Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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

Cytokine-induced neutrophil chemoattractant (CINC), originally identified as a chemoattractant in rat kidney epithelial cells, is related to human 'gro' and murine 'KC'. The proteins encoded by these genes belong to the chemokine alpha superfamily, most of which have neutrophil chemotactic activity. Since brain chemokines may play a significant role in neutrophil accumulation in cerebral ischemia which can contribute to the extent of tissue injury in stroke, we examined the expression of CINC mRNA in the cerebral cortex of rats subjected to focal cerebral ischemia induced by middle cerebral artery occlusion (MCAO). Significant CINC mRNA expression was observed in the ipsilateral (ischemic) cortex from 6 h (17.3 +/- 3.7%, n = 6, P < 0.05) to 24 h (32.1 +/- 3.7%, n = 5, P < 0.01) with a peak at 12 h (43.9 +/- 3.7%, n = 6, P < 0.01) after MCAO. Five days post-MCAO, CINC mRNA levels were no longer elevated. No significant CINC mRNA expression was observed in the contralateral (control) cortex. These studies suggest that message for the neutrophil chemoattractant CINC is induced early in brain tissue subjected to ischemia, and therefore supports the possibility that brain-derived chemokines support the infiltration of circulating inflammatory cells following focal stroke.
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PMID:Cytokine-induced neutrophil chemoattractant mRNA expressed in cerebral ischemia. 815 86

The effects of brain-derived peptides (BDP; Cerebrolysin) upon the amount of brain injury due to focal brain ischemia were assessed. Male Thomae rats were divided randomly into a sham-operated group (n = 5), an ischemic control (untreated) group (n = 7) and an ischemic BDP-treated group (n = 6) and subjected to reversible middle cerebral artery occlusion (MCAO) for 2h followed by 90min of reperfusion. Local cortical blood flow (LCBF) was monitored by Laser-Doppler flowmetry to assess the MCAO and to measure the blood flow in regions peripheral to the infarction. Infarcted areas of the hippocampus and subcortical structures were quantified in hematoxylin and eosin (H&E) stainings. Functional disturbances of the neurons were detected by immunohistochemical staining of the microtubule associated protein MAP2. Moreover, brain edema was estimated morphometrically. LCBF was estimated from the periphery of infarcted areas and was reduced to 55 to 65% of baseline values (p < 0.05). Reperfusion led to LCBF being increased again to baseline values. No differences in LCBF between the control and the BDP-treated animals were found. In the hippocampus, BDP-treated animals showed a significant reduction of loss of MAP2 immunoreactivity in the subiculum and CA1 region by 59% and 64%, respectively, in comparison to control animals (p < 0.05). The amount of irreversibly damaged neurons in these regions was decreased in tendency. However, the inner blade of the dentate gyrus in BDP-treated animals showed a significant reduction of neuronal injury by 98% (p < 0.05). Likewise, BDP treatment reduced the size of the areas showing a loss of MAP2 immunoreactivity in the thalamic and hypothalamic structures by 51% and in the mesencephalon by 81% (p < 0.05). The size of the infarcted areas in these regions (H&E) was reduced in tendency. In the caudate putamen, no protective effect of BDP-treatment could be proven. Cerebral infarction was accompanied by an increase in the volume of the ischemic hemisphere by 10 +/- 1% in the control and 8 +/- 1% in the BDP-treated animals. These findings indicate a beneficial effect for BDP treatment in ameliorating the early effects of focal brain ischemia.
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PMID:Brain-derived peptides reduce the size of cerebral infarction and loss of MAP2 immunoreactivity after focal ischemia in rats. 970 Jun 66

