scholarly journals Interleukin-1 Mediates Induction of Tolerance to Global Ischemia in Gerbil Hippocampal CA1 Neurons

1996 ◽  
Vol 16 (6) ◽  
pp. 1137-1142 ◽  
Author(s):  
Toshiho Ohtsuki ◽  
Christi A. Ruetzler ◽  
Kaoru Tasaki ◽  
John M. Hallenbeck
Keyword(s):  
Intracellular Signaling ◽  
Hippocampal Neurons ◽  
Interleukin 1 ◽  
Tolerance Induction ◽  
Global Ischemia ◽  
Mongolian Gerbils ◽  
Dependent Manner ◽  
Group I ◽  
Induction Of Tolerance

A series of experiments was performed to determine the role of interleukin (IL)-1 in the induction of tolerance to global ischemia in Mongolian gerbils. In Group I, a 2-min “preconditioning” ischemia protected CA1 hippocampal neurons in gerbils subjected to 3.5 min ischemia 3 days later. CA1 neuronal density was: sham, 171 ± 3/mm; 3.5 min ischemia, 30 ± 30/mm; 2 and 3.5 min ischemia 162 ± 6/mm. Experiments in Group II addressed the role of IL-1 in the induction of tolerance by sublethal ischemia. Arterial IL-1α and IL-Iβ became elevated between 1 and 3 days after a 2-min ischemic exposure. IL-1α was: sham, 6.4 ± 0.6 ng/ml; and 2-day, 10.2 ± 1.2 ng/ml. IL-1β was: sham, 6.4 ± 0.5 ng/ml; and 2-day, 17.3 ± 2 ng/ml. Recombinant human IL-1 receptor antagonist (IL-1ra) i.p. blocked ischemic tolerance induction by 2-min preconditioning ischemia: 2-min ischemia + vehicle, 162 ± 6/mm; and 2-min ischemia + IL-1ra, 67 ± 17/mm. Experiments in Group III assessed the capacity of IL-1 to induce tolerance to brain ischemia. IL-1α i.p. (0, 10, 20 μg/kg) for 3 days prior to 3.5-min forebrain ischemia provided significant CA1 neuroprotection in a dose-dependent manner: 2 ± 2, 68 ± 83, and 129 ± 42/mm, respectively. IL-1β (15 μg/kg) in combination with either IL-1ra (100 mg/kg) or IL-1ra vehicle i.p. on the same schedule demonstrated a significant CA1 neuroprotection that could be nullified by IL-1ra: IL-1β + IL-1ra vehicle, 153 ± 16/mm; and IL-1β + IL-1ra, 67 ± 36/mm. Recognition that tolerance arises from stimulation of a known receptor (IL-1RI) permits molecular analysis of the intracellular signaling that is critical for production of that state.

scholarly journals Key Role of Cytochrome C for Apoptosis Detection Using Raman Microimaging in an Animal Model of Brain Ischemia with Insulin Treatment

2019 ◽  
Vol 73 (10) ◽  
pp. 1208-1217 ◽  
Author(s):  
Vanessa Russo ◽  
Patrizio Candeloro ◽  
Natalia Malara ◽  
Gerardo Perozziello ◽  
Michelangelo Iannone ◽  
...  
Keyword(s):  
Cytochrome C ◽  
Brain Ischemia ◽  
Hippocampal Neurons ◽  
Apoptotic Cell ◽  
Resonant Scattering ◽  
Global Ischemia ◽  
Alternative Mechanism ◽  
Mongolian Gerbils ◽  
Incident Wavelength

