scholarly journals Phenylethanoid Glycosides From Callicarpa kwangtungensis Chun Attenuate TNF-α-Induced Cell Damage by Inhibiting NF-κB Pathway and Enhancing Nrf2 Pathway in A549 Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Jing-Na Zheng ◽  
Jian-Yi Zhuo ◽  
Juan Nie ◽  
Yan-Lu Liu ◽  
Bao-Yi Chen ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Cell Model ◽  
A549 Cells ◽  
Caspase 8 ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Caspase 9 ◽  
Phenylethanoid Glycosides ◽  
Tnf Α ◽  
Anti Inflammatory

Background: Acute lung injury (ALI) is a complicated and severe lung disease, which is often characterized by acute inflammation. Poliumoside (POL), acteoside (ACT) and forsythiaside B (FTB) are phenylethanoid glycosides (PGs) with strong antioxidant, anti-inflammatory, and anti-apoptotic properties, which are extracted from Callicarpa kwangtungensis Chun (CK). The aim of this study was to investigate the protective effects of POL, ACT, and FTB against TNF-α-induced damage using an ALI cell model and explore their potential mechanisms.Methods and Results: MTT method was used to measure cell viability. Flow cytometry was used for detecting the apoptosis rate. Reactive oxygen species (ROS) activity was determined using fluorescence microscope. The expression of mRNA in apoptosis-related genes (Caspase 3, Caspase 8, and Caspase 9) were tested by qPCR. The effects of POL, ACT, FTB on the activities of nuclear factor erythroid-2 related factor 2 (Nrf2), nuclear factor kappa-B (NF-κB) and the expression of their downstream genes were assessed by western blotting and RT-PCR in A549 cells. In the current study, POL, ACT, and FTB dose-dependently attenuated TNF-α-induced IL-1β, IL-6 and IL-8 production, cell apoptosis, the expression of apoptosis-related genes (Caspase 3, Caspase 8, and Caspase 9) and ROS activity. POL, ACT, and FTB not only increased in the mRNA levels of antioxidative enzymes NADPH quinone oxidoreductase (NQO1), glutamate cysteine ligase catalytic subunit (GCLC), heme oxygenase (HO-1), but also decreased the mRNA levels of IL-1β, IL-6 and IL-8. Furthermore, they upregulated the expression of Keap1 and enhanced the activation of Nrf2, while decreased the expression of phosphor-IκBα (p-IκBα) and nuclear p65. In addition, no significant changes were observed in anti-inflammatory and antioxidant effects of POL, ACT, FTB following Nrf2 and NF-κB p65 knockdown.Conclusion: Our study revealed that POL, ACT, and FTB alleviated oxidative damage and lung inflammation of TNF-α-induced ALI cell model through regulating the Nrf2 and NF-κB pathways.

scholarly journals Benfotiamine Ameliorates High Carbohydrate Diet-Induced Hepatic Oxidative Stress, Inflammation and Apoptosis in Megalobrama Amblycephala

2020 ◽  
Author(s):  
Chao Xu ◽  
Wen-Bin Liu ◽  
Hua-Juan Shi ◽  
Xiang-Fei Li
Keyword(s):  
Oxidative Stress ◽  
Caspase 3 ◽  
Megalobrama Amblycephala ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Caspase 9 ◽  
Carbohydrate Diet ◽  
High Carbohydrate ◽  
Tnf Α ◽  
Antioxidant Enzymes Activities

