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)

The protooncogene bcl-2 rescues cells from a wide variety of insults. Recent evidence suggests that the mechanism of action of Bcl-2 involves antioxidant activity. The involvement of free radicals in ischemia/reperfusion injury to neural cells has led us to investigate the effect of Bcl-2 in a model of delayed neural cell death. We have examined the survival of control and bcl-2 transfectants of a hypothalamic tumor cell line, GT1-7, exposed to potassium cyanide in the absence of glucose (chemical hypoxia/aglycemia). After 30 min of treatment, no loss of viability was evident in control or bcl-2 transfectants; however, Bcl-2-expressing cells were protected from delayed cell death measured following 24-72 h of reoxygenation. Under these conditions, the rate and extent of ATP depletion in response to treatment with cyanide in the absence of glucose and the rate of recovery of ATP during reenergization were similar in control and Bcl-2-expressing cells. Bcl-2-expressing cells were protected from oxidative damage resulting from this treatment, as indicated by significantly lower levels of oxidized lipids. Mitochondrial respiration in control but not Bcl-2-expressing cells was compromised immediately following hypoxic treatment. These results indicate that Bcl-2 can protect neural cells from delayed death resulting from chemical hypoxia and reenergization, and may do so by an antioxidant mechanism. The results thereby provide evidence that Bcl-2 or a Bcl-2 mimetic has potential therapeutic application in the treatment of neuropathologies involving oxidative stress, including focal and global cerebral ischemia.
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PMID:Bcl-2 protects neural cells from cyanide/aglycemia-induced lipid oxidation, mitochondrial injury, and loss of viability. 759 37

Expression of the proto-oncogene bcl-2 prevents programmed cell death in vitro, but it is not known whether bcl-2 plays a role in determining cell survival after cerebral ischemia. Using immunohistochemistry and Western blot analysis, bcl-2 protein expression was studied in the rat brain 24 h following 60 or 120 min of temporary focal ischemia. Sixty minutes of ischemia induced bcl-2 protein in neurons throughout the frontoparietal cortex in non-infarcted regions, whereas 120 min of ischemia induced bcl-2 in neurons only just outside the margin of the infarction. bcl-2 protein was also induced in glial cells, mainly microglia, border zone of the infarction. In the infarcted regions of caudate and cortex, bcl-2 protein was exclusively induced in endothelial cells and the vessel walls. Western blot revealed a characteristic single band at 26 kDa only in ischemic samples. These data show that bcl-2 is induced in sublethally injured cells and suggest that bcl-2 could play a role in determining cell survival in cerebral ischemia.
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PMID:bcl-2 is expressed in neurons that survive focal ischemia in the rat. 775 35

Focal cerebral ischemia in rats subjected to middle cerebral artery (MCA) occlusion results in apoptotic DNA fragmentation and activation of putative cell death effector genes in neurons and functional impairment of the plexus choroideus. In the present study we investigated whether cerebral ischemia may induce apoptotic cell death in the choroid plexus. Using in situ end-labeling by terminal transferase and fluorescein-dUTP, nuclear DNA breaks were detected in the choroid plexus of the lateral ventricle of the ischemic hemisphere after 6 h but not after 1.5 h of MCA occlusion. Intense cytoplasmic immunostaining for pro-apoptotic Bax protein and moderate immunolabeling for Bcl-X was observed in the epithelium of the choroid plexus of the lateral and third ventricles. However, constitutive expression of Bax and Bcl-X proteins in the plexus choroideus did not change significantly following focal ischemia. Thus, cells of the choroid plexus may die by apoptosis after several hours of cerebral ischemia. Modulation of cell death effector genes of the bcl-2 family however, may not be required for apoptotic cell death to occur.
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PMID:Evidence for apoptotic cell death in the choroid plexus following focal cerebral ischemia. 873 34