The stimulus-transcriptional coupling during ischemia/hypoxia was examined for ATP-stimulated expression of immediate early genes (IEGs; c-fos, zif268, c-myc and nur77) in a rat brain-derived type 2 astrocyte cell line, RBA-2. Incubation of cells with 1 mM of extracellular ATP stimulated time-dependent expression of c-fos and zif268. ATP induced the largest increases in zif268 mRNA and a lesser one in c-fos mRNA. ATP also induced a slight increase in nur77 mRNA but was ineffective in inducing c-myc expression in these cells. Brief exposure of cells to potassium cyanide to simulate chemical hypoxia induced 9-fold and 7-fold transient increases in c-fos and zif268 expression, respectively, but did not affect c-myc or nur77 expression. When cyanide and ATP were added together, the expression of c-fos and zif268 expression was inhibited, and the effect was mimicked by simulating chemical hypoxia with sodium azide. To elucidate the mechanism involved, the effect of cyanide on ATP-stimulated increases in intracellular Ca(2+) concentrations, [Ca(2+)](i), and phospholipase D (PLD) activities were measured. Cyanide induced an increase in [Ca(2&plus);](i) and further enhanced the ATP-stimulated increases in [Ca(2+)](i) and PLD activities. Nevertheless, metabolic inhibitor, iodoacetate, blocked the ATP-induced c-fos and partially inhibited zif268 expression, and deprivation of cells with glucose also inhibited the ATP-induced c-fos expression. Taken together, these results demonstrate that both extracellular ATP and chemical hypoxia induce c-fos and zif268 expression in RBA-2 type 2 astrocytes. The chemical hypoxia inhibited ATP-stimulated c-fos and zif268 expression is not due to alterations in Ca(2+) and PLD signaling, and is at least partially related to metabolic disturbance in these cells.
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PMID:ATP-stimulated c-fos and zif268 mRNA expression is inhibited by chemical hypoxia in a rat brain-derived type 2 astrocyte cell line, RBA-2. 1072 97

Erythropoietin (Epo), the major hormone controlling the hypoxia-induced increase in the number of erythrocytes, has also a functional role in the brain. However, few data exist as to the cellular source of brain-derived Epo as well as to the molecular mechanisms that control Epo expression in the central nervous system. Using patch-clamp and RT-PCR methods, we provide direct evidence that, besides astrocytes, neurons are a source of Epo in the brain. Both the astrocytic and neuronal expression of Epo mRNA are induced not only by hypoxia, but also by desferrioxamine (DFX) and cobalt chloride (CoCl(2)), two agents known to mimic the hypoxic induction of Epo in hepatoma cells. This induction is blocked by cycloheximide suggesting that de novo protein synthesis is required. Furthermore, the addition of H(2)O(2) decreases the hypoxia-induced Epo mRNA levels. These data indicate that, following hypoxia, a common oxygen sensing and signaling pathway leads to increased Epo gene expression in both nervous and hepatoma cells; this pathway would be dependent on the redox-state of the brain. Furthermore, we show that the in vivo administration of CoCl(2) and DFX to mice induces an increased Epo mRNA level in the neocortex. As Epo protects the brain against ischemia, our in vivo experiments suggest that the use of molecules such as CoCl(2) or DFX, that provoke an increased Epo gene expression in the brain, could be useful in the development of potential therapeutic strategies for the treatment of hypoxic or ischemic brain injury.
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PMID:Neurons and astrocytes express EPO mRNA: oxygen-sensing mechanisms that involve the redox-state of the brain. 1075 76

Brain tissue damage due to ischemia/reperfusion has been shown to be caused, in part, by activated macrophages infiltrating into the post-ischemic brain. Using the Middle Cerebral Artery Occlusion (MCAO) mouse model, this study demonstrated that, in vivo, both endothelin-1 (Et-1), a potent vasoconstrictor, and the macrophage chemokine, monocyte chemoattractant factor-1 (MCP-1) are induced in ischemia. Further studies, using human brain-derived endothelial cells (CNS-EC), showed that in vitro, Et-1 can directly stimulate MCP-1 mRNA expression and MCP-1 protein; and this Et-1-induced MCP-1 production is mediated by the ET(A) receptor. Inflammatory cytokines, tumor necrosis factor alpha and interleukin-1beta, functioned additively and synergistically, respectively, with Et-1 to increase this MCP-1 production. Partial elucidation of the signal transduction pathways involved in Et-1-induced MCP-1 production demonstrated that protein kinase C-, but not cAMP-dependent pathways are involved. These data demonstrate that Et-1, functioning as an inflammatory peptide, increased levels of MCP-1, suggesting a mechanism for chemokine regulation during ischemia/reperfusion injury.
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PMID:Endothelin-1 and monocyte chemoattractant protein-1 modulation in ischemia and human brain-derived endothelial cell cultures. 1131 31