Abstract Background: The impairment of immunity induced by high-carbohydrate diet is closely associated with the development of glucose metabolic disorders. In the study of diabetes, benfotiamine can prevent β-cell dysfunction by inhibiting inflammation, thereby improving insulin resistance. However, information regarding the effects of this substance on aquatic animals is extremely scarce.Methods: A 12-week nutritional research was conducted to evaluate the influences of benfotiamine on the growth performance, oxidative stress, inflammation and apoptosis in Megalobrama amblycephala (45.25 ± 0.34 g) fed high-carbohydrate (HC) diets. Six experimental diets were formulated, containing a control diet (30% carbohydrate, C), a HC diet (43% carbohydrate), and the HC diet supplemented with four graded benfotiamine levels (0.7125 (HCB1), 1.425 (HCB2), 2.85 (HCB3), and 5.7 (HCB4) mg/kg).Results: HC diet intake remarkably decreased daily growth coefficient (DGC), growth rate per metabolic body weight (GRMBW), feed intake (FI), liver antioxidant enzymes activities, sirtuin-1 (SIRT1) protein expression as well as liver mRNA levels of SIRT1, nuclear factor erythroid 2-related factor 2 (Nrf2), catalase (CAT), manganese superoxide dismutase (Mn-SOD), interleukin10 (IL10) than those of the control group, but the opposite was true for plasma activities of alanine transaminase (AST) and aspartate aminotransferase (ALT), and contents of interleukin 1β (IL1β) and interleukin 6 (IL6), liver contents of malondialdehyde (MDA), and mRNA levels of kelch-like ECH associating protein 1 (Keap1), nuclear factor kappa B (NF-κB), tumour necrosis factor α (TNF α), IL1β, IL6, Bax, Caspase 3, Caspase 9 and P53. As with benfotiamine supplementation, HCB2 diet remarkably increased DGC, GRMBW, liver antioxidant enzymes activities, SIRT1 protein expression as well as liver mRNA levels of SIRT1, Nrf2, CAT, Mn-SOD, IL10 and Bcl2, while the opposite was true for plasma activities of AST and ALT, and contents of IL1β and IL6, liver MDA contents as well as mRNA levels of Keap1, NF-κB, TNF α, IL1β, IL6, Bax, Caspase 3, Caspase 9 and P53.Conclusion: Benfotiamine at 1.425 mg/kg can improve the growth performance and alleviate the oxidative stress, inflammation and apoptosis of M. amblycephala fed HC diets through the activation of the SIRT1 pathway.

scholarly journals Biological Evaluation of Alkyl Triphenylphosphonium Ostruthin Derivatives as Potential Anti-Inflammatory Agents Targeting the Nuclear Factor κB Signaling Pathway in Human Lung Adenocarcinoma A549 Cells

BioChem ◽  
2021 ◽  
Vol 1 (2) ◽  
pp. 107-121
Author(s):  
Nghia Trong Vo ◽  
Eiichi Kusagawa ◽  
Kaori Nakano ◽  
Chihiro Moriwaki ◽  
Yasunobu Miyake ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Signaling Pathway ◽  
Human Lung ◽  
A549 Cells ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Human Lung Adenocarcinoma ◽  
Tnf Α ◽  
Anti Inflammatory ◽  
Lung Adenocarcinoma A549

Ostruthin (6-geranyl-7-hydroxycoumarin) is one of the constituents isolated from Paramignya trimera and has been classified as a simple coumarin. We recently reported the synthesis of alkyl triphenylphosphonium (TPP) derivatives from ostruthin and evaluated their anticancer activities. In the present study, we demonstrated that alkyl TPP ostruthin derivatives inhibited the up-regulation of cell-surface intercellular adhesion molecule-1 (ICAM-1) in human lung adenocarcinoma A549 cells stimulated with tumor necrosis factor-α (TNF-α) without affecting cell viability, while ostruthin itself exerted cytotoxicity against A549 cells. The heptyl TPP ostruthin derivative (termed OS8) attenuated the up-regulation of ICAM-1 mRNA expression at concentrations higher than 40 µM in TNF-α-stimulated A549 cells. OS8 inhibited TNF-α-induced nuclear factor κB (NF-κB)-responsive luciferase reporter activity at concentrations higher than 40 µM, but did not affect the translocation of the NF-κB subunit RelA in response to the TNF-α stimulation at concentrations up to 100 µM. A chromatin immunoprecipitation assay showed that OS8 at 100 µM prevented the binding of RelA to the ICAM-1 promoter. We also showed that OS8 at 100 µM inhibited the TNF-α-induced phosphorylation of RelA at Ser 536. Moreover, the TNF-α-induced phosphorylation of an inhibitor of NF-κB α and extracellular signal-regulated kinase was reduced by OS8. These results indicate that OS8 has potential as an anti-inflammatory agent that targets the NF-κB signaling pathway.

