Activation of TLR4-Mediated NFB Signaling in Hemorrhagic Brain in Rats

Wang, Teng; Wang, Li‐Shu; Xue, Weishuang; Chen, Guan

doi:10.1155/2009/473276

Cited by 79 publications

(59 citation statements)

References 21 publications

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“…The rat ICH model was established as described by Teng et al 13 Briefly, animals were anesthetized with an intraperitoneal injection of chloral hydrate (100 mg/kg body weight) and placed on a stereotaxic apparatus. A hole was drilled in the skull, and a needle was inserted into the left basal ganglia under stereotactic guidance (coordinates: 0.2-mm anterior, 5.5-mm ventral, and 3.5-mm lateral to the midline), and 100 μL of autologous arterial blood was infused slowly (5 μL/ min) with a microinfusion pump.…”

Section: Rat Ich Modelmentioning

confidence: 99%

Receptor for Advanced Glycation End-Product Antagonist Reduces Blood–Brain Barrier Damage After Intracerebral Hemorrhage

Yang

Wang

Zhang³

et al. 2015

Stroke

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Background and Purpose-To determine whether the receptor for advanced glycation end-products (RAGE) plays a role in early brain injury from intracerebral hemorrhage (ICH), RAGE expression and activation after injury were examined in a rat model of ICH with or without administration of a RAGE-specific antagonist (FPS-ZM1). Methods-Autologous arterial blood was injected into the basal ganglia of rats to induce ICH. The motor function of the rats was examined, and water content was detected after euthanization. Blood-brain barrier permeability was determined by Evans blue staining and colloidal gold nanoparticle tracers. Nerve fiber injury in white matter was determined by diffusion tensor imaging analysis, and the expression of target genes was analyzed by Western blotting and quantitative reverse transcription polymerase chain reaction. FPS-ZM1 was administered by intraperitoneal injection. Results-Expression of RAGE and its ligand high-mobility group protein B1 were increased at 12 hours after ICH, along with blood-brain barrier permeability and perihematomal nerve fiber injury. RAGE and nuclear factor-κB p65 upregulation were also observed when FeCl 2 was infused into the basal ganglia at 24 hours. FPS-ZM1 administration resulted in significant improvements of blood-brain barrier damage, brain edema, motor dysfunction, and nerve fiber injury, and the expression of RAGE, nuclear factor-κB p65, proinflammatory mediators interleukin 1β, interleukin-6, interleukin-8R, cyclooxygenase-2, inducible nitric oxide synthase, and matrix metallopeptidase-9 was attenuated. Moreover, decreases in claudin-5 and occludin expression were partially recovered. FPS-ZM1 also reversed FeCl 2 -induced RAGE and nuclear factor-κB p65 upregulation. Conclusions-RAGE signaling is involved in blood-brain barrier and white matter fiber damage after ICH, the initiation of which is associated with iron. RAGE antagonists represent a novel therapeutic intervention to prevent early brain injury after ICH. .).The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl

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Section: Rat Ich Modelmentioning

confidence: 99%

Receptor for Advanced Glycation End-Product Antagonist Reduces Blood–Brain Barrier Damage After Intracerebral Hemorrhage

Yang

Wang

Zhang³

et al. 2015

Stroke

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“…15,16 In addition, the TLR4/NF-κB signaling pathway is reported to play a crucial role in ICH-induced neurological deficits. 17,18 We previously…”

mentioning

confidence: 99%

Toll-Like Receptor 4 Antagonist Attenuates Intracerebral Hemorrhage–Induced Brain Injury

Wang

Huang

et al. 2013

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139

110

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Background and Purpose-Accumulating evidence indicates that inflammatory responses cause secondary injury after intracerebral hemorrhage (ICH). We recently demonstrated the involvement of toll-like receptor 4 (TLR4) signaling in these processes. The purpose of the current study was to investigate the protective effect and mechanism of TAK-242 (Ethyl (6R)-6-[N-(2-chloro-4-fluorophenyl) sulfamoyl] cyclohex-1-ene-1 -carboxylate, Takeda), a TLR4 antagonist, in an ICH mouse model. Methods-TAK-242 was intraperitoneally injected 6 hours after ICH once daily for 5 successive days. We assessed neurological deficit scores; changes in brain water content; and levels of inflammatory factors, DNA damage, and neuronal degeneration in perihematomal region 1, 3, and 5 days after ICH. Peripheral inflammatory cell infiltration was determined using flow cytometry; and the expression of TLR4 downstream signaling molecules was assessed by Western blot. Results-TAK-242 significantly reduced brain water content, neurological deficit scores, and levels of inflammatory factors.The levels of DNA damage and neuronal degeneration were also significantly decreased, as was peripheral inflammatory cell infiltration. The expression of TLR4 downstream signaling molecules, including myeloid differentiation primary response gene 88, toll/IR-1(TIR)-domain-containing adaptor protein inducing interferon-beta IκBα, nuclear factorκBp65, and phosphorylated nuclear factor-κBp65, was significantly downregulated. Conclusions-The

