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Yu Y, Chen W, Li B, Li Z, Wang Y, Mao Y, Fan W, Bai Y, Hu H, Zhen Q, Sun L. Cutaneous Calcium/Calmodulin-Dependent Protein Kinase II-γ-Positive Sympathetic Nerves Secreting Norepinephrine Dictate Psoriasis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2306772. [PMID: 38544478 PMCID: PMC11187923 DOI: 10.1002/advs.202306772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 03/06/2024] [Indexed: 06/20/2024]
Abstract
Cutaneous sympathetic nerve is a crucial part of neuropsychiatric factors contributing to skin immune response, but its role in the psoriasis pathogenesis remains unclear. It is found that cutaneous calcium/calmodulin-dependent protein kinase II-γ (CAMK2γ), expressed mainly in sympathetic nerves, is activated by stress and imiquimod in mouse skin. Camk2g-deficient mice exhibits attenuated imiquimod-induced psoriasis-like manifestations and skin inflammation. CaMK2γ regulates dermal γδT-cell interleukin-17 production in imiquimod-treated mice, dependent on norepinephrine production following cutaneous sympathetic nerve activation. Adrenoceptor β1, the primary skin norepinephrine receptor, colocalises with γδT cells. CaMK2γ aggravates psoriasiform inflammation via sympathetic nerve-norepinephrine-γδT cell-adrenoceptor β1-nuclear factor-κB and -p38 axis activation. Application of alcaftadine, a small-molecule CaMK2γ inhibitor, relieves imiquimod-induced psoriasis-like manifestations in mice. This study reveals the mechanisms of sympathetic-nervous-system regulation of γδT-cell interleukin-17 secretion, and provides insight into neuropsychiatric factors dictating psoriasis pathogenesis and new potential targets for clinical psoriasis treatment.
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Affiliation(s)
- Yafen Yu
- Department of Dermatologythe First Affiliated Hospital of Anhui Medical UniversityHefei230032China
- Key Laboratory of DermatologyAnhui Medical UniversityMinistry of EducationHefei230032China
- The Center for Scientific Researchthe First Affiliated Hospital of Anhui Medical UniversityHefei230032China
| | - Weiwei Chen
- Department of Dermatologythe First Affiliated Hospital of Anhui Medical UniversityHefei230032China
- Key Laboratory of DermatologyAnhui Medical UniversityMinistry of EducationHefei230032China
| | - Bao Li
- The Comprehensive LabCollege of BasicAnhui Medical UniversityHefei230032China
| | - Zhuo Li
- Department of Dermatologythe First Affiliated Hospital of Anhui Medical UniversityHefei230032China
- Key Laboratory of DermatologyAnhui Medical UniversityMinistry of EducationHefei230032China
| | - Yirui Wang
- Department of Dermatologythe First Affiliated Hospital of Anhui Medical UniversityHefei230032China
- Key Laboratory of DermatologyAnhui Medical UniversityMinistry of EducationHefei230032China
| | - Yiwen Mao
- Department of Dermatologythe First Affiliated Hospital of Anhui Medical UniversityHefei230032China
- Key Laboratory of DermatologyAnhui Medical UniversityMinistry of EducationHefei230032China
| | - Wencheng Fan
- Department of Dermatologythe First Affiliated Hospital of Anhui Medical UniversityHefei230032China
- Key Laboratory of DermatologyAnhui Medical UniversityMinistry of EducationHefei230032China
| | - Yuanming Bai
- Department of Dermatologythe First Affiliated Hospital of Anhui Medical UniversityHefei230032China
- Key Laboratory of DermatologyAnhui Medical UniversityMinistry of EducationHefei230032China
| | - Hongbo Hu
- Center for Immunology and HematologyState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu610065China
| | - Qi Zhen
- North China University of Science and Technology Affiliated HospitalTangshan063210China
- Health Science CenterNorth China University of Science and TechnologyTangshan063210China
- School of Public HealthNorth China University of Science and TechnologyTangshan063210China
| | - Liangdan Sun
- Department of Dermatologythe First Affiliated Hospital of Anhui Medical UniversityHefei230032China
- North China University of Science and Technology Affiliated HospitalTangshan063210China
- Health Science CenterNorth China University of Science and TechnologyTangshan063210China
- School of Public HealthNorth China University of Science and TechnologyTangshan063210China
- Inflammation and Immune Diseases Laboratory of North China University of Science and TechnologyTangshan063210China
- Key Laboratory of DermatologyAnhui Medical UniversityMinistry of EducationHefei230032China