Brain ischemia represents a leading cause of death and disability in industrialized countries. To date, therapeutic intervention is largely unsatisfactory and novel strategies are required for getting better protection of neurons injured by cerebral blood flow restriction. Recent evidence suggests that brain insulin leads to protection of neuronal population undergoing apoptotic cell death via modulation of oxidative stress and mitochondrial cytochrome c (CytC), an effect to be better clarified. In this work, we investigate on the effect of insulin given intracerebroventricular (ICV) before inducing a transient global ischemia by bilateral occlusion of the common carotid arteries (BCCO) in Mongolian gerbils (MG). The transient (3 min) global ischemia in MG is observed to produce neurodegenerative effect mainly into CA3 hippocampal region, 72 h after cerebral blood restriction. Intracerebroventricular microinfusion of insulin significantly prevents the apoptosis of CA3 hippocampal neurons. Histological observation, after hematoxylin and eosin staining, puts in evidence the neuroprotective role of insulin, but Raman microimaging provides a clearer insight in the CytC mechanism underlying the apoptotic process. Above all, CytC has been revealed to be an outstanding, innate Raman marker for monitoring the cells status, thanks to its resonant scattering at 530 nm of incident wavelength and to its crucial role in the early stages of cells apoptosis. These data support the hypothesis of an insulin-dependent neuroprotection and antiapoptotic mechanism occurring in the brain of MG undergoing transient brain ischemia. The observed effects occurred without any peripheral change on serum glucose levels, suggesting an alternative mechanism of insulin-induced neuroprotection.

scholarly journals Metformin Alleviated Aβ-Induced Apoptosis via the Suppression of JNK MAPK Signaling Pathway in Cultured Hippocampal Neurons

2016 ◽  
Vol 2016 ◽  
pp. 1-8 ◽  
Author(s):  
Bin Chen ◽  
Ying Teng ◽  
Xingguang Zhang ◽  
Xiaofeng Lv ◽  
Yanling Yin
Keyword(s):  
P38 Mapk ◽  
Hippocampal Neurons ◽  
Mapk Signaling ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Ldh Assay ◽  
Underlying Mechanisms ◽  
Induced Apoptosis ◽  
Positive Effect

Both diabetes and hyperinsulinemia are confirmed risk factors for Alzheimer’s disease. Some researchers proposed that antidiabetic drugs may be used as disease-modifying therapies, such as metformin and thiazolidinediones, although more evidence was poorly supported. The aim of the current study is to investigate the role of metformin in Aβ-induced cytotoxicity and explore the underlying mechanisms. First, the experimental results show that metformin salvaged the neurons exposed to Aβin a concentration-dependent manner with MTT and LDH assay. Further, the phosphorylation levels of JNK, ERK1/2, and p38 MAPK were measured with western blot analysis. It was investigated that Aβincreased phospho-JNK significantly but had no effect on phospho-p38 MAPK and phospho-ERK1/2. Metformin decreased hyperphosphorylated JNK induced by Aβ; however, the protection of metformin against Aβwas blocked when anisomycin, the activator of JNK, was added to the medium, indicating that metformin performed its protection against Aβin a JNK-dependent way. In addition, it was observed that metformin protected the neurons via the suppression of apoptosis. Taken together, our findings demonstrate that metformin may have a positive effect on Aβ-induced cytotoxicity, which provides a preclinical strategy against AD for elders with diabetes.

scholarly journals TheGαoActivator Mastoparan-7 Promotes Dendritic Spine Formation in Hippocampal Neurons

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Valerie T. Ramírez ◽  
Eva Ramos-Fernández ◽  
Nibaldo C. Inestrosa
Keyword(s):  
Protein Kinase ◽  
Dendritic Spine ◽  
Hippocampal Neurons ◽  
Biological Effects ◽  
Critical Role ◽  
Head Width ◽  
Dependent Manner ◽  
Spine Density ◽  
Dendritic Spine Density