Oxymatrine inhibits lipopolysaccharide-induced inflammation by down-regulating Toll-like receptor 4/nuclear factor-kappa B in macrophages

2015 ◽  
Vol 93 (4) ◽  
pp. 253-260 ◽  
Author(s):  
Yu Zhang ◽  
Ruhong Yan ◽  
Yae Hu
Keyword(s):  
Nitric Oxide ◽  
Interleukin 1 ◽  
Chinese Herb ◽  
Mrna Levels ◽  
Nuclear Factor ◽  
Toll Like Receptor ◽  
Toll Like Receptor 4 ◽  
Necrosis Factor Alpha ◽  
Tnf Α ◽  
Anti Inflammatory

Oxymatrine (OMT) is the quinolizidine alkaloid extracted from the Chinese herb Sophora flavescens Ait. that has many pharmacological effects and is used for the treatment of some inflammatory diseases. In this study, RAW264.7 cells and THP-1 differentiated macrophages were pretreated with various concentrations of OMT at 2 h prior to treatment with lipopolysaccharide (LPS) (1.0 μg/mL) for different durations. We detected the anti-inflammatory effect of OMT in LPS-stimulated macrophages and investigated the molecular mechanism. We showed that OMT pretreatment significantly inhibited the LPS-induced secretion of nitric oxide (NO), interleukin-1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) in supernatant, attenuated the mRNA levels of inducible nitric oxide synthase (iNOS), IL-1β, TNF-α, and Toll-like receptor 4 (TLR4), increased TLR4 and phosphorylation of inhibitor of kappa B-alpha (p-IBα) in cytosol, and decreased the nuclear level of nuclear factor-κB (NF-κB) p65 in macrophages. In conclusion, OMT exerts anti-inflammatory properties in LPS-stimulated macrophages by down-regulating the TLR4/NF-κB pathway.

The extrinsic caspase pathway modulates endotoxin-induced diaphragm contractile dysfunction

2007 ◽  
Vol 102 (4) ◽  
pp. 1649-1657 ◽  
Author(s):  
Gerald S. Supinski ◽  
Xinying Ji ◽  
Wenyi Wang ◽  
Leigh A. Callahan
Keyword(s):  
Caspase 3 ◽  
Death Receptor ◽  
Interferon Γ ◽  
Caspase 8 ◽  
Contractile Dysfunction ◽  
Tnf Receptor ◽  
Caspase Activation ◽  
Caspase 9 ◽  
Diaphragm Dysfunction ◽  
Tnf Α

The mechanisms by which infections induce diaphragm dysfunction remain poorly understood. The purpose of this study was to determine which caspase pathways (i.e., the extrinsic, death receptor-linked caspase-8 pathway, and/or the intrinsic, mitochondrial-related caspase-9 pathway) are responsible for endotoxin-induced diaphragm contractile dysfunction. We determined 1) whether endotoxin administration (12 mg/kg IP) to mice induces caspase-8 or -9 activation in the diaphragm; 2) whether administration of a caspase-8 inhibitor ( N-acetyl-Ile-Glu-Thr-Asp-CHO, 3 mg/kg iv) or a caspase-9 inhibitor ( N-acetyl-Leu-Glu-His-Asp-CHO, 3 mg/kg iv) blocks endotoxin-induced diaphragmatic weakness and caspase-3 activation; 3) whether TNF receptor 1-deficient mice have reduced caspase activation and diaphragm dysfunction following endotoxin; and 4) whether cytokines (TNF-α or cytomix, a mixture of TNF-α, interleukin-1β, interferon-γ, and endotoxin) evoke caspase activation in C2C12 myotubes. Endotoxin markedly reduced diaphragm force generation ( P < 0.001) and induced increases in caspase-3 and caspase-8 activity ( P < 0.03), but failed to increase caspase-9. Inhibitors of caspase-8, but not of caspase-9, prevented endotoxin-induced reductions in diaphragm force and caspase-3 activation ( P < 0.01). Mice deficient in TNF receptor 1 also had reduced caspase-8 activation ( P < 0.001) and less contractile dysfunction ( P < 0.01) after endotoxin. Furthermore, incubation of C2C12 cells with either TNF-α or cytomix elicited significant caspase-8 activation. The caspase-8 pathway is strongly activated in the diaphragm following endotoxin and is responsible for caspase-3 activation and diaphragm weakness.

scholarly journals Nuclear Factor κB Protects against Host Cell Apoptosis during Rickettsia rickettsii Infection by Inhibiting Activation of Apical and Effector Caspases and Maintaining Mitochondrial Integrity

2003 ◽  
Vol 71 (7) ◽  
pp. 4127-4136 ◽  
Author(s):  
Suresh G. Joshi ◽  
Charles W. Francis ◽  
David J. Silverman ◽  
Sanjeev K. Sahni
Keyword(s):  
Host Cell ◽  
Cell Apoptosis ◽  
Caspase 3 ◽  
Nuclear Factor Κb ◽  
Caspase 8 ◽  
Nuclear Factor ◽  
Caspase 9 ◽  
Rickettsia Rickettsii ◽  
Mitochondrial Integrity ◽  
Host Cell Apoptosis