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Khan D, Bedner P, Müller J, Lülsberg F, Henning L, Prinz M, Steinhäuser C, Muhammad S. TGF-β Activated Kinase 1 (TAK1) Is Activated in Microglia After Experimental Epilepsy and Contributes to Epileptogenesis. Mol Neurobiol 2023; 60:3413-3422. [PMID: 36862288 PMCID: PMC10122619 DOI: 10.1007/s12035-023-03290-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Accepted: 02/19/2023] [Indexed: 03/03/2023]
Abstract
Increasing evidence suggests that inflammation promotes epileptogenesis. TAK1 is a central enzyme in the upstream pathway of NF-κB and is known to play a central role in promoting neuroinflammation in neurodegenerative diseases. Here, we investigated the cellular role of TAK1 in experimental epilepsy. C57Bl6 and transgenic mice with inducible and microglia-specific deletion of Tak1 (Cx3cr1CreER:Tak1fl/fl) were subjected to the unilateral intracortical kainate mouse model of temporal lobe epilepsy (TLE). Immunohistochemical staining was performed to quantify different cell populations. The epileptic activity was monitored by continuous telemetric electroencephalogram (EEG) recordings over a period of 4 weeks. The results show that TAK1 was activated predominantly in microglia at an early stage of kainate-induced epileptogenesis. Tak1 deletion in microglia resulted in reduced hippocampal reactive microgliosis and a significant decrease in chronic epileptic activity. Overall, our data suggest that TAK1-dependent microglial activation contributes to the pathogenesis of chronic epilepsy.
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Affiliation(s)
- Dilaware Khan
- Department of Neurosurgery, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany.,Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Venusberg Campus 1, 53127, Bonn, Germany
| | - Peter Bedner
- Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Venusberg Campus 1, 53127, Bonn, Germany
| | - Julia Müller
- Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Venusberg Campus 1, 53127, Bonn, Germany
| | - Fabienne Lülsberg
- Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Venusberg Campus 1, 53127, Bonn, Germany
| | - Lukas Henning
- Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Venusberg Campus 1, 53127, Bonn, Germany
| | - Marco Prinz
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Center for Basics in NeuroModulation (NeuroModulBasics), Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
| | - Christian Steinhäuser
- Institute of Cellular Neurosciences, Medical Faculty, University of Bonn, Venusberg Campus 1, 53127, Bonn, Germany
| | - Sajjad Muhammad
- Department of Neurosurgery, Medical Faculty and University Hospital Düsseldorf, Heinrich-Heine-University, Düsseldorf, Germany. .,Department of Neurosurgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
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Grahl MVC, Uberti AF, Broll V, Bacaicoa-Caruso P, Meirelles EF, Carlini CR. Proteus mirabilis Urease: Unsuspected Non-Enzymatic Properties Relevant to Pathogenicity. Int J Mol Sci 2021; 22:ijms22137205. [PMID: 34281258 PMCID: PMC8268090 DOI: 10.3390/ijms22137205] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 06/25/2021] [Accepted: 06/29/2021] [Indexed: 12/22/2022] Open
Abstract
Infection by Proteus mirabilis causes urinary stones and catheter incrustation due to ammonia formed by urease (PMU), one of its virulence factors. Non-enzymatic properties, such as pro-inflammatory and neurotoxic activities, were previously reported for distinct ureases, including that of the gastric pathogen Helicobacter pylori. Here, PMU was assayed on isolated cells to evaluate its non-enzymatic properties. Purified PMU (nanomolar range) was tested in human (platelets, HEK293 and SH-SY5Y) cells, and in murine microglia (BV-2). PMU promoted platelet aggregation. It did not affect cellular viability and no ammonia was detected in the cultures’ supernatants. PMU-treated HEK293 cells acquired a pro-inflammatory phenotype, producing reactive oxygen species (ROS) and cytokines IL-1β and TNF-α. SH-SY5Y cells stimulated with PMU showed high levels of intracellular Ca2+ and ROS production, but unlike BV-2 cells, SH-SY5Y did not synthesize TNF-α and IL-1β. Texas Red-labeled PMU was found in the cytoplasm and in the nucleus of all cell types. Bioinformatic analysis revealed two bipartite nuclear localization sequences in PMU. We have shown that PMU, besides urinary stone formation, can potentially contribute in other ways to pathogenesis. Our data suggest that PMU triggers pro-inflammatory effects and may affect cells beyond the renal system, indicating a possible role in extra-urinary diseases.
