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 release of the proinflammatory cytokines IL-1 beta, IL-6, TNF-alpha and soluble TNF-receptors p55 and p75 in peripheral blood was serially determined in 19 patients with acute cerebral ischemia. Only patients admitted within 4 h following onset of symptoms were studied. In contrast to serum levels of IL-1 beta, TNF-alpha and TNF-receptors, which did not exhibit a significant response, IL-6 showed a significant increase of serum levels already within the first hours following onset of disease and reached a plateau at 10 h until day 3 and returned to baseline by day 7. The increase of levels of this cytokine was significantly (P < 0.05) correlated with increasing volumes of brain lesion and was also significantly (P < 0.005) associated with poor functional and neurological outcome. The increase of levels of IL-6 despite a considerable dilution in peripheral blood shown in this preliminary study suggests an early inflammatory response in ischemic brain lesion.
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PMID:Proinflammatory cytokines in serum of patients with acute cerebral ischemia: kinetics of secretion and relation to the extent of brain damage and outcome of disease. 802 95

Cerebral ischemia is caused by reduced blood supply at the microcirculatory level. In the microvessels, the main elements of the reperfusion injury following brain ischemia are the transformation of endothelial cell-surface from anticoagulant to procoagulant property, leukocyte adhesion, sludge or clot formation. There is a paucity of information on how hemostatic factors, cytokines, lipoprotein(a) (Lp(a)) and endothelin-1 (ET-1), being responsible for ischemic/reperfusion injury, interact with human brain microvessel endothelium (HBEC). There are no data furthermore about the expression of complement proteins of HBEC influenced by cytokines or fibrinolytic factors. Previously we established optimal conditions for culturing HBEC. Cell contraction induced by thrombin, plasmin, miniplasmin was recorded. The reassembly of F-actin was observed after thrombin treatment. ICAM-1 upregulation was measured following TNF-alpha, IL-1-alpha and thrombin incubation. Plasmin and miniplasmin downregulated the ICAM-1 in our cell culture system. Lp(a) modulated the thromboresistant cell-surface by reduction of t-PA and u-PA, but PAI-1 remained unchanged. Lp(a) modulated the ET-1 production by early increasing and late decreasing, in a bimodal manner. The increased secretion of ET-1 by cytokines (TNF-alpha, IL-1-alpha) was reduced in the presence of Lp(a). Gradual increase of complement proteins (factor H, factor B, C4) was induced by cytokines. Plasmin and miniplasmin augmented a rapid increase of C4. Some factors of complex relationship between regulators and modulators of endothelial adhesion molecules have been demonstrated in a human cell culture system prepared from brain microvessel endothelium. A unified concept of sequential events of ischemia/reperfusion in the brain has not yet developed.
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PMID:Human brain microvessel endothelial cell culture as a model system to study vascular factors of ischemic brain. 889 62

