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

The study investigated whether estradiol can prevent release of cytochrome c from mitochondria and induction of apoptosis after 30 and 60 min stop-flow heart ischemia in Langendorff-perfused female rat hearts. Pre-perfusion of hearts with 100 nM 17beta-estradiol prevented the loss of cytochrome c from mitochondria, its accumulation in cytosol, and inhibition of respiration during ischemia. Estradiol strongly reduced activation of caspase-3-like activity and decreased DNA strand breaks in the nuclei of cardiomyocytes (measured by TUNEL staining). The results show that 17beta-estradiol prevents the ischemia-induced release of cytochrome c from mitochondria, subsequent inhibition of mitochondrial respiration, and inhibits caspase activation and apoptosis. Therefore, inhibition of the intrinsic, mitochondria-mediated apoptotic pathway may be one of the mechanisms by which estrogens protect the heart against ischemic damage.
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PMID:Estradiol prevents release of cytochrome c from mitochondria and inhibits ischemia-induced apoptosis in perfused heart. 1658 Aug 5

During cerebral ischemia, part of the damage associated with the hyperactivation of glutamate receptors results from the hyperphosphorylation of the microtubule-associated protein Tau. Previous studies have shown that estradiol treatment reduces neural damage after cerebral ischemia. Here, we show that transient occlusion of the middle cerebral artery results in the hyperphosphorylation of Tau and in a significant increase in the association of Tau with glycogen synthase kinase-3beta and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid type glutamate receptor subunits 2/3 in the hippocampus. Estradiol treatment decreased hippocampal injury, inhibited glycogen synthase kinase-3beta and decreased the hyperphosphorylation of Tau and the interaction of Tau with glycogen synthase kinase-3beta and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor. These findings suggest that ischemia produces a strong association between Tau and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor, and estradiol can exert at least part of its neuroprotective activity through inhibition of glycogen synthase kinase-3beta.
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PMID:Estrogen dissociates Tau and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor subunit in postischemic hippocampus. 1695 81

The importance of hormone therapy in affording protection against the sequelae of global ischemia in postmenopausal women remains controversial. Global ischemia arising during cardiac arrest or cardiac surgery causes highly selective, delayed death of hippocampal CA1 neurons. Exogenous estradiol ameliorates global ischemia-induced neuronal death and cognitive impairment in male and female rodents. However, the molecular mechanisms by which estrogens intervene in global ischemia-induced apoptotic cell death are unclear. Here we show that estradiol acts via the classical estrogen receptors, the IGF-I receptor, and the ERK/MAPK signaling cascade to protect CA1 neurons in ovariectomized female rats and gerbils. We demonstrate that global ischemia promotes early dephosphorylation and inactivation of ERK1 and the transcription factor cAMP-response element binding protein (CREB), subsequent down-regulation of the antiapoptotic protein Bcl-2, a known gene target of estradiol and CREB, and activation of caspase-3. Estradiol treatment increases basal phosphorylation of both ERK1 and ERK2 in hippocampal CA1 and prevents ischemia-induced dephosphorylation and inactivation of ERK1 and CREB, down-regulation of Bcl-2 and activation of the caspase death cascade. Whereas ERK/MAPK signaling is critical to CREB activation and neuronal survival, the impact of estradiol on Bcl-2 levels is ERK independent. These findings support a model whereby estradiol acts via the classical estrogen receptors and IGF-I receptors, which converge on activation of ERK/MAPK signaling and CREB to promote neuronal survival in the face of global ischemia.
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PMID:MAPK signaling is critical to estradiol protection of CA1 neurons in global ischemia. 1713 46

Estradiol can act to protect against hippocampal damage resulting from transient global ischemia, but little is known about the functional consequences of such neuroprotection. The present study examines whether acute estradiol administered prior to the induction of transient global ischemia protects against hippocampal cell death and deficits in performance on a spatial learning task. Ovariectomized female rats were primed with estradiol benzoate or oil vehicle 48 and 24 h prior to experiencing one of three durations of 4-vessel occlusion (0, 5, or 10 min). Performance on the cued and hidden platform versions of the Morris water maze was assessed 1 week following ischemia. On the cued platform task, neither hormone treatment nor ischemia significantly influenced acquisition. When tested on the hidden platform task, however, oil-treated rats exhibited impairments in spatial learning after either 5 or 10 min of ischemia while estradiol-treated rats showed no impairments after 5 min of ischemia and only mild impairments after 10 min of ischemia. Immediately following behavioral testing, rats were perfused and survival of CA1 pyramidal cells was assessed. Ischemia was associated with the loss of CA1 pyramidal cells but rats that received estradiol prior to ischemia showed less severe damage. Furthermore, the extent of cell loss was correlated with degree of spatial bias expressed on a probe trial following hidden platform training. These findings indicate that acute exposure to estradiol prior to ischemia is both neuroprotective and functionally protective.
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PMID:Acute pretreatment with estradiol protects against CA1 cell loss and spatial learning impairments resulting from transient global ischemia. 1723 78