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Affiliation(s)
- Matheus V. C. Grahl
- Laboratory of Neurotoxins, Brain Institute of Rio Grande do Sul (BRAINS) and Graduate Program in Medicine and Health Sciences, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre CEP 90610-000, RS, Brazil; (M.V.C.G.); (A.F.U.)
| | - Augusto F. Uberti
- Laboratory of Neurotoxins, Brain Institute of Rio Grande do Sul (BRAINS) and Graduate Program in Medicine and Health Sciences, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre CEP 90610-000, RS, Brazil; (M.V.C.G.); (A.F.U.)
| | - Valquiria Broll
- Graduate Program in Cellular and Molecular Biology, Center of Biotechnology, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre CEP 91501-970, RS, Brazil;
| | - Paula Bacaicoa-Caruso
- Laboratory of Neurotoxins, Brain Institute of Rio Grande do Sul (BRAINS) and Graduate Program in Cellular and Molecular Biology, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre CEP 90610-000, RS, Brazil;
| | - Evelin F. Meirelles
- Laboratory of Neurotoxins, Brain Institute of Rio Grande do Sul (BRAINS), Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre CEP 90610-000, RS, Brazil;
| | - Celia R. Carlini
- Laboratory of Neurotoxins, Brain Institute of Rio Grande do Sul (BRAINS) and School of Medicine, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre CEP 90610-000, RS, Brazil
- Correspondence: ; Tel.: +55-51-33205986
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Kaswan NK, Mohd Suhaimi NS, Mohammed Izham NA, Tengku Mohamad TAS, Sulaiman MR, Perimal EK. Cardamonin inhibits nitric oxide production modulated through NMDA receptor in LPS-Induced SH-SY5Y cell in vitro model. LIFE SCIENCES, MEDICINE AND BIOMEDICINE 2020. [DOI: 10.28916/lsmb.4.9.2020.58] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022] Open
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Lipids Nutrients in Parkinson and Alzheimer's Diseases: Cell Death and Cytoprotection. Int J Mol Sci 2020; 21:ijms21072501. [PMID: 32260305 PMCID: PMC7178281 DOI: 10.3390/ijms21072501] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Revised: 03/26/2020] [Accepted: 04/01/2020] [Indexed: 12/11/2022] Open
Abstract
Neurodegenerative diseases, particularly Parkinson’s and Alzheimer’s, have common features: protein accumulation, cell death with mitochondrial involvement and oxidative stress. Patients are treated to cure the symptoms, but the treatments do not target the causes; so, the disease is not stopped. It is interesting to look at the side of nutrition which could help prevent the first signs of the disease or slow its progression in addition to existing therapeutic strategies. Lipids, whether in the form of vegetable or animal oils or in the form of fatty acids, could be incorporated into diets with the aim of preventing neurodegenerative diseases. These different lipids can inhibit the cytotoxicity induced during the pathology, whether at the level of mitochondria, oxidative stress or apoptosis and inflammation. The conclusions of the various studies cited are oriented towards the preventive use of oils or fatty acids. The future of these lipids that can be used in therapy/prevention will undoubtedly involve a better delivery to the body and to the brain by utilizing lipid encapsulation.