The proto-oncogenes bcl-2 and bcl-x-long have been shown to suppress apoptotic cell death in a variety of in vitro systems and cell lines, including neurons. An alternatively spliced from of bcl-x, bcl-x-short, is a promoter of apoptotic death. Whether these genes are induced after ischemia or play any role in determining the fate of ischemic neurons is unknown. To begin to address this issue, we studied the expression of bcl-2, and bcl-x mRNA and protein after global ischemia in the rat. Ischemia was induced in isoflurane-anesthetized rats by the four-vessel occlusion method. mRNA expression was studied by Northern blot analysis at 24 h after ischemia and by in situ hybridization at 2, 4, 8, 24, and 72 h after 15 min of global ischemia. Protein expression was studied using both immunocytochemistry at 4, 8, 16, 24, and 72 h after ischemia and Western blot analysis from tissue harvested at 16, 24, and 72 h after ischemia. Western blots showed that bcl-x-long is the predominant form of bcl-x protein expressed in both normal and ischemic brain. Both bcl-2 and bcl-x-long mRNA were expressed in CA1, CA3, and the molecular layer of the dentate after ischemia. However, bcl-2 and bcl-x protein were expressed only in CA3 and dentate. Thus, while bcl-2 and bcl-x-long mRNA were expressed in both surviving and dying neurons, their proteins were expressed in neurons destined to survive. These results support potential roles for these two apoptosis suppressor proteins in promoting survival after cerebral ischemia.
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PMID:Apoptosis repressor genes Bcl-2 and Bcl-x-long are expressed in the rat brain following global ischemia. 897 81

Changes in gene expression including that of c-fos occur following cerebral ischemia. Proto-oncogenes c-myc and s-myc and oncosuppressor gene p53 are known to induce apoptosis in some types of cells, whereas proto-oncogene bcl-2 inhibits apoptosis. Possible induction of mRNAs for c-myc, N-myc, s-myc, c-fos, p53 and bcl-2 was examined following focal ischemia in the rat anterior cortex, hippocampus, thalamus and cerebellum by Northern blot analysis. Animals were decapitated 1, 2, 6, 12, and 24 hours following the left middle cerebral artery (MCA) occlusion. In sham-operated control rats, the mRNAs for c-myc, N-myc, c-fos and p53 were present in the anterior cortex, hippocampus, thalamus on both sides, and in the cerebellum, whereas those for s-myc and bcl-2 were not. The c-myc gene expression was rapidly and markedly induced by the MCA occlusion in the ipsilateral anterior cortex, hippocampus and thalamus in a time-dependent manner. In these regions, the c-fos gene expression was also induced as early as 1 hour after the MCA occlusion. The p-53 mRNA was induced in the ipsilateral hippocampus at 24 hours after MCA occlusion. In contrast, mRNAs for N-myc, s-myc and bcl-2 were not induced following MCA occlusion. These results indicate a possibility that high-level expression of the c-myc gene may be involved in the ischemic cellular events including apoptosis.
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PMID:Up-regulation of c-myc gene expression following focal ischemia in the rat brain. 898 58