ABSTRACT Apoptotic host cell death is a critical determinant in the progression of microbial infections and outcome of resultant diseases. The potentially fatal human infection caused by Rickettsia rickettsii, the etiologic agent of Rocky Mountain spotted fever, involves the vascular endothelium of various organ systems of the host. Earlier studies have shown that survival of endothelial cells (EC) during this infection depends on their ability to activate the transcription factor nuclear factor κB (NF-κB). Here, we investigated the involvement of caspase cascades and associated signaling pathways in regulation of host cell apoptosis by NF-κB. Infection of cultured human EC with R. rickettsii with simultaneous inhibition of NF-κB induced the activation of apical caspases 8 and 9 and also the executioner enzyme, caspase 3, whereas infection alone had no significant effect. Inhibition of either caspase-8 or caspase-9 with specific cell-permeating peptide inhibitors caused a significant decline in the extent of apoptosis, confirming their importance. The peak caspase-3 activity occurred at 12 h postinfection and led to cleavage of poly(ADP-ribose) polymerase, followed by DNA fragmentation and apoptosis. However, the activities of caspases 6 and 7, other important downstream executioners, remained unchanged. Caspase-9 activation was mediated through the mitochondrial pathway of apoptosis, as evidenced by loss of transmembrane potential and cytoplasmic release of cytochrome c. These findings suggest that activation of NF-κB is required for maintenance of mitochondrial integrity of host cells and protection against infection-induced apoptotic death by preventing activation of caspase-9- and caspase-8-mediated pathways. Targeted inhibition of NF-κB may therefore be exploited to enhance the clearance of infections with R. rickettsii and other intracellular pathogens with similar survival strategies.

Biologic sequelae of nuclear factor–κB blockade in multiple myeloma: therapeutic applications

Blood ◽  
2002 ◽  
Vol 99 (11) ◽  
pp. 4079-4086 ◽  
Author(s):  
Nicholas Mitsiades ◽  
Constantine S. Mitsiades ◽  
Vassiliki Poulaki ◽  
Dharminder Chauhan ◽  
Paul G. Richardson ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Nuclear Translocation ◽  
Nuclear Factor Κb ◽  
Inhibitor Of Apoptosis ◽  
Caspase 8 ◽  
Nuclear Factor ◽  
Inhibitor Of Apoptosis Protein ◽  
Tnf Α ◽  
Apoptosis Protein ◽  
Induced Apoptosis

The transcription factor nuclear factor–κB (NF-κB) confers significant survival potential in a variety of tumors. Several established or novel anti–multiple myeloma (anti-MM) agents, such as dexamethasone, thalidomide, and proteasome inhibitors (PS-341), inhibit NF-κB activity as part of their diverse actions. However, studies to date have not delineated the effects of specific inhibition of NF-κB activity in MM. We therefore investigated the effect of SN50, a cell-permeable specific inhibitor of NF-κB nuclear translocation and activity, on MM cells. SN50 induced apoptosis in MM cell lines and patient cells; down-regulated expression of Bcl-2, A1, X-chromosome–linked inhibitor-of-apoptosis protein (XIAP), cellular inhibitor-of-apoptosis protein 1 (cIAP-1), cIAP-2, and survivin; up-regulated Bax; increased mitochondrial cytochromec release into the cytoplasm; and activated caspase-9 and caspase-3, but not caspase-8. We have previously demonstrated that tumor necrosis factor–α (TNF-α) is present locally in the bone marrow microenvironment and induces NF-κB–dependent up-regulation of adhesion molecules on both MM cells and bone marrow stromal cells, with resultant increased adhesion. In this study, TNF-α alone induced NF-κB nuclear translocation, cIAP-1 and cIAP-2 up-regulation, and MM cell proliferation; in contrast, SN50 pretreatment sensitized MM cells to TNF-α–induced apoptosis and cleavage of caspase-8 and caspase-3, similar to our previous finding of SN50-induced sensitization to apoptosis induced by the TNF-α family member TNF-related apoptosis-inducing ligand (TRAIL)/Apo2L. Moreover, SN50 inhibited TNF-α–induced expression of another NF-κB target gene, intercellular adhesion molecule–1. Although the p38 inhibitor PD169316 did not directly kill MM cells, it potentiated the apoptotic effect of SN50, suggesting an interaction between the p38 and NF-κB pathways. Our results therefore demonstrate that NF-κB activity in MM cells promotes tumor-cell survival and protects against apoptotic stimuli. These studies provide the framework for targeting NF-κB activity in novel biologically based therapies for MM.