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Ignatowski TA, Spengler RN. Targeting tumor necrosis factor in the brain relieves neuropathic pain. World J Anesthesiol 2018; 7:10-19. [DOI: 10.5313/wja.v7.i2.10] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 05/28/2018] [Accepted: 06/02/2018] [Indexed: 02/06/2023] Open
Abstract
Neuropathic pain is a chronic syndrome caused by direct damage to or disease of the somatosensory nervous system. The lack of safe, adequate and sustained pain relief offered by present analgesic treatments is most alarming. While many treatment options are available to manage chronic pain, such as antidepressants, non-steroidal anti-inflammatory agents, opioids, and anticonvulsants, chronic neuropathic pain remains largely unmanaged. Compounding the dilemma of ineffective chronic pain treatments is the need to provide relief from suffering and yet not contribute to the scourge of drug abuse. A recent epidemic of addiction and accidental drug prescription overdoses parallel the increased use of opioid treatment, even though opioids are rarely an effective treatment of relieving chronic pain. To make matters worse, opioids may contribute to exacerbating pain, and side-effects such as cognitive impairment, nausea, constipation, development of tolerance, as well as their potential for addiction and overdose deaths exist. Clearly, there is an urgent need for alternative, non-opiate treatment of chronic pain. Innovative discoveries of pertinent brain mechanisms and functions are key to developing effective, safe treatments. Pioneering work has revealed the essential effects of the pleiotropic mediator tumor necrosis factor (TNF) on brain functioning. These studies establish that TNF inhibits norepinephrine release from hippocampal neurons, and show that excess TNF production within the hippocampus occurs during neuropathic pain, which mobilizes additional mechanisms that further inhibit norepinephrine release. Significantly, it has been verified that elevated levels of TNF in the brain are actually required for neuropathic pain development. Since TNF decreases norepinephrine release in the brain, enhanced TNF levels would prevent engagement of the norepinephrine descending inhibitory neuronal pain pathways. Increased levels of TNF in the brain are therefore critical to the development of neuropathic pain. Therefore, strategies that decrease this enhanced TNF expression in the brain will have superior analgesic efficacy. We propose this novel approach of targeting the pathologically high levels of brain TNF as an effective strategy in the treatment of the devastating syndrome of chronic pain.
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Affiliation(s)
- Tracey A Ignatowski
- Department of Pathology and Anatomical Sciences and Program for Neuroscience, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14203, United States
- NanoAxis, LLC, Clarence, NY 14031, United States
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Chistyakov DV, Azbukina NV, Lopachev AV, Kulichenkova KN, Astakhova AA, Sergeeva MG. Rosiglitazone as a Modulator of TLR4 and TLR3 Signaling Pathways in Rat Primary Neurons and Astrocytes. Int J Mol Sci 2018; 19:E113. [PMID: 29301276 PMCID: PMC5796062 DOI: 10.3390/ijms19010113] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 12/25/2017] [Accepted: 12/27/2017] [Indexed: 01/06/2023] Open
Abstract
An antidiabetic drug of the thiazolidinedione class, rosiglitazone (RG) demonstrates anti-inflammatory properties in various brain pathologies. The mechanism of RG action in brain cells is not fully known. To unravel mechanisms of RG modulation of toll-like receptor (TLR) signaling pathways, we compare primary rat neuron and astrocyte cultures stimulated with the TLR4 agonist lipopolysaccharide (LPS) and the TLR3 agonist poly I:C (PIC). Both TLR agonists induced tumor necrosis factor (TNFα) release in astrocytes, but not in neurons. Neurons and astrocytes released interleukin-10 (IL-10) and prostaglandin E2 (PGE₂) in response to LPS and PIC. RG decreased TLR-stimulated TNFα release in astrocytes as well as potentiated IL-10 and PGE₂ release in both astrocytes and neurons. RG induced phosphorylation of p38 and JNK MAPK (mitogen-activated protein kinase) in neurons. The results reveal new role of RG as a modulator of resolution of neuroinflammation.
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Affiliation(s)
- Dmitry V Chistyakov
- Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119992, Russia.
- Laboratory of electrophysiology, Pirogov Russian National Research Medical University, Moscow 117997, Russia.
| | - Nadezda V Azbukina
- Faculty of Bioengineering and Bioinformatics, Moscow Lomonosov State University, Moscow 119234 Russia.
| | | | | | - Alina A Astakhova
- Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119992, Russia.
| | - Marina G Sergeeva
- Belozersky Institute of Physico-Chemical Biology, Moscow State University, Moscow 119992, Russia.