Preconditioning adaptation induced by transient ischemia can increase brain tolerance to oxidative stress, but the underlying neuroprotective mechanisms are not fully understood. Recently, we developed a human brain-derived cell model to investigate preconditioning mechanism in SH-SY5Y neuroblastoma cells.(1) Our results demonstrate that a non-lethal serum deprivation-stress for 2 h (preconditioning stress) enhanced the tolerance to a subsequent lethal oxidative stress (24 h serum deprivation) and also to 1-methyl-4-phenyl-pyridinium (MPP(+)).(2) Two-hour non-lethal preconditioning stress increased the expression of neuronal nitric oxide (NOS1/nNOS) mRNA, Fos, Ref-1, NOS protein, and then nitric oxide (*NO) production. As well as MnSOD expression, the *NO-cGMP-PKG pathway mediated the preconditioning-induced upregulation of antiapoptotic protein Bcl-2 and the downregulation of adaptor protein p66(shc). We also propose that cGMP-mediated preconditioning-induced adaptation against oxidative stress may be due to the synthesis of a new protein, such as thioredoxin (Trx) since the protective effect can be blocked by Trx reductase inhibitor.(3) The antioxidative potency of Trx was approximately 100 and 1,000 times greater than GSNO and GSH, respectively. These results suggest that *NO-cGMP-PKG signaling pathway plays an important role in the preconditioning-induced neuroprotection, and perhaps cardioprotection, against oxidative stress.
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PMID:Preconditioning-mediated neuroprotection: role of nitric oxide, cGMP, and new protein expression. 1207 58

The original neuroprotective hypothesis of estrogen was based on the gender difference in brain response to the ischemia-reperfusion injury. Additional clinical reports also suggest that estrogen may improve cognition in patients with Alzheimer disease. 17beta-Estradiol is the most potent endogenous ligand of estrogen, which protects against neurodegeneration in both cell and animal models. Estrogen-mediated neuroprotection is probably mediated by both receptor-dependent and -independent mechanisms. Binding of estrogen such as 17beta-estradiol to estrogen receptors (ERs) activates the homodimers of ER-DNA and its binding to estrogen response elements in the promoter region of genes such as neuronal nitric oxide synthase (NOS1) for regulating gene expression in target brain cells. In addition to the induction of NOS1, estrogen increases the expression of antiapoptotic protein such as bcl-2. Furthermore, our recent observations provide new molecular biologic and pharmacologic evidence suggesting that physiologic concentrations of 17beta-estradiol (<10 nM) activate ERs (ERbeta > ERalpha) and upregulate a cyclic guanosine 5'- monophosphate (cGMP)-dependent thioredoxin (Trx) and MnSOD expression following the induction of NOS1 in human brain-derived SH-SY5Y cells. We thus proposed that the estrogen-mediated gene induction of Trx plays a pivotal role in the promotion of neuroprotection because Trx is a multifunctional antioxidative and antiapoptotic protein. For managing progressive neurodegeneration such as Alzheimer dementia, our estrogen proposal of the signaling pathway of cGMP-dependent protein kinase (PKG) in mediating estrogen-induced cytoprotective genes thus fosters research and development of the new estrogen ligands devoid of female hormonal side effects such as carcinogenesis.
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PMID:Induction of antioxidative and antiapoptotic thioredoxin supports neuroprotective hypothesis of estrogen. 1277

Previous studies have demonstrated that the expression of several growth factors including glial cell-derived neurotrophic factor (GDNF), brain-derived growth factor (BDNF), and neurotrophin-3 (NT-3) play an important role in defining neuronal survival after brain ischemia. In the present study, using a well-defined model of transient spinal ischemia in rat, we characterized the changes in spinal GDNF, BDNF, and NT-3 expression as defined by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence coupled with deconvolution microscopy. In control animals, baseline levels of GDNF, BDNF, and NT-3 (74 +/- 22, 3,600 +/- 270, 593 +/- 176 pg/g tissue, respectively) were measured. In the ischemic group, 6 min of spinal ischemia resulted in a biphasic response with increases in tissue GDNF and BDNF concentrations at the 2-hr and 72-hr points after ischemia. No significant differences in NT-3 concentration were detected. Deconvolution analysis revealed that the initial increase in tissue GDNF concentration corresponded to a neuronal upregulation whereas the late peak seen at 72 hr corresponded with increased astrocyte-derived GDNF synthesis. Increased expression of BDNF was seen in neurons, astrocytes, and oligodendrocytes. These data suggest that the early increase in neuronal GDNF/BDNF expression likely modulates neuronal resistance/recovery during the initial period of postischemic reflow. Increased astrocyte-derived BDNF/GDNF expression corresponds with transient activation of astrocytes and may play an active role in neuronal plasticity after non-injurious intervals of spinal ischemia.
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PMID:Changes in spinal GDNF, BDNF, and NT-3 expression after transient spinal cord ischemia in the rat. 1459 99