Using in vitro models, our laboratory in collaboration with those of Pierluigi Nicotera (University of Konstanz, Germany) and Stan Orrenius (Karolinska Institute) has recently shown that fulminant insults to the nervous system from excitotoxins or free radicals result in neuronal cell death from necrosis, while more subtle insults result in delayed apoptosis. Over the past dozen or so years, mounting evidence has suggested that excitotoxins, such as glutamate, result in neuronal cell death after stroke. More recent evidence has suggested that in addition to necrotic cell death in the ischemic core, a number of neurons may also undergo apoptosis. Thus, the hypothesis that intense injury leads to necrosis while mild insult (perhaps in the penumbra) leads to apoptosis may hold in focal cerebral ischemia. Another neurological malady with mounting evidence for a pathogenesis that is mediated at least in part by excitotoxins is HIV-1-associated cognitive/motor complex (originally termed the AIDS Dementia Complex and, for convenience, designated here AIDS dementia). AIDS dementia appears to be associated with several neuropathological abnormalities, including giant cell formation by microglia, astrogliosis, and neuronal injury or loss. Recently, neuronal and other cell injury in AIDS brains has been shown to result in apoptotic-like cell death. How can HIV-1 result in neuronal damage if neurons themselves are only rarely, if ever, infected by the virus? Experiments from several different laboratories, including our group in collaboration with that of Howard Gendelman (University of Nebraska Medical Center), have lent support to the existence of HIV- and immune-related toxins in a variety of in vitro and in vivo paradigms. In one recently defined pathway to neuronal injury, HIV-infected macrophages/ microglia as well as macrophages activated by HIV-1 envelope protein gp120 appear to secrete excitants/ neurotoxins. These substances may include arachidonic acid, platelet-activating factor, free radicals (NO. and O2.-), glutamate, quinolinate, cysteine, cytokines (TNF-alpha, IL1-beta, IL-6), amines, and as yet unidentified factors emanating from stimulated macrophages and possibly reactive astrocytes. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke and several neurodegenerative diseases. This mechanism involves excessive activation of N-methyl-D-aspartate (NMDA) receptor-operated channels, with resultant excessive influx of Ca2+ and the generation of free radicals, leading to neuronal damage. With the very recent development of clinically-tolerated NMDA antagonists, as discussed here, there is hope for future pharmacological intervention.
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PMID:Similarity of neuronal cell injury and death in AIDS dementia and focal cerebral ischemia: potential treatment with NMDA open-channel blockers and nitric oxide-related species. 894 20

Selective adenosine receptor agonists and antagonists have marked effects on the outcome of cerebral ischemia, and adenosine receptors are expressed on astrocytes. In this study we examined the effects of various adenosine receptor agonists on the production of nitric oxide and the induction of iNOS in astrocytes activated by LPS/IFN-gamma and TNF-alpha/IL-1beta and on the production of TNF-alpha. Treatment of the cells with the A2A receptor agonist CGS 21680 inhibited both NO production and iNOS expression induced by stimulation with either LPS/IFN-gamma or TNF-alpha/IL-1beta, whereas the A1 and A3 receptor agonists, CPA and Cl-IB-MECA, respectively, did not have significant inhibitory effects. The inhibitory effect of the A2A receptor agonist was antagonized by the specific A2A receptor antagonist CSC. The A2A agonist also exerted a small inhibitory effect on the production of TNF-alpha. Similar inhibitory effects on the production of NO were obtained by cyclic AMP-elevating reagents, such as forskolin and dibutyryl cyclic AMP. Our findings suggest that activation of the A2A receptor inhibits NO production and iNOS expression likely via increased cAMP.
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PMID:Activation of the A2A adenosine receptor inhibits nitric oxide production in glial cells. 965 May 77

Broad spectrum caspase inhibitors have been found to reduce neurodegeneration caused by cerebral ischemia. We studied whether blockade of group I caspases, mainly caspase-1, using the inhibitor Ac-YVAD.cmk reduced infarct volume and produced prolonged neuroprotection. Ac-YVAD.cmk (300 ng/rat) was injected intracerebroventricularly 10 min after permanent middle cerebral artery occlusion in the rat. Drug treatment induced a significant reduction of infarct volume not only 24 hr after ischemia (total damage, percentage of hemisphere volume: control, 41.1 +/- 2.3%; treated, 26.5 +/- 2.1%; p < 0.05) but also 6 d later (total damage: control, 30.6 +/- 2.2%; treated, 23.0 +/- 2.2%; p < 0.05). Ac-YVAD. cmk treatment resulted in a reduction not only of caspase-1 (control, 100 +/- 20.3%; treated, 3.4 +/- 10.4%; p < 0.01) but also of caspase-3 (control, 100 +/- 30.3%; treated, 13.2 +/- 9.5%; p < 0.05) activity at 24 hr and led to a parallel decrease of apoptosis as measured by nucleosome quantitation (control, 100 +/- 11.8%; treated, 47 +/- 5.9%; p < 0.05). Six days after treatment no differences in these parameters could be detected between control and treated animals. Likewise, brain levels of the proinflammatory cytokines IL-1beta and TNF-alpha were reduced at 24 hr (39.5 +/- 23.7 and 51.9 +/- 10.3% of control, respectively) but not at 6 d. Other cytokines, IL-10, MCP-1, MIP-2, and the gaseous mediator nitric oxide, were not modified by the treatment. These findings indicate that blockade of caspase-1-like activity induces a long-lasting neuroprotective effect that, in our experimental conditions, takes place in the early stages of damage progression. Finally, this effect is achieved by interfering with both apoptotic and inflammatory mechanisms.
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PMID:Inhibition of caspase-1-like activity by Ac-Tyr-Val-Ala-Asp-chloromethyl ketone induces long-lasting neuroprotection in cerebral ischemia through apoptosis reduction and decrease of proinflammatory cytokines. 1084 8