Mastoparan-7 (Mas-7), an analogue of the peptide mastoparan, which is derived from wasp venom, is a direct activator ofPertussis toxin-(PTX-) sensitive G proteins. Mas-7 produces several biological effects in different cell types; however, little is known about how Mas-7 influences mature hippocampal neurons. We examined the specific role of Mas-7 in the development of dendritic spines, the sites of excitatory synaptic contact that are crucial for synaptic plasticity. We report here that exposure of hippocampal neurons to a low dose of Mas-7 increases dendritic spine density and spine head width in a time-dependent manner. Additionally, Mas-7 enhances postsynaptic density protein-95 (PSD-95) clustering in neurites and activatesGαosignaling, increasing the intracellular Ca2+concentration. To define the role of signaling intermediates, we measured the levels of phosphorylated protein kinase C (PKC), c-Jun N-terminal kinase (JNK), and calcium-calmodulin dependent protein kinase IIα(CaMKIIα) after Mas-7 treatment and determined that CaMKII activation is necessary for the Mas-7-dependent increase in dendritic spine density. Our results demonstrate a critical role forGαosubunit signaling in the regulation of synapse formation.

Intracellular Responses of Glial Cells To Monomeric Tau Protein Are Closely Mediated By Heparan Sulfate Proteoglycans (HSPGs)

2021 ◽  
Author(s):  
Liqing Song ◽  
Daniel E. Oseid ◽  
Evan A. Wells ◽  
Troy Coaston ◽  
Anne S Robinson
Keyword(s):  
Gene Expression ◽  
Heparan Sulfate ◽  
Glial Cells ◽  
Neurofibrillary Tangles ◽  
Tau Protein ◽  
Intracellular Signaling ◽  
Heparan Sulfate Proteoglycans ◽  
C6 Glioma Cells ◽  
Dependent Manner

Abstract The conversion of soluble tau protein to insoluble, hyperphosphorylated neurofibrillary tangles is a major hallmark leading to neuronal death observed in neurodegenerative tauopathies. Recent work suggests that extracellular, soluble tau binds to negatively charged heparan sulfate proteoglycans (HSPGs) available on the cell surface. In addition, LRP1 has recently been recognized as a major tau receptor, mediating tau uptake and spread. We hypothesized based on this data that monomeric tau would be endocytosed in both an HSPG- and LRP-dependent manner, activating intracellular signaling pathways that would regulate cellular phenotypes. Using live-cell confocal microscopy and flow cytometry, we show that soluble 0N4R monomers were rapidly endocytosed by SH-SY5Y and C6 glioma cells, via actin-dependent macropinocytosis. We also demonstrated the crucial role of HSPGs and LRP1 in cellular endocytosis of monomeric tau by observing reduced tau uptake in C6 glial cells with genetic knockouts of xylosyltransferase-1 – a key enzyme in HSPG synthesis – and LRP1. An ERK1/2 inhibition experiment showed that inhibiting the MEK-ERK1/2 signaling pathway attenuated IL-6 and IL-1β gene expression but not TNF-α . An LRP1 knockdown experiment led to an attenuated propensity for tau uptake and further elevated IL-6 gene expression. Collectively, our data suggest that tau has multiple extracellular binding partners that mediate its internalization through distinct mechanisms. Additionally, this study demonstrates the important role of both HSPG and LRP1 in regulating cellular immune responses to tau protein monomer, which provides a novel target for alleviating the neuroinflammatory environment before the formation of neurofibrillary tangles.

scholarly journals Downregulated KLF2 in PV and ET May Induce Prothrombotic Gene Expression

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 13-14
Author(s):  
Jihyun Song ◽  
Jahnavi Gollamudi ◽  
Soo Jin Kim ◽  
Radhika Gangaraju ◽  
Tsewang Tashi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tissue Factor ◽  
Research Funding ◽  
Interleukin 1 ◽  
Negative Regulator ◽  
Mrna Levels ◽  
Dependent Manner ◽  
Inherited Disorders ◽  
History Of