Global forebrain ischemia arising from brief occlusion of the carotid arteries in gerbils produces selective hippocampal CA1 neuronal loss. Pre-treatment with 17beta-estradiol ameliorates, in part, ischemia-induced damage in young animals. Because stroke and cardiac arrest are more likely to occur among elderly individuals, neuroprotective studies in older animals have compelling clinical relevance. We investigated whether estradiol would attenuate ischemia-induced hippocampal neuronal injury in middle-aged (12-14 months) male, intact female, ovariectomized (OVX) female and OVX females treated for 14 days with estradiol. Core temperature telemetry probes were also implanted at the time that estradiol was initiated. Ischemia was induced by bilateral occlusion of the common carotid arteries (5 min), during which time skull temperature was maintained under normothermic conditions. Estradiol blocked the modest spontaneous hyperthermia that normally follows ischemia. However, all four groups exhibited substantial neuronal cell loss in the CA1, assessed at 7 after ischemia. These findings indicate that estradiol pre-treatment under conditions that produce neuroprotection in young animals does not protect against ischemia-induced CA1 cell loss in middle-aged female gerbils.
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PMID:Failure of estradiol to ameliorate global ischemia-induced CA1 sector injury in middle-aged female gerbils. 1746 7

Ion transporters of blood-brain barrier (BBB) endothelial cells play an important role in regulating the movement of ions between the blood and brain. During ischemic stroke, reduction in cerebral blood flow is accompanied by transport of Na and Cl from the blood into the brain, with consequent brain edema formation. We have shown previously that a BBB Na-K-Cl cotransporter (NKCC) participates in ischemia-induced brain Na and water uptake and that a BBB Na/H exchanger (NHE) may also participate. While the abrupt reduction of blood flow is a prominent component of ischemia, the effects of flow on BBB NKCC and NHE are not known. In the present study, we examined the effects of changes in shear stress on NKCC and NHE protein levels in cerebral microvascular endothelial cells (CMECs). We have shown previously that estradiol attenuates both ischemia-induced cerebral edema and CMEC NKCC activity. Thus, in the present study, we also examined the effects of estradiol on NKCC and NHE protein levels in CMECs. Exposing CMECs to steady shear stress (19 dyn/cm(2)) increased the abundance of both NKCC and NHE. Estradiol abolished the shear stress-induced increase in NHE but not NKCC. Abrupt reduction of shear stress did not alter NKCC or NHE abundance in the absence of estradiol, but it decreased NKCC abundance in estradiol-treated cells. Our results indicate that changes in shear stress modulate BBB NKCC and NHE protein levels. They also support the hypothesis that estradiol attenuates edema formation in ischemic stroke in part by reducing the abundance of BBB NKCC protein.
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PMID:Shear stress and 17beta-estradiol modulate cerebral microvascular endothelial Na-K-Cl cotransporter and Na/H exchanger protein levels. 1795 24

The protection from ischemic brain injury enjoyed by females is linked to the female sex hormone 17beta-estradiol. We tested the hypothesis that neuroprotection by estradiol entails the prevention of ischemia-induced inflammatory response, through suppression of the P450 eicosanoids-metabolizing enzyme soluble epoxide hydrolase (sEH). Ovariectomized female rats with and without estradiol replacement underwent 2-hour middle cerebral artery occlusion (MCAO). SEH expression was determined using Western blot, and inflammatory cytokine mRNA levels were measured at 6, 24 and 48 hours after MCAO. Cytokine mRNA was also measured in sEH-knockout mice, and in rats treated with sEH inhibitors. Estradiol reduced basal and post-ischemic sEH expression. MCAO strongly induced mRNA levels of tumor necrosis factor-alpha, interleukin 6, and interleukin 1beta, which was attenuated in sEH-knockouts, but not by sEH inhibitors. Estradiol replacement exhibited a bimodal effect on cytokine mRNA, with increased early and reduced delayed expression. While estradiol suppresses cerebral sEH expression, and sEH suppression diminishes inflammation after MCAO, our findings suggest that the effect of estrogen on inflammation is complex, and only partially explained by sEH suppression.
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PMID:Soluble epoxide hydrolase: regulation by estrogen and role in the inflammatory response to cerebral ischemia. 1798 57

