UMLS:C0022116 - FACTA Search

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

Recently, a 22 kDa protein termed p75(NTR)-associated death executor (NADE) was discovered to be a necessary factor for p75(NTR)-mediated apoptosis in certain cells. However, the possible role for p75(NTR)/NADE in pathological neuronal death has yet been undetermined. In the present study, we have examined this possibility in vivo and in vitro. Exposure of cortical cultures to zinc induced both p75(NTR) and NADE in neurons, whereas exposure to NMDA, ionomycin, iron, or H(2)O(2) induced neither. In addition, zinc exposure increased neuronal NGF expression and its release into the medium. A function-blocking antibody of p75(NTR) (REX) inhibited association between p75(NTR) and NADE as well as neuronal death induced by zinc. Conversely, NGF augmented zinc-induced neuronal death. Caspase inhibitors reduced zinc-induced neuronal death, indicating that caspases were involved. Because reduction of NADE expression with cycloheximide or NADE antisense oligonucleotides attenuated zinc-induced neuronal death, NADE appears to contribute to p75(NTR)-induced cortical neuronal death as shown in other cells. Because zinc neurotoxicity may be a key mechanism of neuronal death after transient forebrain ischemia, we next examined this model. After ischemia, p75(NTR) and NADE were induced in degenerating rat hippocampal CA1 neurons. There was a close correlation between zinc accumulation and p75(NTR)/NADE induction. Suggesting the role of zinc here, injection of a metal chelator, CaEDTA, into the lateral ventricle completely blocked the induction of p75(NTR) and NADE. Our results suggest that co-induction of p75(NTR) and NADE plays a role in zinc-triggered neuronal death in vitro and in vivo.
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PMID:Co-induction of p75NTR and p75NTR-associated death executor in neurons after zinc exposure in cortical culture or transient ischemia in the rat. 1112 86

Detailed quantitative analysis of the vulnerability of different hippocampal and striatal neurons to global forebrain ischemia has not previously been performed. Here we have studied the survival of immunocytochemically identified neurons using an unbiased stereological method in rats subjected to global forebrain ischemia for 30 min and sacrificed 48 h, 1 week or 4 weeks thereafter. Within the hippocampal formation, there was extensive, progressive loss of CA1 pyramidal neurons and dentate hilar neuropeptide Y (NPY)-positive interneurons. In contrast, no reduction of the number of CA3 and CA4 pyramidal neurons or hilar parvalbumin-positive interneurons was detected. In the dorsolateral striatum, the insult caused a major loss of projection neurons immunoreactive to dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein with a molecular weight of 32 kilodalton (DARPP-32). The number of parvalbumin-positive striatal interneurons was significantly reduced, while NPY-positive interneurons were resistant. All striatal cholinergic interneurons survived the ischemic insult. At 48 h following the ischemia, the cholinergic interneurons within the lesioned striatum transiently expressed the p75 neurotrophin receptor (p75(NTR)), as shown by double-label immunocytochemistry. Furthermore, there was a significant increase in the number of choline acetyltransferase (ChAT)- and TrkA-immunoreactive interneurons at 4 weeks after the insult. Injections with the cell mitotic division marker BrdU provided no evidence that the elevated cholinergic cell number was due to neurogenesis. Probably, the higher number of ChAT- and TrkA-positive interneurons reflected increased intracellular levels of the corresponding proteins leading to more cells detectable with immunocytochemistry. This study gives the first quantitative description of the vulnerability of defined hippocampal and striatal neurons after global forebrain ischemia. The ischemia-induced increases of p75(NTR), TrkA and ChAT in cholinergic striatal interneurons at various time points after the insult suggest that neurotrophin signaling might be important for the survival and function of these cells in the post-ischemic phase.
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PMID:Stereological assessment of vulnerability of immunocytochemically identified striatal and hippocampal neurons after global cerebral ischemia in rats. 1154 75