Heme oxygenase-1 (HO-1, HSP32) is an early gene that is responsive to an array of pathological conditions including, but not limited to, hypoxia and cerebral ischemia. HO-1 cleaves the heme molecule and produces carbon monoxide (CO) and biliverdin (an antioxidant) and is essential for iron homeostasis. The purpose of this study was to investigate, using transgenic (Tg) mice, whether overexpression of HO-1 in the brain augments or attenuates cellular injury caused by ischemic stroke. Homozygous HO-1 Tg mice that overexpress HO-1 under the control of the neuron-specific enolase promoter (characterized previously) were used. Under halothane anesthesia and normothermic conditions, wild-type nontransgenic (nTg; n = 22) and HO-1 Tg (n = 24) mice were subjected to middle cerebral artery occlusion (MCAo). Six hours after induction of ischemia, Tg and nTg mice developed infarcts that were 39 +/- 6 and 63 +/- 9 mm3, respectively (p < 0.01). No significant difference between the two strains was observed in the values of brain edema (11.3 +/- 4% in Tg vs. 14.6 +/- 5% in nTg; p < 0.1). At 24 h after MCAo, Tg mice exhibited significant neuroprotection as determined by the stroke volumes (41 +/- 2 mm3 in Tg vs. 74 +/- 5 mm3 in nTg; p < 0.01) and values of ischemic cerebral edema (21 +/- 6% in Tg vs. 35 +/- 11% in nTg; p < 0.01). Data suggest that neuroprotection in Tg mice was, at least in part, related to the following findings: (a) constitutively up-regulated cyclic GMP and bcl-2 levels in neurons; (b) inhibition of nuclear localization of p53 protein; and (c) antioxidant action of HO-1, as detected by postischemic neuronal expression of ferritin, and decreases in iron staining and tissue lipid peroxidation. We suggest that pharmacological stimulation of HO-1 activity may constitute a novel therapeutic approach in the amelioration of ischemic injury during the acute period of stroke.
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PMID:Overexpression of heme oxygenase-1 is neuroprotective in a model of permanent middle cerebral artery occlusion in transgenic mice. 1003 92

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

Proteins of the bcl-2 family are important regulators of apoptosis in many tissues of the embryo and adult and may play a role in cell death following stroke. The recently isolated bcl-w gene encodes a pro-survival member of the bcl-2 family, which is widely expressed. However, it is not known whether bcl-w plays a role in determining cell survival after cerebral ischemia. Using Western blot analysis and immunocytochemistry, regional bcl-w protein expression was studied in rat brain 2, 6, 24 and 72 h following 20 min temporary middle cerebral artery occlusion (MCAO). Focal cerebral ischemia increased bcl-w protein expression within the caudate putamen and parietal cortex, as well as causing milder increases within frontal cortex. Immunocytochemically bcl-w was expressed within neurons (frontal and parietal cortex) and glia (caudate putamen) 24 h after MCAO. These data suggest that bcl-w could play a role in determining cell survival after cerebral ischemia.
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PMID:Bcl-w expression is increased in brain regions affected by focal cerebral ischemia in the rat. 1068 62

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

Increasing evidence has demonstrated striking sex differences in the pathophysiology of and outcome after acute neurological injury. Lesser susceptibility to postischemic and posttraumatic brain injury in females has been observed in experimental models. Additional evidence suggests this sex difference extends to humans as well. The greater neuroprotection afforded to females is likely due to the effects of circulating estrogens and progestins. In fact, exogenous administration of both hormones has been shown to improve outcome after cerebral ischemia and traumatic brain injury in experimental models. The neuroprotection provided by periinjury administration of these hormones extends to males as well. The mechanisms by which estrogen and progesterone provide such neuroprotection are likely multifactorial, and probably depend on the type and severity of injury as well as the type and concentration of hormone present. Both genomic and nongenomic mechanisms may be involved. Estrogen's putative effects include preservation of autoregulatory function, an antioxidant effect, reduction of A beta production and neurotoxicity, reduced excitotoxicity, increased expression of the antiapoptotic factor bcl-2, and activation of mitogen activated protein kinase pathways. It is hypothesized that several of these neuroprotective mechanisms can be linked back to estrogen's ability to act as a potent chemical (i.e., electron-donating) antioxidant. Progesterone, on the other hand, has a membrane stabilizing effect that also serves to reduce the damage caused by lipid peroxidation. In addition, it may also provide neuroprotection by suppressing neuronal hyperexcitability. The following review will discuss experimental and clinical evidence for sex differences in outcome after acute brain trauma and stroke, review the evidence implicating estrogens and progestins as mediators of this neuroprotection following acute neurological injury, and finally, address the specific mechanisms by which these hormones may protect the brain following acute neurological injury.
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PMID:Gender differences in acute CNS trauma and stroke: neuroprotective effects of estrogen and progesterone. 1083 57


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