scholarly journals Investigation of Neuroprotective Potential of Anti-Diabetic Agents in Ischemic Brain Proteomics Through In-Silico Molecular Simulation Studies

2021 ◽  
Vol 12 (4) ◽  
pp. 5347-5362
Keyword(s):  
Molecular Docking ◽  
Molecular Simulation ◽  
In Silico ◽  
Caspase 3 ◽  
Caspase 8 ◽  
Caspase 9 ◽  
Discovery Studio ◽  
Tnf Α ◽  
Screening And Identification ◽  
Neuroprotective Actions

Defective neurotransmission, impaired synaptic plasticity, and progressive neurodegeneration triggered by diabetes and stroke. The computational designing of a therapeutic agent, molecular dynamic (MD) simulation, and molecular docking are essential, along with streamlined and inexpensive techniques which enable the potential therapeutic targets for the novel drug discovery process in specific pathology. Molecular docking software such as AutoDock tool v1.5.6, PyRx v8.0, Discovery Studio Visualizer v19.1.0.18287, and PyMOL v2.3.1 has been used for virtual screening and identification of structural based molecular interactions. The 3D co-crystal structures of receptor/target therapeutic proteins (BCl-2, Caspase-3, Caspase-8, Caspase-9, IL6, MAPKERK, PI3K, TGF- β, TNF- α, and ZO-1) with attached ligand were gained from the RCSB-PDB website in PDB format. The obtained structures comprise a ligand and a water molecule, which must be removed before docking from the receptor using Discovery Studio Visualizer and finally transformed into macromolecules by AutoDock Vina of PyRx. The active residues were recognized through previously published literature. In-Silico molecular simulation study of anti-diabetic agents with stroke and neurodegeneration-associated proteins gave a strong hypothesis to the neuroprotective actions of the anti-diabetic drugs. Moreover, higher binding energy with all biomarker proteins directs us of exerting strong therapeutic action of the selected class of anti-diabetic agents, i.e., voglibose, saxagliptin, repaglinide, and Dapagliflozin with BCl-2, Caspase-3, Caspase-8, Caspase-9, IL6, MAPK/ERK, PI3K, TGF- β, TNF- α and ZO-1. The current study elucidates the strong anti-stroke potential of selected anti-diabetic agents and can claim a strong candidature as anti-stroke therapeutics in specific hyperglycemic conditions.

Cadmium inhibits both intrinsic and extrinsic apoptotic pathways in renal mesangial cells

2006 ◽  
Vol 290 (5) ◽  
pp. F1074-F1082 ◽  
Author(s):  
C. Geeth Gunawardana ◽  
Raul E. Martinez ◽  
Weiqun Xiao ◽  
Douglas M. Templeton
Keyword(s):  
Caspase 3 ◽  
Mesangial Cell ◽  
Mesangial Cells ◽  
Experimental Models ◽  
Caspase 8 ◽  
Caspase 9 ◽  
Nuclear Condensation ◽  
Tnf Α ◽  
Convergence Point ◽  
Apoptotic Pathways

Cadmium is a potent nephrotoxin that has been shown to induce apoptosis in some cells but also to prevent it under certain circumstances. In several clinical situations and experimental models of injury to the renal glomerulus, pathological proliferation of mesangial cells is followed by resolution involving mesangial cell apoptosis. We investigated the effects of Cd2+ on rat mesangial cells induced to undergo apoptosis through either the extrinsic receptor-mediated pathway or the intrinsic mitochondrial-dependent pathway. Camptothecin initiated the intrinsic pathway with activation of caspase-9 and caspase-dependent cleavage of procaspase-3. Tumor necrosis factor-α (TNF-α) initiated caspase-8 activity and cleavage of pro-caspase-3 at the convergence point of the two pathways. However, pro-caspase-8 levels were low, and caspase-9 was also activated in response to TNF-α, characteristic of what have been termed type II cells. With both TNF-α and camptothecin, concurrent exposure to 10 μM CdCl2 suppressed DNA laddering, nuclear condensation, and pro-caspase-3 cleavage. It also decreased activity of both caspase-8 and caspase-9, prevented caspase-8-dependent cleavage of the proapoptotic factor Bid, and suppressed release of cytochrome c from mitochondria. At this 10-μM concentration, Cd2+ was unique among a number of metal ions in preventing DNA fragmentation. We conclude that Cd2+ is anti-apoptotic in rat mesangial cells, acting by a mechanism that may involve general caspase inhibition. This may have consequences for the resolution of nephritis in situations of mesangial cell hyperproliferation.