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“…A growing body of experimental and clinical evidence shows that inflammation drives restenosis 1,2) . Toll-like receptor 4 (TLR4)-mediated nuclear factor kappa B (NF B) signaling plays a crucial role in the induction of inflammatory responses in the hemorrhagic rat brain 3) . Further, the expression of TLR4 has been found to regulate VSMC proliferation related to restenosis 4) , which can be upregulated by lipopolysaccharides (LPSs) in human aortic smooth muscle cells (HASMCs) in a dose-and time-dependent manner 5) .…”

Section: Drug Administrationmentioning

confidence: 99%

Interleukin-1 Receptor-Associated Kinase 1/4 as a Novel Target for Inhibiting Neointimal Formation After Carotid Balloon Injury

Bai

Zhou

et al. 2015

JAT

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Aim:Interleukin-1 receptor-associated kinase 1 (IRAK1) and IRAK4 play essential roles in the induction of inflammatory gene products. We aimed to investigate the effect of the inhibition of IRAK1 and IRAK4 kinase activities on neointimal formation in rats with carotid artery balloon injuries using the IRAK1/4 inhibitor N-(2-Morpholinylethyl)-2-(3-nitrobenzoylamido)-benzimidazole, a cell-permeable benzimidazole compound. Methods: Wistar rats and vascular smooth muscle cells (VSMCs) isolated from the thoracic aortas were used. Toll-like receptor 4 (TLR4)-mediated nuclear factor kappa B (NF B) signaling pathway was revealed by microarrays analysis. In addition, the differential expression of the TLR4 pathway genes, including TLR4, IRAK1, I B , and interleukin-1 (IL-1 ), was confirmed by quantitative real-time polymerase chain reaction. Immunohistochemical staining, elastic-van Gieson and Masson staining, 5-ethynyl-2´-deoxyuridine staining, enzyme-linked immunosorbent assay, transwell migration assay and western blotting were also contributed for relevant detection. Results:The expression of TLR4 protein gradually increased at days 1, 3, 7, and 21 after balloon injury compared with the uninjured group. The dual inhibition of IRAK1 and IRAK4 attenuated neointimal formation and fibrotic remodeling after injury in vivo and suppressed VSMC proliferation and migration in vitro. The production of mediators such as tumor necrosis factor-and IL-1 in injured arteries were also reduced by the inhibition of IRAK1 and IRAK4. The expression of NF B p65-and F4/80-positive cells in inhibitor rats were fewer than those in control rats at day 7, while IRAK1 expression was markedly higher at day 3 in inhibitor rats. Furthermore, western blotting analysis revealed that the IRAK1/4 inhibitor suppressed the IRAK1 and IRAK4 kinase activities and the activation of the TLR4-mediated NF B pathway in vivo and in vitro. Conclusions: This study suggested that IRAK1/4 could serve as a potential therapeutic target to suppress neointimal formation in carotid arteries after balloon injury through the TLR4/NF B signaling pathway. IntroductionRestenosis is a healing response of the arterial wall to mechanical injury after percutaneous coronary intervention (PCI). Vascular smooth muscle cell (VSMC) proliferation and migration are critical to 1318 tion of IRAK1 and IRAK4 kinase activities would be predicted to leave some degree of host defense intact while still reducing inflammatory responses 18) . A novel cell-permeable benzimidazole compound can act as a potent and selective inhibitor of IRAK1 and IRAK4 and has been tested in plasmacytoid dendritic cells from systemic lupus erythematosus and rheumatoid arthritis patients 19) , human primary small airway epithelial cells in chronic obstructive pulmonary disease 20) , and rat brain hypoxia/ischemiainduced neuronal injury 21) ; however, it has not yet been employed in vascular research. To the best of our knowledge, there are no published studies on the role of IRAK1 and IRAK4 kinase activities in...

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Activation of TLR4-Mediated NFB Signaling in Hemorrhagic Brain in Rats

Cited by 79 publications

References 21 publications

Receptor for Advanced Glycation End-Product Antagonist Reduces Blood–Brain Barrier Damage After Intracerebral Hemorrhage

Receptor for Advanced Glycation End-Product Antagonist Reduces Blood–Brain Barrier Damage After Intracerebral Hemorrhage

Toll-Like Receptor 4 Antagonist Attenuates Intracerebral Hemorrhage–Induced Brain Injury

Interleukin-1 Receptor-Associated Kinase 1/4 as a Novel Target for Inhibiting Neointimal Formation After Carotid Balloon Injury

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