In vivo, pathological conditions such as ischemia and ischemia/reperfusion are known to damage the blood-brain barrier (BBB) leading to the development of vasogenic brain edema. Using an in vitro model of the BBB, consisting of brain-derived microvascular endothelial cells (BMEC), it was demonstrated that hypoxia-induced paracellular permeability was strongly aggravated by reoxygenation (H/R), which was prevented by catalase suggesting that H2O2 is the main mediator of the reoxygenation effect. Therefore, mechanisms leading to H2O2-induced hyperpermeability were investigated. N-acetylcysteine and suramin and furthermore usage of a G protein antagonist inhibited H202 effects suggesting that activation of cell surface receptors coupled to G proteins may mediate signal initiation by H2O2. Further, H2O2 activated phospholipase C (PLC) and increased the intracellular Ca2+ release because U73122, TMB-8, and the calmodulin antagonist W7 inhibited H2O2-induced hyperpermeability. H2O2 did not activate protein kinase C (PKC), nitric-oxide synthase (NOS), and phosphatidyl-inositol-3 kinase (PI3-K/Akt). Inhibition of the extracellular signal-regulated kinase (ERK1/ERK2 or p44/42 MAPK), but not of the p38 and of the c-jun NH2-terminal kinase (JNK), inhibited hyperpermeability by H2O2 and H/R completely. Corresponding to H2O2- and H/R-induced permeability changes the phosphorylation of the p44/42 MAP kinase was inhibited by the specific MAP kinase inhibitor PD98059 and by TMB-8 and W7. Paracellular permeability changes by H2O2 correlated to changes of the localization of the tight junction (TJ) proteins occludin, zonula occludens 1 (ZO-1), and zonula occludens 2 (ZO-2) which were prevented by blocking the p44/p42 MAP kinase activation. Results suggest that H2O2 is the main inducer of H/R-induced permeability changes. The hyperpermeability is caused by activation of PLC via receptor activation leading to the intracellular release of Ca2+ followed by activation of the p44/42 MAP kinase and paracellular permeability changes mediated by changes of the localization of TJ proteins.
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PMID:H2O2 induces paracellular permeability of porcine brain-derived microvascular endothelial cells by activation of the p44/42 MAP kinase pathway. 1610 12

Mitochondrial permeability transition (MPT) is an intracellular event that is closely related to apoptosis and necrosis. However, whether this process underlies the recently reported neuroprotective potency of mitochondrial potassium channel openers applied in vivo remains uncertain. This study aims to clarify this issue by determining the effects of potassium channel openers on MPT dynamics in vitro along with their in vivo effects. Male Sprague-Dawley rats were subjected to middle cerebral artery occlusion (MCAO) for 90 min, followed by reperfusion. 30&#956;l of diazoxide, an opener of the mitochondrial adenosine triphosphate-sensitive K⁺channel (mitoK<inf>ATP</inf>), or NS1619, an opener of the mitochondrial Ca²⁺-activated potassium channel (mitoK<inf>Ca</inf>) (2 mM and 0.1 mM respectively), was infused into the right lateral cerebral ventricle 15 min before the induction of ischemia. Neurological scores were assessed 24 h after MCAO and then infarct area was determined by standard 2,3,5-triphenyltetrazolium chloride staining techniques. To further clarify the capacity of diazoxide and NS1619 to protect mitochondria from Ca²⁺-induced MPT, we isolated brain-derived non-synaptosomal mitochondria and evaluated the effects of diazoxide and NS1619 on Ca²⁺-induced MPT dynamics through measurement of spectrophotometric alterations in light scattering at 520 nm. Neurological scores and infarct size were improved in animals pretreated with diazoxide and NS1619. In isolated mitochondria, MPT was readily induced by 200 &#956;M Ca²⁺and was effectively inhibited by diazoxide and NS1619. The specific MPT pore opener atractyloside abolished the inhibitory effects. According to time-constant analysis, MPT dynamics was in accordance with the neuroprotective effects of channel openers in vivo.
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PMID:Mitochondrial permeability transition dynamics: an indicator of mitochondrial potassium channel opener. 1728 70


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