estradiol protected brains from insult-induced Alzheimer's disease (AD) neuropathology, including activation of apoptosis, stimulation of Abeta production, hyperphosphorylation of tau, activation of cyclin-dependent kinases, and activation of catastrophic attempts at neuronal mitosis. Collectively, these results demonstrate that nonfeminizing estrogens are neuroprotective and protect the brain from the induction of AD-like neuropathology in an animal model. These features of nonfeminizing estrogens make them attractive compounds for assessment of efficacy in AD and stroke, because they are not expected to show the side effects of chronic estrogen therapy that are ER mediated in the liver, uterus, and breast.
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PMID:Role of nonfeminizing estrogens in brain protection from cerebral ischemia: an animal model of Alzheimer's disease neuropathology. 1602 66


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