The importance of postmenopausal estrogen replacement therapy in affording protection against the selective and delayed neuronal death associated with cardiac arrest or cardiac surgery in women remains controversial. Here we report that exogenous estrogen at levels that are physiological for hormone replacement in postmenopausal women affords protection against global ischemia-induced neuronal death and prevents activation of apoptotic signaling cascades in the hippocampal CA1 of male gerbils. Global ischemia induced a marked increase in activated caspase-3 in CA1, evident at 6 hr after ischemia. Global ischemia induced a marked upregulation of the proapoptotic neurotrophin receptor p75(NTR) in CA1, evident at 48 hr. p75(NTR) expression was induced primarily in terminal deoxynucleotidyl transferase-mediated UTP nick-end labeling-positive cells, indicating expression in neurons undergoing apoptosis. Global ischemia also induced a marked downregulation of mRNA encoding the AMPA receptor GluR2 subunit in CA1. Caspase-3, p75(NTR), and GluR2 were not significantly changed in CA3 and dentate gyrus, indicating that the ischemia-induced changes in gene expression were cell specific. Exogenous estrogen attenuated the ischemia-induced increases in activated caspase-3 and blocked the increase in p75(NTR) in post-ischemic CA1 neurons but did not prevent ischemia-induced downregulation of GluR2. These findings demonstrate that long-term estrogen at physiological levels ameliorates ischemia-induced hippocampal injury and indicate that estrogen intervenes at the level of apoptotic signaling cascades to prevent onset of death in neurons otherwise "destined to die."
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PMID:Estrogen protects against global ischemia-induced neuronal death and prevents activation of apoptotic signaling cascades in the hippocampal CA1. 1189 51

The alpha-2-adrenergic receptor agonist brimonidine has been shown to increase survival of retinal ganglion cells following ischemic injury to the rat retina. Increased expression of growth factors has been suggested to be involved in this action. We investigated expressional changes of growth factors and their receptors following transient retinal ischemia induced by selective ligature of ophthalmic vessels in rats pre-treated with vehicle or 0.5% brimonidine. In addition, analysis of expression in retinal samples following unilateral administration of brimonidine to normal tissue was performed. Tissue samples of retina and superior colliculus were collected at time points between 6h and 14 days of retinal reperfusion. Analysis of mRNA levels of the ligands BDNF, NT3, CNTF, FGF1, FGF2, FGF9 and HGF; as well as the receptors TrkB, TrkC, p75(NTR), CNTFRalpha, FGFR1, FGFR3, FGFR4 and HGFR were performed using qRT-PCR. The cell specific markers Thy1 and GFAP were analysed. We report transiently increased retinal levels of BDNF, NT3, p75(NTR), FGFR1 and HGFR and decreased levels of FGF9, HGF, TrkB, TrkC, FGFR4 and Thy1 following ischemia. The decreases were counteracted by brimonidine. Brimonidine treatment gave an increase in BDNF, NT3 and CNTF levels compared to the vehicle treated group. In superior colliculus increased levels of growth factor mRNA were found. In conclusion, transient ischemia has a profound effect on gene expression in rat retina. Alterations can also be seen in the superior colliculus but are smaller. Brimonidine pre-treatment attenuates an acute injury-induced response by decreasing the expression of several genes, among them p75(NTR). Brimonidine also causes a prolonged increase of several growth factors as well as receptors in retina and superior colliculus compared to the ischemic situation. The increased expression of several growth factors represents a coordinated growth factor system response that differs from the ischemia-induced changes and is likely part of the neuroprotective activity that is elicited by BMD pre-treatment.
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PMID:The growth factor response in ischemic rat retina and superior colliculus after brimonidine pre-treatment. 1711 48