Cytokines orchestrate T cell-mediated immune responses. In experimental autoimmune encephalomyelitis (EAE) the proinflammatory cytokines interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, IL-12 and IL-18 are critically involved in the initiation and amplification of the local immune response in the CNS which is counter-balanced by upregulation of antiinflammatory cytokines such as IL-10. The predicted function of individual cytokines during EAE has recently been challenged by transgenic animal studies and neutralization experiments. Cytokine induction is not restricted to autoimmunity in the nervous system. Cytokines are involved in nerve regeneration and induced in focal cerebral ischemia both at the site of infarction and in remote nonischemic brain regions. In cerebral ischemia TNF-alpha and IL-1beta probably have dual functions: In concert with upregulation of inducible NO synthase (iNOS) they exert neurotoxicity while in the absence of iNOS, TNF-alpha and IL-1beta may contribute to neuroprotection and plasticity. The interplay between glial cells, infiltrating leukocytes and induced cytokines leading to CNS pathology is complex and incompletely understood. Further assessment of the functional contribution of cytokines critically depends on the elucidation of downstream secondary signaling mechanisms.
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PMID:Cytokines in CNS disorders: neurotoxicity versus neuroprotection. 1096 21

Within the central nervous system, the proinflammatory cytokine tumor necrosis factor (TNF)-alpha is best characterized by its ability to directly foment signals of death. However, recent evidence suggests that TNF-alpha also promotes neurodegeneration through inhibition of a vital survival signal, insulin-like growth factor-I (IGF-I). By inhibiting essential components of the IGF-I survival response, such as phosphatidylinositol 3'-kinase (PI 3-kinase), low nontoxic concentrations of TNF-alpha indirectly trigger the death of neurons. We suggest that this inhibition of survival signaling is a pathophysiologically relevant action of TNF-alpha in the brain. This type of cross-talk by which vastly different receptors utilize shared intracellular substrates is potentially applicable to a broad number of receptors that are coexpressed on the same cell. The use of neuronal growth factors in the treatment of neurodegenerative diseases, such as cerebral ischemia and the AIDS dementia complex, may prove much more effective if the elevated expression of TNF-alpha in these disorders is neutralized.
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PMID:Tumor necrosis factor-alpha induces neuronal death by silencing survival signals generated by the type I insulin-like growth factor receptor. 1126 46

Previous work in primary cell culture has shown that TNF-alpha and ceramide are involved in the signaling that induces tolerance to brain ischemia (Ginis et al., 1999; Liu et al., 2000). To validate the in vitro studies, the authors administered cell permeable analogs of ceramides intracisternally or intravenously to examine their effect on neuroprotection after focal cerebral ischemia. Permanent middle cerebral artery occlusion (MCAO) was performed in spontaneously hypertensive rats. Infarct volumes were assessed at 24 hours after surgery. D-erythro-N-acetylsphingosine (C2-ceramide) or its vehicle was infused intracisternally for 1 hour before MCAO. In a second set of studies, D-erythro-N-octanoylsphingosine (C8-ceramide) or its vehicle was injected intravenously 48 or 24 hours before MCAO to mimic preconditioning (PC) and was also injected 5 minutes after MCAO. C2-ceramide infusion significantly reduced infarct volumes by approximately 14% (P < 0.05). C8-ceramide injection reduced infarct volumes approximately 17% compared with controls. This effect was constant and significant compared with controls over the time periods examined (P < 0.01). This work supports findings in primary brain cell cultures that implicate ceramide as a downstream signal that is proximate to development of tolerance to brain ischemia. Because the degree of protection represents approximately 50% of the maximal infarct reduction observed in this model, there are probably additional signaling pathways that subserve tolerance.
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PMID:Cell permeable exogenous ceramide reduces infarct size in spontaneously hypertensive rats supporting in vitro studies that have implicated ceramide in induction of tolerance to ischemia. 1129 77