scholarly journals Study of RNA Interference Targeting NET-1 Combination with Sorafenib for Hepatocellular Carcinoma TherapyIn VitroandIn Vivo

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Song He ◽  
Ying-ze Wei ◽  
Gui-lan Wang ◽  
Yu-yin Xu ◽  
Jia-ming Zhou ◽  
...  
Keyword(s):  
Rna Interference ◽  
Caspase 3 ◽  
Migration And Invasion ◽  
Caspase 8 ◽  
Ras Signaling ◽  
Mrna Levels ◽  
Caspase 9 ◽  
Tumor Tissues

The aim of this study is to explore the inhibitory effects of RNA interference (RNAi) targeting NET-1 or combined with sorafenib on HCCin vitroandin vivoand the possible underlying mechanisms. The expressions of NET-1 mRNA and protein were detected by RT-QPCR and western blot. The ability of proliferation was determined by CCK-8 assay. Apoptosis was examined by flow cytometry (FCM). Abilities of migration and invasion were measured by scratch-wound assay and transwell assay. MHCC97H cells with stable transfection of NET-1shRNA were injected subcutaneously to prepare nude mice model of HCC and Caspase-3, Caspase-8, and Caspase-9 mRNAs of tumor tissues in different groups were examined. NET-1 mRNA and protein were reduced sharply in MHCC97H cells transfected with NET-1shRNA. The abilities of proliferation and migration were inhibited and apoptosis was promoted in either NET-1shRNA or sorafenib as compared with untreated cellsin vitroandin vivo(P<0.05). The mRNA levels of caspase-3, caspase-8, and caspase-9 of tumor tissues were reduced in different treatment groups compared with untreated group, particularly in combination group. (P<0.05). The combination NET-1shRNA with sorafenib dramatically enhanced the effects of sorafenib antitumor ,which may involve in blocking ras signaling pathway and stimulating apoptotic pathways simultaneously.

Amiloride Alleviates Neurological Deficits Following Transient Global Ischemia and Engagement of Central IL-6 and TNF-α Signal

2019 ◽  
Vol 19 (8) ◽  
pp. 597-604
Author(s):  
Li Pang ◽  
Shouqin Ji ◽  
Jihong Xing
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Caspase 3 ◽  
Global Ischemia ◽  
Neurological Deficits ◽  
Global Cerebral Ischemia ◽  
Caspase 9 ◽  
Tnf Α ◽  
The Central Nervous System ◽  
Transient Global Ischemia

Background: Central pro-inflammatory cytokine (PIC) signal is involved in neurological deficits after transient global ischemia induced by cardiac arrest (CA). The present study was to examine if blocking acid sensing ion channels (ASICs) using amiloride in the Central Nervous System can alleviate neurological deficits after the induction of CA and further examine the participation of PIC signal in the hippocampus for the effects of amiloride. Methods: CA was induced by asphyxia and then cardiopulmonary resuscitation was performed in rats. Western blot analysis and ELISA were used to determine the protein expression of ASIC subunit ASIC1 in the hippocampus, and the levels of PICs. As noted, it is unlikely that this procedure is clinically used although amiloride and other pharmacological agents were given into the brain in this study. Results: CA increased ASIC1 in the hippocampus of rats in comparison with control animals. This was associated with the increase in IL-1β, IL-6 and TNF-α together with Caspase-3 and Caspase-9. The administration of amiloride into the lateral ventricle attenuated the upregulation of Caspase-3/Caspase-9 and this further alleviated neurological severity score and brain edema. Inhibition of central IL-6 and TNF-α also decreased ASIC1 in the hippocampus of CA rats. Conclusion: Transient global ischemia induced by CA amplifies ASIC1a in the hippocampus likely via PIC signal. Amiloride administered into the Central Nervous System plays a neuroprotective role in the process of global ischemia. Thus, targeting ASICs (i.e., ASIC1a) is suggested for the treatment and improvement of CA-evoked global cerebral ischemia.

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