The mechanisms initiating post-spinal cord injury (SCI) apoptotic cell death remain incompletely understood. The p75 neurotrophin receptor (p75(NTR)) has been shown to exert both pro-survival and pro-apoptotic effects on neural cells in vitro. While a previous study had shown that there is decreased oligodendrocyte apoptosis distal to a clean partial transection injury of the cord in mice with nonfunctional p75(NTR), most human spinal cord injuries do not involve partial transections but are rather due to compression/contusion injuries with significant perilesional ischemia. Therefore, we sought to examine the role of the p75(NTR) in a clinically relevant clip compression model of SCI in p75 null mice with an exon III mutation. Mice with a functional p75(NTR) had increased caspase-9 activation at 3 days after SCI in comparison to the functionally deficient p75(NTR) mice. However, at 7 days following SCI there was no difference in the activation of the effector caspases (caspase-3 and caspase-6) at the spinal cord lesion. Moreover, at 7 days after injury, there was increased terminal deoxynucleotidyl transferase-mediated dUTP nick-end (TUNEL) positive cell death at the injury site in the functionally deficient p75(NTR) mice. Using double labeling with TUNEL and cell specific markers we showed that the absence of p75(NTR) function increased the extent of neuronal but not oligodendroglial cell death at the injury site. This selective loss of neuronal cells after SCI was confirmed with a decrease in levels of microtubule-associated protein 2 in the p75 null mice. Furthermore, the wild-type animals had dramatically improved survival and enhanced locomotor recovery at 8 weeks after SCI when compared with the p75(NTR) null mice. Also at 8 weeks, there were significantly more neurons present at the injury site of wild-type mice when compared with p75 null mice. We conclude that the p75(NTR) receptor is integral to neuronal cell survival and endogenous reparative mechanisms after compressive/contusive SCI.
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PMID:The p75 neurotrophin receptor is essential for neuronal cell survival and improvement of functional recovery after spinal cord injury. 1770 65

Elevated introcular pressure (IOP)-induced retinal neuron ischemic death includes an early phase of necrosis and prolonged phase of apoptosis. We used this ischemic model to observe the changes of sortilin and p75(NTR) protein expressions in rat retina. The results of Western blot analysis showed the expression of p75(NTR) at the band of 75 (mature form), 60 (non-glycosylated pieces) and 50 kDa (ectodomain shedding pieces), and the expression of sortilin at the 95 and 90 kDa (the mature form). The protein expressions of p75(NTR) (60 and 50 kDa pieces) and sortilin (90 kDa) increased significantly (p < 0.05) at days 3, 5 and 7 after retinal ischemia. This effect was also confirmed by immunofluorescence staining. Sortilin was primarily present in cell membrane of the ganglion cells layer (GCL) and large ganglion cell bodies by immunofluorescence labeling. There was little expression of p75(NTR) in the normal retina, while expression increased extensively in GCL, inner plexiform layer (IPL) and inner nuclear layer (INL) after retinal ischemia. p75(NTR) was shown to co-localize with neurofilament in the axons of neuronal cells by double-labeling. These results suggested that the protein expressions of 60 and 50 kDa forms of p75(NTR), and the 90 kDa mature form of sortilin increased in ischemia-induced retinal neuron of rats.
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PMID:Enhanced protein expressions of sortilin and p75NTR in retina of rat following elevated intraocular pressure-induced retinal ischemia. 1799 40

Diabetes impairs endothelial function and reparative neovascularization. The p75 receptor of neurotrophins (p75(NTR)), which is scarcely present in healthy endothelial cells (ECs), becomes strongly expressed by capillary ECs after induction of peripheral ischemia in type-1 diabetic mice. Here, we show that gene transfer-induced p75(NTR) expression impairs the survival, proliferation, migration, and adhesion capacities of cultured ECs and endothelial progenitor cells (EPCs) and inhibits angiogenesis in vitro. Moreover, intramuscular p75(NTR) gene delivery impairs neovascularization and blood flow recovery in a mouse model of limb ischemia. These disturbed functions are associated with suppression of signaling mechanisms implicated in EC survival and angiogenesis. In fact, p75(NTR) depresses the VEGF-A/Akt/eNOS/NO pathway and additionally reduces the mRNA levels of ITGB1 [beta (1) integrin], BIRC5 (survivin), PTTG1 (securin) and VEZF1. Diabetic mice, which typically show impaired postischemic muscular neovascularization and blood perfusion recovery, have these defects corrected by intramuscular gene transfer of a dominant negative mutant form of p75(NTR). Collectively, our data newly demonstrate the antiangiogenic action of p75(NTR) and open new avenues for the therapeutic use of p75(NTR) inhibition to combat diabetes-induced microvascular liabilities.
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PMID:Neurotrophin p75 receptor (p75NTR) promotes endothelial cell apoptosis and inhibits angiogenesis: implications for diabetes-induced impaired neovascularization in ischemic limb muscles. 1856 44

