Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inflammatory reaction plays an important role in cerebral ischemia-reperfusion injury, however, its mechanism is still unclear. Our study aims to explore the function of Toll-like receptor 4 (TLR4) in the process of cerebral ischemia-reperfusion. We made middle cerebral artery ischemia-reperfusion model in mice with line embolism method. Compared with C3H/OuJ mice, scores of cerebral water content, cerebral infarct size and neurologic impairment in C3H/Hej mice were obviously lower after 6 h ischemia and 24 h reperfusion. Light microscopic and electron microscopic results showed that cerebral ischemia-reperfusion injury in C3H/Hej mice was less serious than that in C3H/OuJ mice. TNF-alpha and IL-6 contents in C3H/HeJ mice were obviously lower than that in C3H/OuJ mice with ELISA. The results showed that TLR4 participates in the process of cerebral ischemia-reperfusion injury probably through decrease of inflammatory cytokines. TLR4 may become a new target for prevention of cerebral ischemia-reperfusion injury. Our study suggests that TLR4 is one of the mechanisms of cerebral ischemia-reperfusion injury besides its important role in innate immunity.
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PMID:Reduced cerebral ischemia-reperfusion injury in Toll-like receptor 4 deficient mice. 1718 46

A significant up-regulation of Toll-like-receptor (TLR) mRNAs between 3 and 48 h reperfusion time after induction of transient focal cerebral ischemia for 1h was revealed by applying global gene expression profiling in postischemic mouse brains. Compared to TLR4 and TLR9, TLR2 proved to be the most significantly up-regulated TLR in the ipsilateral brain hemisphere. TLR2-protein was found to be expressed mainly in microglia in the postischemic brain tissue, but also in selected endothelial cells, neurons, and astrocytes. Additionally, TLR2-related genes with pro-inflammatory and pro-apoptotic capabilities were induced. Therefore we hypothesized that TLR2-signaling could exacerbate the primary brain damage after ischemia. Two days after induction of transient focal cerebral ischemia (1h), we found a significant decrease of the infarct volume in TLR2 deficient mice compared to wild type mice (75+/-5 vs. 42+/-7 mm(3)). We conclude that TLR2 up-regulation and TLR2-signaling are important events in focal cerebral ischemia and contribute to the deterioration of ischemic damage.
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PMID:TLR2 has a detrimental role in mouse transient focal cerebral ischemia. 1754 55

Toll-like receptors (TLRs) play a critical role in the induction of innate immune responses which have been implicated in neuronal death induced by global cerebral ischemia/reperfusion (GCI/R). The present study investigated the role and mechanisms-of-action of TLR4 signaling in ischemia-induced hippocampal neuronal death. Neuronal damage, activation of the TLR4 signaling pathway, expression of pro-inflammatory cytokines and activation of the PI3K/Akt signaling pathway in the hippocampal formation (HF) were assessed in wild type (WT) mice and TLR4 knockout (TLR4(-/-)) mice after GCI/R. GCI/R increased expression of TLR4 protein in the hippocampal formation (HF) and other brain structures in WT mice. Phosphorylation of the inhibitor of kappa B (p-IkappaB) as well as activation of nuclear factor kappa B (NFkappaB) increased in the HF of WT mice. In contrast, there were lower levels of p-IkappaB and NFkappaB binding activity in TLR4(-/-) mice subjected to GCI/R. Pro-inflammatory cytokine expression was also decreased, while phosphorylation of Akt and GSK3beta were increased in the HF of TLR4(-/-) mice after GCI/R. These changes correlated with decreased neuronal death/apoptosis in TLR4(-/-) mice following GCI/R. These data suggest that activation of TLR4 signaling contributes to ischemia-induced hippocampal neuronal death. In addition, these data suggest that modulation of TLR4 signaling may attenuate ischemic injury in hippocampal neurons.
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PMID:Activation of Toll-like receptor 4 signaling contributes to hippocampal neuronal death following global cerebral ischemia/reperfusion. 1788 82

The pattern recognition receptor toll-like receptor (TLR)-4 mediates innate danger signaling in the brain, being activated in response to lipopolysaccharide. Until now, its role in the degenerating brain remained unknown. We here examined effects of a loss-of-function mutation of TLR-4 in mice submitted to transient focal cerebral ischemia and retinal ganglion cell (RGC) axotomy, which are highly reproducible and clinically relevant in vivo models of acute and subacute neuronal degeneration. We show that TLR-4 deficiency protects mice against ischemia and axotomy-induced RGC degeneration. Decreased phosphorylation levels of the mitogen-activated kinases ERK-1/-2, JNK-1/-2 and p38 together with reduced inducible NO synthase levels in injured neurons of TLR-4 mutant mice suggests that TLR-4 deficiency downscales parenchymal stress responses, thereby enhancing neuronal survival. At the same time, densities of MPO+ neutrophils and Iba1+ microglial cells were increased in the brains of TLR-4 mutant animals, pointing towards a futile inflammatory response aiming to compensate lost functions. Our data indicate that innate immunity may represent an attractive target for neuroprotective treatments in stroke and neurodegeneration.
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PMID:TLR-4 deficiency protects against focal cerebral ischemia and axotomy-induced neurodegeneration. 1848 83