Polycythemia vera (PV) and essential thrombocythemia (ET) patients have a higher risk of arterial and venous thrombosis than healthy individuals; thromboses are their principal cause of morbidity and mortality. We reported increased transcription of prothrombotic and inflammatory genes in granulocytes and platelets of PV and ET. There were differences in the expression of prothrombotic genes between platelets and granulocytes, suggesting that these cells have cell-specific contributions to thrombosis in PV and ET. Some of these prothrombotic genes are regulated by hypoxia inducible factors (HIFs) (PMID: 32203583). However, the molecular mechanism of thrombosis in PV and ET remains unknown. KLF2 (Kruppel like factor 2) is a transcription factor regulating primitive erythropoiesis and inflammation. Knockdown of KLF2 in cultured endothelial cells increases prothrombotic gene expression and reduces blood clotting time and flow rates (PMID: 15718498). Targeted deletion of KLF2 in neutrophils increases thrombosis by inducing the expression and activity of tissue factor (Blood, 2018, 132:75). To study the role of KLF2 in PV and ET thrombosis, we measured KLF2 mRNA in granulocytes from 53 PV and ET patients (25 with a history of thrombosis) and in platelets from 40 patients (21 with a history of thrombosis). We also measured KLF2 mRNA in granulocytes from 38 controls and platelets from 18 controls. Althrough the role of KLF2 in thrombosis has been studied in neutrophils, we also tested KLF2 mRNA in platelets since we previously observed a different pattern of expression of prothrombotic genes between granulocytes and platelets in PV and ET. We found lower KLF2 mRNA in both granulocytes and platelets of PV and ET patients compared to the controls (Fig. 1A and B). Compared to patients without thrombosis, those with thrombosis had lower KLF2 mRNA in platelets but not granulocytes. KLF2 mRNA in these cells correlated inversely with JAK2V617F allele burden in granulocytes (Fig. 1C and D). We then measured mRNA of prothrombotic genes: F3 (tissue factor), SELP (P-selectin), IRAK1 (interleukin 1 receptor associated kinase 1), IL1RAP (interleukin 1 receptor accessory protein), VEGFA (vascular endothelial growth factor-A), THSB1 (thrombospondin 1), SERPINE1 (encoding plasminogen activator inhibitor 1 [PAI-1]). The mRNA levels of these prothrombotic genes correlated inversely with KLF2 mRNA in platelets while SELP and THSB1 transcripts correlated inversely with KLF2 mRNA in granulocytes. KLF2 and HIFs are reported to interact (PMID: 19491109, PMID: 21565532). In order to elucidate the regulatory machanism of KLF2 in thrombosis, we measured KLF2 mRNA in patients with two inherited disorders of hypoxia sensing characterized by thrombosis: 1) Chuvash erythrocytosis (CE) due to homozygous mutation of VHLR200W (13 patients) and 2) erythrocytosis due to gain-of-function mutation of HIF-2a (two patients with HIF2AM535V and two patients HIF2AE548K). KLF2 mRNA levels did not differ in granulocytes and platelets between these patients and controls. However, two CE patients and two patients with HIF2AM535V with a history of thrombosis had lower KLF2 mRNA levels compared to patients without thrombosis (ASH this meeting, 2020 Song J). In conclusion, we report here that KLF2 transcripts are down regulated in both granulocytes and platelets from PV and ET patients and they correlate inversely with the transcripts of prothrombotic genes and JAK2V617F allelic burden, suggesting that KLF2 might be a negative regulator of thrombotic gene expression in PV and ET. Here we did not detect any changes of KLF2 transcripts in congential disorders with elevated HIFs. However, two CE patients and 2 patients with HIF2AM535V with thrombosis had less KLF2 expression compared to those without thrombosis. These results suggest that, by inference from findings in congenital disorders with elevated HIFs, KLF2 in PV and ET granulocytes and platelets may be regulated in a HIF-independent manner but that thrombosis may be regulated in a HIF-dependent manner. Thus, KLF2 may be a novel therapeutic target to prevent thrombosis in PV and ET, but confirmation by further studies is needed. The upstream regulation of KLF2 in PV and ET granulocytes and platelets needs to be elucidated. *PT &JTP contributed equally Disclosures Gangaraju: Sanofi Genzyme, Consultant for Cold Agglutinin Disease: Consultancy. Gordeuk:CSL Behring: Consultancy, Research Funding; Global Blood Therapeutics: Consultancy, Research Funding; Imara: Research Funding; Ironwood: Research Funding; Novartis: Consultancy.