Ischemic preconditioning (PC) of the brain is a phenomenon by which mild ischemic insults render neurons resistant to subsequent strong insults. Key steps in ischemic PC of the brain include caspase-3 activation and poly(ADP-ribose) polymerase-1 (PARP-1) cleavage, but upstream events have not been clearly elucidated. We have tested whether endogenous zinc is required for ischemic PC of the brain in rats. Mild, transient zinc accumulation was observed in certain neurons after ischemic PC. Moreover, intraventricular administration of CaEDTA during ischemic PC abrogated both zinc accumulation and the protective effect against subsequent full ischemia. To elucidate the mechanism of the zinc-triggered PC (Zn PC) effect, cortical cultures were exposed to sublethal levels of zinc, and 18 h later to lethal levels of zinc or NMDA. Zn PC exhibited the characteristic features of ischemic PC, including caspase-3 activation, PARP-1 cleavage, and HSP70 induction, all of which are crucial for subsequent neuroprotection against NMDA or zinc toxicity. HSP70 induction was necessary for protection, as it halted caspase-3 activation before apoptosis. Interestingly, in both Zn PC in vitro and ischemic PC in vivo, p75(NTR) was necessary for neuroprotection. These results suggest that caspase-3 activation during ischemic PC, a necessary event for subsequent neuroprotection, may result from mild zinc accumulation and the consequent p75(NTR) activation in neurons.
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PMID:Essential role for zinc-triggered p75NTR activation in preconditioning neuroprotection. 1894 99

Neurotrophins were christened in consideration of their actions on the nervous system and, for a long time, they were the exclusive interest of neuroscientists. However, more recently, this family of proteins has been shown to possess essential cardiovascular functions. During cardiovascular development, neurotrophins and their receptors are essential factors in the formation of the heart and critical regulator of vascular development. Postnatally, neurotrophins control the survival of endothelial cells, vascular smooth muscle cells, and cardiomyocytes and regulate angiogenesis and vasculogenesis, by autocrine and paracrine mechanisms. Recent studies suggest the capacity of neurotrophins, via their tropomyosin-kinase receptors, to promote therapeutic neovascularization in animal models of hindlimb ischemia. Conversely, the neurotrophin low-affinity p75(NTR) receptor induces apoptosis of endothelial cells and vascular smooth muscle cells and impairs angiogenesis. Finally, nerve growth factor looks particularly promising in treating microvascular complications of diabetes or reducing cardiomyocyte apoptosis in the infarcted heart. These seminal discoveries have fuelled basic and translational research and thus opened a new field of investigation in cardiovascular medicine and therapeutics. Here, we review recent progress on the molecular signaling and roles played by neurotrophins in cardiovascular development, function, and pathology, and we discuss therapeutic potential of strategies based on neurotrophin manipulation.
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PMID:Cardiovascular actions of neurotrophins. 1912 59

Treatment of acute cardiac ischemia focuses on reestablishment of blood flow in coronary arteries. However, impaired microvascular perfusion damages peri-infarct tissue, despite arterial patency. Identification of cytokines that induce microvascular dysfunction would provide new targets to limit microvascular damage. Pro-nerve growth factor (NGF), the precursor of NGF, is a well characterized cytokine in the brain induced by injury. ProNGF activates p75 neurotrophin receptor (p75(NTR)) and sortilin receptors to mediate proapoptotic responses. We describe induction of proNGF by cardiomyocytes, and p75(NTR) in human arterioles after fatal myocardial infarction, but not with unrelated pathologies. After mouse cardiac ischemia-reperfusion (I-R) injury, rapid up-regulation of proNGF by cardiomyocytes and p75(NTR) by microvascular pericytes is observed. To identify proNGF actions, we generated a mouse expressing a mutant Ngf allele with impaired processing of proNGF to mature NGF. The proNGF-expressing mouse exhibits cardiac microvascular endothelial activation, a decrease in pericyte process length, and increased vascular permeability, leading to lethal cardiomyopathy in adulthood. Deletion of p75(NTR) in proNGF-expressing mice rescues the phenotype, confirming the importance of p75(NTR)-expressing pericytes in the development of microvascular injury. Furthermore, deficiency in p75(NTR) limits infarct size after I-R. These studies identify novel, nonneuronal actions for proNGF and suggest that proNGF represents a new target to limit microvascular dysfunction.
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PMID:ProNGF, a cytokine induced after myocardial infarction in humans, targets pericytes to promote microvascular damage and activation. 2309 Nov 65

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