Estrogen is protective in experimental cerebral ischemia, yet the mechanism remains unclear. Fas-mediated apoptosis has been shown to be induced after cerebral ischemia and significantly contribute to ischemic brain damage. In this study, we tested if estrogen is protective against cerebral ischemia by suppressing Fas-mediated apoptosis. 17Beta-estradiol-treated and untreated ovariectomized (OVX) female mice were subjected to 2 h middle cerebral artery occlusion (MCAO). Expression of Fas and Fas-associated death domain (FADD) were measured at 3, 6 and 12 h of reperfusion by RT-PCR and Western blot, respectively. Post-ischemic activities of caspase-8 and -3 activities, the two downstream effectors of Fas-induced apoptosis, were also assayed at same time points by ELISA. Finally, Fas antibody-induced cell death in primary cortical neurons was assayed by fluorescence activated cell sorter (FACS) in the presence and absence of estradiol. Our data showed that estradiol-treated OVX female mice sustained smaller infarct compared to untreated OVX mice. Ischemia upregulated Fas and FADD expression, and increased caspase-8 and -3 activities in OVX female mouse cortex, which were significantly attenuated by estradiol. Estradiol also significantly inhibited Fas antibody-induced neuronal cell apoptosis. Our data suggests that inhibition of ischemia-induced Fas-mediated apoptosis is an important mechanism of neuroprotection by estrogen in cerebral ischemia.
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PMID:Estrogen inhibits Fas-mediated apoptosis in experimental stroke. 1895 Jun 22

Global ischemia arising during cardiac arrest or cardiac surgery causes highly selective, delayed death of hippocampal CA1 neurons. Exogenous estradiol ameliorates global ischemia-induced neuronal death and cognitive impairment in male and female rodents. However, the molecular mechanisms by which a single acute injection of estradiol administered after the ischemic event intervenes in global ischemia-induced apoptotic cell death are unclear. Here we show that acute estradiol acts via the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling cascade to protect CA1 neurons in ovariectomized female rats. We demonstrate that global ischemia promotes early activation of glycogen synthase kinase-3beta (GSK3beta) and forkhead transcription factor of the O class (FOXO)3A, known Akt targets that are related to cell survival, and activation of caspase-3. Estradiol prevents ischemia-induced dephosphorylation and activation of GSK3beta and FOXO3A, and the caspase death cascade. These findings support a model whereby estradiol acts by activation of PI3K/Akt signaling to promote neuronal survival in the face of global ischemia.
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PMID:Acute estradiol protects CA1 neurons from ischemia-induced apoptotic cell death via the PI3K/Akt pathway. 2011 38

We have previously reported that estradiol can protect heart mitochondria from the ischemia-induced mitochondrial permeability transition pore-related release of cytochrome c and subsequent apoptosis. In this study we investigated whether the effect of 17-beta-estradiol on ischemia-induced mitochondrial dysfunctions and apoptosis is mediated by activation of signaling protein kinases in a Langendorff-perfused rat heart model of stop-flow ischemia. We found that pre-perfusion of non-ischemic hearts with 100nM estradiol increased the resistance of subsequently isolated mitochondria to the calcium-induced opening of mitochondrial permeability transition pore and this was mediated by protein kinase G. Loading of the hearts with estradiol prevented ischemia-induced loss of cytochrome c from mitochondria and respiratory inhibition and these effects were reversed in the presence of the inhibitor of Akt kinase, NO synthase inhibitor L-NAME, guanylyl cyclase inhibitor ODQ and protein kinase G inhibitor KT5823. Estradiol prevented ischemia-induced activation of caspases and this was also reversed by KT5823. These findings suggest that estradiol may protect the heart against ischemia-induced injury activating the signaling cascade which involves Akt kinase, NO synthase, guanylyl cyclase and protein kinase G, and results in blockage of mitochondrial permeability transition pore-induced release of cytochrome c from mitochondria, respiratory inhibition and activation of caspases.
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PMID:Estradiol-induced protection against ischemia-induced heart mitochondrial damage and caspase activation is mediated by protein kinase G. 2038 50


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