scholarly journals Optogenetic control of excitatory post-synaptic differentiation through neuroligin-1 tyrosine phosphorylation

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
Mathieu Letellier ◽  
Matthieu Lagardère ◽  
Béatrice Tessier ◽  
Harald Janovjak ◽  
Olivier Thoumine
Keyword(s):  
Tyrosine Phosphorylation ◽  
Intracellular Signaling ◽  
Hippocampal Neurons ◽  
Tyrosine Kinase Receptor ◽  
Dependent Manner ◽  
Spine Density ◽  
Light Stimulation ◽  
Knock Out ◽  
Synaptic Differentiation ◽  
The Impact

Neuroligins (Nlgns) are adhesion proteins mediating trans-synaptic contacts in neurons. However, conflicting results around their role in synaptic differentiation arise from the various techniques used to manipulate Nlgn expression level. Orthogonally to these approaches, we triggered here the phosphorylation of endogenous Nlgn1 in CA1 mouse hippocampal neurons using a photoactivatable tyrosine kinase receptor (optoFGFR1). Light stimulation for 24 hr selectively increased dendritic spine density and AMPA-receptor-mediated EPSCs in wild-type neurons, but not in Nlgn1 knock-out neurons or when endogenous Nlgn1 was replaced by a non-phosphorylatable mutant (Y782F). Moreover, light stimulation of optoFGFR1 partially occluded LTP in a Nlgn1-dependent manner. Combined with computer simulations, our data support a model by which Nlgn1 tyrosine phosphorylation promotes the assembly of an excitatory post-synaptic scaffold that captures surface AMPA receptors. This optogenetic strategy highlights the impact of Nlgn1 intracellular signaling in synaptic differentiation and potentiation, while enabling an acute control of these mechanisms.

Role of metabotropic glutamate receptors in vasopressin and oxytocin release

2001 ◽  
Vol 281 (2) ◽  
pp. R452-R458 ◽  
Author(s):  
Delmore J. Morsette ◽  
Hanna Sidorowicz ◽  
Celia D. Sladek
Keyword(s):  
Metabotropic Glutamate Receptors ◽  
Metabotropic Glutamate Receptor ◽  
Dependent Manner ◽  
Hormone Release ◽  
Concentration Dependent Manner ◽  
Group Iii ◽  
Metabotropic Glutamate ◽  
Group I ◽  
Oxytocin Release

The effect of metabotropic glutamate receptor (mGluR) activation on vasopressin (VP) and oxytocin (OT) release was evaluated using explants of the hypothalamoneurohypophysial system. (+/−)-1-Aminocyclopentane- trans-1,3-dicarboxylic acid (t-ACPD), an agonist at groups I and II mGluRs, increased VP and OT release in a concentration-dependent manner. A role for group I mGluRs in VP and OT release was demonstrated by the ability of a group I-specific mGluR antagonist, 1-aminoindan-1,5-idicarboxylic acid (AIDA), to block the effect of t-ACPD and the ability of a group I-specific agonist, ( R, S)-3,5-dihydroxyphenylglycine, to significantly increase both VP ( P = 0.0029) and OT ( P = 0.0032) release. However, AIDA did not alter VP or OT release induced by a ramp increase in osmolality of the perifusion medium. The role of group III mGluRs was examined using L(+)-2-amino-4-phosphonobutyric acid (L-AP4), an agonist of these receptors. L-AP4 did not change basal release of VP or OT and did not prevent osmotically stimulated hormone release. Thus mGluR activation stimulates VP and OT release, but it is not required for osmotic stimulation of hormone release.