In the present study, we observed the expression of toll-like receptor 4 (TLR4) and its downstream signal pathway in peripheral blood monocytes (PBMs) from patients with acute cerebral infarct (ACI). The expression of TLR4 and MyD88 by PBMs was determined by flow cytometry and reverse transcriptase-polymerase chain reaction, and nuclear factor-kappaB (NF-kappaB) activity was detected by electrophoretic mobility shift assay. Ischemia/reperfusion injury-induced cerebral edema, infarction area, and neurologic impairment scores were determined in MyD88 gene knockout mice. The results indicated a significant increase in circulating TLR4(+) monocytes in ACI patients as compared with the control group and the transient ischemia attack (TIA) group. This change paralleled an elevation in TLR4mRNA transcription and serum tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)-6 in the ACI and TIA groups. Correlation analysis showed TLR4 expression to significantly correlate with cytokine levels and stroke severity. MyD88mRNA differed insignificantly among the three groups. Compared with wild-type mice, 6 h of cerebral ischemia followed by 24 h of reperfusion did not significantly change cerebral edema, cerebral infarction area, and neurologic impairment scores in MyD88 gene knockout mice. Compared with the control group, serum heat shock protein (HSP) 60 increased significantly in the ACI and TIA groups, leading to NF-kappaB activation in TLR4/CD14-transfected HEK293 cells. It is suggested that upregulated TLR4 expression on PMBs may act as one of the peripheral mechanisms of inflammatory injury after ACI. Moreover, circulating HSP60 may be a ligand for TLR4, which is involved in the peripheral mechanism of inflammatory injury after ACI, possibly through an MyD88-independent signal pathway.
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PMID:Upregulated expression of toll-like receptor 4 in monocytes correlates with severity of acute cerebral infarction. 1852 39

To study whether the signaling pathway is activated in the inflammatory reaction of cerebral ischemia-reperfusion and its mechanism. The mice were randomly divided into sham group, ischemia-reperfusion group and TLR4-blocked group with different time points of reperfusion 12h, 24h, 48h and 72h group. We observed the different expression of TLR4 mRNA and MyD88 mRNA, activation of NF-kappaB and the TNF-alpha and IL-1beta protein levels in each group at different time point after ischemia-reperfusion. Mice cerebral ischemia was induced by occlusion of common carotid arteries (CCA) bilaterally. TLR4 signaling pathway could be inhibited by specific anti-TLR4 binding protein to prevent TLR4 from interacting with its receptors. We determined the result of TLR4 antibodies-blocking and mice cerebral ischemia-reperfusion injuries by Western blot, and evaluated neuronal damage in cortex. We also determined the expression of TLR4 mRNA and MyD88 mRNA by in situ hybridization (ISH), the activation of NF-kappaB by EMSA, and the expression of TNF-alpha protein by Western blot. Anti-TLR4 binding TLR4 receptors before reperfusion was effective; There was distinct difference among each group respecting neuronal damage; The expression of TLR4 mRNA and MyD88 mRNA, the activation of NF-kappaB, and the expression of TNF-alpha protein showed clear difference as well. LR4-mediated MyD88-dependent signaling pathway activated by ischemia-reperfusion may be involved in the mechanism of ischemia-reperfusion through upregulation of NF-kappaB and TNF-alpha.
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PMID:TLR4-mediated MyD88-dependent signaling pathway is activated by cerebral ischemia-reperfusion in cortex in mice. 1880 39

Recent studies have shown that Toll-like receptors (TLRs) are involved in cerebral ischemia/reperfusion (I/R) injury. This study was to investigate the role of TLR2 and TLR4 in acute focal cerebral I/R injury. Cerebral infarct size, neurological function and mortality were evaluated. NFsmall ka, CyrillicB binding activity, phosphorylation of Ismall ka, CyrillicBalpha, Akt and ERK1/2 were examined in ischemic cerebral tissue by EMSA and Western blots. Compared to wild type (WT) mice, in TLR4 knockout (TLR4KO) mice, brain infarct size was decreased (2.6+/-1.18% vs 11.6+/-1.97% of whole cerebral volume, p<0.05) and neurological function was maintained (7.3+/-0.79 vs 4.7+/-0.68, p<0.05). However, compared to TLR4KO mice, TLR2 knockout (TLR2KO) mice showed higher mortality (38.2% vs 13.0%, p<0.05), decreased neurological function (2.9+/-0.53 vs 7.3+/-0.79, p<0.05) and increased brain infarct size (19.1+/-1.33% vs 2.6+/-1.18%, p<0.05). NFsmall ka, CyrillicB activation and Ismall ka, CyrillicBalpha phosphorylation were attenuated in TLR4KO mice (1.09+/-0.02 and 1.2+/-0.04) compared to TLR2KO mice (1.31+/-0.02 and 2.2+/-0.32) after cerebral ischemia. Compared to TLR4KO mice, in TLR2KO mice, the phosphorylation of Akt (0.2+/-0.03 vs 0.9+/-0.16, p<0.05) and ERK1/2 (0.8+/-0.06 vs 1.3+/-0.17) evoked by cerebral I/R was attenuated. The present study demonstrates that TLR2 and TLR4 play differential roles in acute cerebral I/R injury. Specifically, TLR4 contributes to cerebral I/R injury, while TLR2 appears to be neuroprotective by enhancing the activation of protective signaling in response to cerebral I/R.
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PMID:Differential roles of TLR2 and TLR4 in acute focal cerebral ischemia/reperfusion injury in mice. 1940 Nov 58