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Joana PT, Amaia A, Arantza A, Garikoitz B, Eneritz GL, Larraitz G. Central immune alterations in passive strategy following chronic defeat stress. Behav Brain Res 2016; 298:291-300. [DOI: 10.1016/j.bbr.2015.11.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Revised: 11/06/2015] [Accepted: 11/10/2015] [Indexed: 02/03/2023]
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Fasick V, Spengler RN, Samankan S, Nader ND, Ignatowski TA. The hippocampus and TNF: Common links between chronic pain and depression. Neurosci Biobehav Rev 2015; 53:139-59. [PMID: 25857253 DOI: 10.1016/j.neubiorev.2015.03.014] [Citation(s) in RCA: 140] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2014] [Revised: 02/02/2015] [Accepted: 03/28/2015] [Indexed: 02/07/2023]
Abstract
Major depression and chronic pain are significant health problems that seriously impact the quality of life of affected individuals. These diseases that individually are difficult to treat often co-exist, thereby compounding the patient's disability and impairment as well as the challenge of successful treatment. The development of efficacious treatments for these comorbid disorders requires a more comprehensive understanding of their linked associations through common neuromodulators, such as tumor necrosis factor-α (TNFα), and various neurotransmitters, as well as common neuroanatomical pathways and structures, including the hippocampal brain region. This review discusses the interaction between depression and chronic pain, emphasizing the fundamental role of the hippocampus in the development and maintenance of both disorders. The focus of this review addresses the hypothesis that hippocampal expressed TNFα serves as a therapeutic target for management of chronic pain and major depressive disorder (MDD).
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Affiliation(s)
- Victoria Fasick
- Department of Pathology and Anatomical Sciences, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, United States
| | | | - Shabnam Samankan
- Department of Pathology and Anatomical Sciences, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, United States
| | - Nader D Nader
- Department of Pathology and Anatomical Sciences, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, United States; Department of Anesthesiology, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, United States
| | - Tracey A Ignatowski
- Department of Pathology and Anatomical Sciences, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, United States; NanoAxis, LLC, Clarence, NY 14031, United States; Program for Neuroscience, School of Medicine and Biomedical Science, University at Buffalo, The State University of New York, Buffalo, NY 14214, United States.
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10
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Coquenlorge S, Duchalais E, Chevalier J, Cossais F, Rolli-Derkinderen M, Neunlist M. Modulation of lipopolysaccharide-induced neuronal response by activation of the enteric nervous system. J Neuroinflammation 2014; 11:202. [PMID: 25497784 PMCID: PMC4279994 DOI: 10.1186/s12974-014-0202-7] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Accepted: 11/14/2014] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Evidence continues to mount concerning the importance of the enteric nervous system (ENS) in controlling numerous intestinal functions in addition to motility and epithelial functions. Nevertheless, little is known concerning the direct participation of the ENS in the inflammatory response of the gut during infectious or inflammatory insults. In the present study we analyzed the ENS response to bacterial lipopolysaccharide, in particular the production of a major proinflammatory cytokine, tumor necrosis factor-alpha (TNF-α). METHODS TNF-α expression (measured by qPCR, quantitative Polymerase Chain Reaction) and production (measured by ELISA) were measured in human longitudinal muscle-myenteric plexus (LMMP) and rat ENS primary cultures (rENSpc). They were either treated or not treated with lipopolysaccharide (LPS) in the presence or not of electrical field stimulation (EFS). Activation of extracellular signal-regulated kinase (ERK) and 5'-adenosine monophosphate-activated protein kinase (AMPK) pathways was analyzed by immunocytochemistry and Western blot analysis. Their implications were studied using specific inhibitors (U0126, mitogen-activated protein kinase kinase, MEK, inhibitor and C compound, AMPK inhibitor). We also analyzed toll-like receptor 2 (TLR2) expression and interleukin-6 (IL-6) production after LPS treatment simultaneously with EFS or TNF-α-neutralizing antibody. RESULTS Treatment of human LMMP or rENSpc with LPS induced an increase in TNF-α production. Activation of the ENS by EFS significantly inhibited TNF-α production. This regulation occurred at the transcriptional level. Signaling analyses showed that LPS induced activation of ERK but not AMPK, which was constitutively activated in rENSpc neurons. Both U0126 and C compound almost completely prevented LPS-induced TNF-α production. In the presence of LPS, EFS inhibited the ERK and AMPK pathways. In addition, we demonstrated using TNF-α-neutralizing antibody that LPS-induced TNF-α production increased TLR2 expression and reduced IL-6 production. CONCLUSIONS Our results show that LPS induced TNF-α production by enteric neurons through activation of the canonical ERK pathway and also in an AMPK-dependent manner. ENS activation through the inhibition of these pathways decreased TNF-α production, thereby modulating the inflammatory response induced by endotoxin.