The role of cytokines in the lipopolysaccharide-induced sick euthyroid syndrome in mice

1995 ◽  
Vol 146 (3) ◽  
pp. 475-483 ◽  
Author(s):  
A Boelen ◽  
M C Platvoet-ter Schiphorst ◽  
O Bakker ◽  
W M Wiersinga
Keyword(s):  
Single Dose ◽  
Synergistic Effects ◽  
Interleukin 1 ◽  
Lethal Dose ◽  
Acute Administration ◽  
Dependent Manner ◽  
Dose Dependent ◽  
Serum Tsh ◽  
Sick Euthyroid

Abstract To evaluate the role of cytokines in the sick euthyroid syndrome, we tried to establish an animal model of non-thyroidal illness in mice by the administration of a sub-lethal dose of bacterial endotoxin (lipopolysaccharide; LPS) which induces a variety of cytokines, including tumour necrosis factor (TNFα), interleukin-1 (IL-1α), interleukin-6 (IL-6) and interferon-γ (IFNγ). When compared with pair-fed controls, a single dose of LPS resulted in (a) systemic illness, (b) induction of TNFα and IL-6 and (c) a decrease of liver 5′-deiodinase mRNA from 4 h onwards followed by a decrease of serum tri-iodothyronine (T3) and thyroxine (T4) at 8 h and of serum free T3 (fT3) and free T4 (fT4) at 24 h; serum TSH remained unchanged. We then studied whether a single dose or a combination of IL-1α, TNFα, IL-6 or IFNγ could induce the sick euthyroid syndrome in mice, again using pair-fed controls. None of the cytokines except IL-1α caused systemic illness, and IL-1α was the only cytokine that decreased liver 5′-deiodinase mRNA transiently. IL-1α, TNFα or IL-6 did not decrease serum T3, T4 and TSH, but administration of IFNγ decreased serum T4, T3 and fT3 in a dose-dependent manner without changes in serum TSH. Administration of all four cytokines together had no synergistic effects; observed changes were of a smaller magnitude than after LPS. The following conclusions were reached. (1) Administration of LPS in mice is a suitable experimental model for the acute induction of the sick euthyroid syndrome. (2) Acute administration of IL-1α, TNFα or IL-6 in mice does not induce changes in thyroid hormones but IFNγ results in a dose-dependent decrease of serum T4, T3 and fT3 and IL-1α decreases liver 5′-deiodinase mRNA transiently. (3) Combined administration of IL-1α, TNFα, IL-6 and IFNγ had no synergistic effects; observed changes were of a smaller magnitude than after LPS. (4) The LPS-induced sick euthyroid syndrome is currently best explained by a direct thyroidal inhibition due to IFNγ and an extrathyroidal inhibition of liver 5′-deiodinase due to IL-1α, but other still unidentified factors seem to be involved as well. Journal of Endocrinology (1995) 146, 475–483

scholarly journals Activity-regulated synaptic targeting of lncRNA ADEPTR mediates structural plasticity by localizing Sptn1 and AnkB in dendrites

2021 ◽  
Vol 7 (16) ◽  
pp. eabf0605
Author(s):  
Eddie Grinman ◽  
Yoshihisa Nakahata ◽  
Yosef Avchalumov ◽  
Isabel Espadas ◽  
Supriya Swarnkar ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Noncoding Rna ◽  
Molecular Motor ◽  
Structural Plasticity ◽  
Dependent Manner ◽  
Protein Coding ◽  
Synaptic Targeting ◽  
Conserved Sequence ◽  
Activity Dependent

Activity-dependent structural plasticity at the synapse requires specific changes in the neuronal transcriptome. While much is known about the role of coding elements in this process, the role of the long noncoding transcriptome remains elusive. Here, we report the discovery of an intronic long noncoding RNA (lncRNA)—termed ADEPTR—that is up-regulated and synaptically transported in a cAMP/PKA-dependent manner in hippocampal neurons, independently of its protein-coding host gene. Loss of ADEPTR function suppresses activity-dependent changes in synaptic transmission and structural plasticity of dendritic spines. Mechanistically, dendritic localization of ADEPTR is mediated by molecular motor protein Kif2A. ADEPTR physically binds to actin-scaffolding regulators ankyrin (AnkB) and spectrin (Sptn1) via a conserved sequence and is required for their dendritic localization. Together, this study demonstrates how activity-dependent synaptic targeting of an lncRNA mediates structural plasticity at the synapse.

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