High-mobility group box-1 (HMGB1) was originally identified as a ubiquitously expressed, abundant, nonhistone DNA-binding protein. It has well-established functions in the maintenance of nuclear homeostasis. The HMGB1 can either be passively released into the extracellular milieu in response to necrotic signals or actively secreted in response to inflammatory signals. Extracellular HMGB1 interacts with receptors, including those for advanced glycation endproducts (RAGEs) as well as Toll-like receptor 2 (TLR2) and TLR4. The HMGB1 functions in a synergistic manner with other proinflammatory mediators and acts as a potent proinflammatory cytokine-like factor that contributes to the pathogenesis of diverse inflammatory and infectious disorders. Numerous reports point to HMGB1 as a novel player in the ischemic brain. This review provides an appraisal of the emerging roles of HMGB1 in cerebral ischemia injury, highlighting the relevance of HMGB1-blocking agents as potent therapeutic tools for neuroprotection.
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PMID:High-mobility group protein box-1 and its relevance to cerebral ischemia. 1979 2

The Toll-like receptor 4 (TLR4)-mediated myeloid differentiation factor 88 (MyD88)-dependent signaling pathway plays an essential role in inflammation resulting from invading microbes. However, whether the signaling pathway is activated in the inflammatory reaction of cerebral ischemia-reperfusion and its mechanism is still unclear. In this experiment mice were randomly divided into sham group, ischemia/reperfusion group and TLR4-blocked group with different time points of reperfusion at 12, 24, 48 and 72 h . Mice cerebral ischemia was induced by occlusion of common carotid arteries (CCA) bilaterally. TLR4 signaling pathway was inhibited using specific anti-TLR4 binding protein to prevent TLR4 from interacting with its receptors. We determined the result of TLR4 antibodies-blocking and mice cerebral ischemia-reperfusion injuries by Western blot, and evaluated neuronal damage in the hippocampus. We also determined expression of TLR4 mRNA and MyD88 mRNA by in situ hybridization (ISH), activation of nuclear factor (NF)-kappaB by electrophoretic mobility-shift analysis (EMSA), and expression of interrleukin (IL)-1beta protein by Western blot. The results demonstrated that TLR4-mediated MyD88-dependent signaling pathway activated by ischemia-reperfusion may be involved in the mechanism of ischemia-reperfusion through upregulation of NF-kappaB, IL-1beta.
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PMID:Toll-like receptor 4-mediated myeloid differentiation factor 88-dependent signaling pathway is activated by cerebral ischemia-reperfusion in hippocampal CA1 region in mice. 1980 25

Several reports have recently demonstrated a detrimental role of Toll-like receptors (TLR) in cerebral ischemia, while there is little information about the endogenous ligands which activate TLR-signaling. The myeloid related proteins-8 and-14 (Mrp8/S100A8; Mrp14/S100A9) have recently been characterized as endogenous TLR4-agonists, and thus may mediate TLR-activation in cerebral ischemia. Interestingly, not only TLR-mRNAs, but also Mrp8 and Mrp14 mRNA were found to be induced in mouse brain between 3 and 48 h after transient 1 h focal cerebral ischemia/reperfusion. Mrp-protein was expressed in the ischemic hemisphere, and co-labeled with CD11b-positive cells. To test the hypothesis that Mrp-signaling contributes to the postischemic brain damage, we subjected Mrp14-deficient mice, which also lack Mrp8 protein expression, to focal cerebral ischemia. Mrp14-deficient mice had significantly smaller lesion volumes when compared to wild-type littermates (130+/-16 mm(3) vs. 105+/-28 mm(3)) at 2 days after transient focal cerebral ischemia (1 h), less brain swelling, and a reduced macrophage/microglia cell count in the ischemic hemisphere. We conclude that upregulation and signaling of Mrp-8 and-14 contribute to neuroinflammation and the progression of ischemic damage.
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PMID:Mrp-8 and -14 mediate CNS injury in focal cerebral ischemia. 1983 55


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