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Affiliation(s)
- Sabrina Coquenlorge
- Neuropathies of the enteric nervous system and digestive diseases, INSERM UMR913, School of Medicine, University of Nantes, 1, rue Gaston Veil, Nantes, F-44035, France. .,University of Nantes, 1 quai de Tourville, BP 13522, Nantes, Cedex 1, F-44035, France. .,Institut des Maladies de l'Appareil Digestif, Centre Hospitalier Universitaire, Nantes, Hopital Hôtel-Dieu, 1 place Alexis Ricordeau, Nantes, F-44093, France. .,Centre de Recherche en Nutrition Humaine, Hopital Hôtel-Dieu, 1 place Alexis Ricordeau, Nantes, F-44093, France.
| | - Emilie Duchalais
- Neuropathies of the enteric nervous system and digestive diseases, INSERM UMR913, School of Medicine, University of Nantes, 1, rue Gaston Veil, Nantes, F-44035, France. .,University of Nantes, 1 quai de Tourville, BP 13522, Nantes, Cedex 1, F-44035, France. .,Institut des Maladies de l'Appareil Digestif, Centre Hospitalier Universitaire, Nantes, Hopital Hôtel-Dieu, 1 place Alexis Ricordeau, Nantes, F-44093, France. .,Centre de Recherche en Nutrition Humaine, Hopital Hôtel-Dieu, 1 place Alexis Ricordeau, Nantes, F-44093, France.
| | - Julien Chevalier
- Neuropathies of the enteric nervous system and digestive diseases, INSERM UMR913, School of Medicine, University of Nantes, 1, rue Gaston Veil, Nantes, F-44035, France. .,University of Nantes, 1 quai de Tourville, BP 13522, Nantes, Cedex 1, F-44035, France. .,Institut des Maladies de l'Appareil Digestif, Centre Hospitalier Universitaire, Nantes, Hopital Hôtel-Dieu, 1 place Alexis Ricordeau, Nantes, F-44093, France. .,Centre de Recherche en Nutrition Humaine, Hopital Hôtel-Dieu, 1 place Alexis Ricordeau, Nantes, F-44093, France.
| | - Francois Cossais
- Neuropathies of the enteric nervous system and digestive diseases, INSERM UMR913, School of Medicine, University of Nantes, 1, rue Gaston Veil, Nantes, F-44035, France. .,University of Nantes, 1 quai de Tourville, BP 13522, Nantes, Cedex 1, F-44035, France. .,Institut des Maladies de l'Appareil Digestif, Centre Hospitalier Universitaire, Nantes, Hopital Hôtel-Dieu, 1 place Alexis Ricordeau, Nantes, F-44093, France. .,Centre de Recherche en Nutrition Humaine, Hopital Hôtel-Dieu, 1 place Alexis Ricordeau, Nantes, F-44093, France.
| | - Malvyne Rolli-Derkinderen
- Neuropathies of the enteric nervous system and digestive diseases, INSERM UMR913, School of Medicine, University of Nantes, 1, rue Gaston Veil, Nantes, F-44035, France. .,University of Nantes, 1 quai de Tourville, BP 13522, Nantes, Cedex 1, F-44035, France. .,Institut des Maladies de l'Appareil Digestif, Centre Hospitalier Universitaire, Nantes, Hopital Hôtel-Dieu, 1 place Alexis Ricordeau, Nantes, F-44093, France. .,Centre de Recherche en Nutrition Humaine, Hopital Hôtel-Dieu, 1 place Alexis Ricordeau, Nantes, F-44093, France.
| | - Michel Neunlist
- Neuropathies of the enteric nervous system and digestive diseases, INSERM UMR913, School of Medicine, University of Nantes, 1, rue Gaston Veil, Nantes, F-44035, France. .,University of Nantes, 1 quai de Tourville, BP 13522, Nantes, Cedex 1, F-44035, France. .,Institut des Maladies de l'Appareil Digestif, Centre Hospitalier Universitaire, Nantes, Hopital Hôtel-Dieu, 1 place Alexis Ricordeau, Nantes, F-44093, France. .,Centre de Recherche en Nutrition Humaine, Hopital Hôtel-Dieu, 1 place Alexis Ricordeau, Nantes, F-44093, France.