Activation of the extracellular-signal-responsive kinase (ERK 1/2) by MAP kinase/ERK kinase (MEK1/2) following ischemia/reperfusion in the brain has been associated with cell death since inhibition of MEK1/2 provides neuroprotection in cerebral ischemia injury. Since inflammation has been implicated in ischemic brain injury, the present study investigated whether MEK1/2 modifies expression of two key inflammatory cytokines, IL-1beta and TNFalpha, that have been shown to exacerbate ischemic brain injury. A mouse model of transient cerebral ischemia was deployed to test the effect of selective MEK1/2 inhibitor (SL327) on infarct size and cytokine expression. SL327 (100 mg/kg, i.p.) administered 15 min prior to ischemia resulted in 64% reduction in infarct size over controls (n = 8, P < 0.01). Under the same condition, SL327 significantly reduced peak expression of IL-1beta mRNA (59% reduction compared to vehicle, P < 0.01, n = 4) but not TNF-alpha mRNA. A parallel reduction in IL-1beta protein (67%, P < 0.05, n = 6) was also observed using ELISA analysis. These data suggest that the neuroprotective effect of MEK1/2 inhibition may be mediated by suppression of IL-1beta. The study also demonstrates for the first time that these two cytokines are differentially regulated by kinase mediated signaling pathways.
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PMID:Differential regulation of IL-1beta and TNF-alpha RNA expression by MEK1 inhibitor after focal cerebral ischemia in mice. 1152 79

Apoptosis of brain cells is triggered by traumatic brain injury (TBI) and is blocked by caspase inhibitors. The neuronal apoptosis inhibitor protein (NAIP), which has been shown to inhibit apoptosis by both caspase-dependant and caspase-independent mechanisms, is neuroprotective in rat models of cerebral ischemia and axotomy. In order to gain a better appreciation of CNS apoptosis following head injury in general and the possible involvement of NAIP specifically, we have configured a mouse model of TBI. In addition to demonstrating apoptosis, the spatiotemporal expression or levels of a number of proteins with apoptosis modulating effects have been determined. Apoptosis of neurons and oligodendrocytes following TBI was observed in brain sections which were triple-stained with in situ end labeling, bisbenzimide and immunofluorescent stain for neuron specific nuclear protein and myelin-associated glycoprotein, respectively. Further evidence for apoptosis following TBI in this model was obtained in brain samples using ligation-mediated PCR amplification of DNA fragments and gel electrophoresis. The temporal profile of apoptosis was similar to the temporal profile of microglial activation determined by CD11b staining and TNFa expression induced by TBI. NAIP staining in sections of cerebral cortex and subcortical white matter increased at 6 h and decreased towards control levels at 24 h post-TBI. Temporal changes in the expression of NAIP were also observed using Western blot analysis of brain samples removed from injured cortex and sub-cortical white matter. At the time that NAIP expression decreased markedly (24 h post-TBI), procaspase-3 levels also decreased, PARP cleavage increased, and the highest levels of apoptosis were observed. These findings have implications in our understanding of traumatically induced programmed cell death and may be useful in the configuration of therapies for this common injury state.
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PMID:Neuronal apoptosis inhibitory protein expression after traumatic brain injury in the mouse. 1178 Aug 64


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