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Campbell A, Daher N, Solaimani P, Mendoza K, Sioutas C. Human brain derived cells respond in a type-specific manner after exposure to urban particulate matter (PM). Toxicol In Vitro 2014; 28:1290-5. [DOI: 10.1016/j.tiv.2014.06.015] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2014] [Revised: 06/24/2014] [Accepted: 06/26/2014] [Indexed: 01/27/2023]
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Wang L, Sun Y, Yang W, Lindo P, Singh BR. Type A botulinum neurotoxin complex proteins differentially modulate host response of neuronal cells. Toxicon 2014; 82:52-60. [PMID: 24560879 DOI: 10.1016/j.toxicon.2014.02.004] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Revised: 01/24/2014] [Accepted: 02/06/2014] [Indexed: 12/26/2022]
Abstract
Type A Botulinum neurotoxin (BoNT/A), the most potent poison known to mankind, is produced by Clostridium botulinum type A as a complex with neurotoxin-associated proteins (NAPs). Currently BoNT/A in purified and complex forms are both available in therapeutic and cosmetic applications to treat neuromuscular disorders. Whereas Xeomin(®) (incobotulinumtoxin A, Merz Pharmaceuticals, Germany) is free from complexing proteins, Botox(®) (onabotulinumtoxin A, Allergan, USA) contains NAPs, which by themselves have no known role in the intracellular biochemical process involved in the blockade of neurotransmitter release. Since the fate and possible interactions of NAPs with patient tissues after intramuscular injection are not known, it was the aim of this study to evaluate the binding of BoNT/A and/or the respective NAPs to cells derived from neuronal and non-neuronal human tissues, and to further explore neuronal cell responses to different components of BoNT/A. BoNT/A alone, the complete BoNT/A complex, and the NAPs alone, all bind to neuronal SH-SY5Y cells. The BoNT/A complex and NAPs additionally bind to RMS13 skeletal muscle cells, TIB-152 lymphoblasts, Detroit 551 fibroblasts besides the SH-SY5Y cells. However, no binding to these non-neuronal cells was observed with pure BoNT/A. Although BoNT/A, both in its purified and complex forms, bind to SH-SY5Y, the intracellular responses of the SH-SY5Y cells to these BoNT/A components are not clearly understood. Examination of inflammatory cytokine released from SH-SY5Y cells revealed that BoNT/A did not increase the release of inflammatory cytokines, whereas exposure to NAPs significantly increased release of IL-6, and MCP-1, and exposure to BoNT/A complex significantly increased release of IL-6, MCP-1, IL-8, TNF-α, and RANTES vs. control, suggesting that different components of BoNT/A complex induce significantly differential host response in human neuronal cells. Results suggest that host response to different compositions of BoNT/A based therapeutics may play important role in local and systemic symptoms in patients.
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Affiliation(s)
- Lei Wang
- Prime Bio Inc., Dartmouth, MA 02747, USA.
| | - Yi Sun
- Prime Bio Inc., Dartmouth, MA 02747, USA
| | | | - Paul Lindo
- Prime Bio Inc., Dartmouth, MA 02747, USA
| | - Bal Ram Singh
- Prime Bio Inc., Dartmouth, MA 02747, USA; Department of Chemistry and Biochemistry, University of Massachusetts Dartmouth, Dartmouth, MA 02747, USA
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Serpente M, Bonsi R, Scarpini E, Galimberti D. Innate immune system and inflammation in Alzheimer's disease: from pathogenesis to treatment. Neuroimmunomodulation 2014; 21:79-87. [PMID: 24557039 DOI: 10.1159/000356529] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Immune activation and inflammation, likely triggered by amyloid-beta (Aβ) deposition, play a remarkable role in the pathogenesis of Alzheimer's disease (AD), which is the most frequent cause of dementia in the elderly. The principal cellular elements of the brain innate immune system likely to be involved in such processes are microglia. In an attempt to search for new disease-modifying drugs, the immune system has been addressed, with the aim of removing deposition of Aβ or tau by developing vaccines and humanized monoclonal antibodies. The aim of this review is to summarize the current evidence regarding the role played by microglia and inflammatory molecules in the pathogenesis of AD. In addition, we will discuss the main active and passive immunotherapeutic approaches.
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Affiliation(s)
- Maria Serpente
- Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy
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Takei Y, Laskey R. Intracellular and Intercellular Cross Talk Between NGF and TNF. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2011; 691:559-65. [DOI: 10.1007/978-1-4419-6612-4_58] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Girgis EH, Mahoney JP, Khalil RH, Soliman MR. Effect of thalidomide and arsenic trioxide on the release of tumor necrosis factor-α and vascular endothelial growth factor from the KG-1a human acute myelogenous leukemia cell line. Oncol Lett 2010; 1:663-667. [PMID: 22966360 DOI: 10.3892/ol_00000116] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2010] [Accepted: 03/29/2010] [Indexed: 12/24/2022] Open
Abstract
Studies conducted in our lab have indicated that thalidomide cytotoxicity in the KG-1a human acute myelogenous leukemia (AML) cell line was enhanced by combining it with arsenic trioxide. The current investigation was conducted in order to evaluate the effect of thalidomide either alone or in combination with arsenic trioxide on the release of tumor necrosis factor-α (TNF-α) and vascular endothelial growth factor (VEGF) from this cell line in an attempt to clarify its possible cytotoxic mechanism(s). Human AML cell line KG-1a was used in this study. The cells were cultured for 48 h in the presence or absence of thalidomide (5 mg/l), and or arsenic trioxide (4 μM). The levels of TNF-α and VEGF in the supernatant were determined by ELISA. Results obtained indicate that the levels of TNF-α in the supernatant of KG-1a cell cultures incubated with thalidomide, arsenic trioxide, or combination were statistically lower than those observed in the supernatant of control cells (2.89, 5.07, 4.15 and 16.88 pg/ml, respectively). However, the levels of VEGF in the supernatant of thalidomide-treated cells were statistically higher than those in the supernatant of control cells (69.61 vs. 11.48 pg/l). Arsenic trioxide, whether alone or in combination with thalidomide, did not produce any statistically significant difference in the levels of VEGF as compared to the control or thalidomide-treated cell supernatant. These findings indicate that thalidomide and the arsenic trioxide inhibition of TNF-α production by KG-1a cells may play an important role in their cytotoxic effect.
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Affiliation(s)
- Erian H Girgis
- College of Pharmacy, Florida A and M University, Tallahassee, FL 32307
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16
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Tumor necrosis factor-alpha impairs the recovery of synaptic transmission from hypoxia in rat hippocampal slices. J Neuroimmunol 2009; 218:21-7. [PMID: 19942300 DOI: 10.1016/j.jneuroim.2009.11.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2009] [Revised: 10/15/2009] [Accepted: 11/05/2009] [Indexed: 01/20/2023]
Abstract
Cerebral ischaemia is a common occurrence in a range of pathological conditions, including stroke and traumatic brain injury. Two of the components in ischaemia are tissue hypoxia and the release of pro-inflammatory agents such as TNF-alpha. The role of TNF-alpha in an ischaemic/hypoxic episode is still controversial, although deleterious effects of pro-inflammatory cytokines in the area of injury are well documented. One of the prime adaptive mechanisms in response to hypoxia is the cellular activation of adenosine 1 receptors (A1Rs), which inhibits excitatory synaptic transmission. In the present study we have examined the effect of TNF-alpha application on synaptic transmission during hypoxic exposure and re-oxygenation using extracellular recordings in the CA1 region of the rat hippocampal slice. Hypoxia caused a reversible depression of the field EPSP (29.6+/-9.7% of control, n=5), which was adenosine A(1) receptor-dependent (85.7+/-4.3%, in the presence of DPCPX (200 nM), the adenosine A(1) receptor antagonist). DPCPX inhibited the maintenance of long-term potentiation obtained 30 min post hypoxia (143.8+/-8.2% versus 96.4+/-10.6% respectively, 1h post tetanus; n=5; p<0.005). In TNF-alpha (150 pM) treated slices hypoxic depression was similar to controls but a reduction in fEPSP slope was observed during re-oxygenation (66.8+/-1.4%, n=5). This effect was reversed by pre-treatment with SB 203580 (1 microM), a p38 MAP kinase inhibitor (91.8+/-6.9%, n=5). These results demonstrate a novel p38 MAPK dependent role for TNF-alpha in attenuating synaptic transmission after a hypoxic episode.
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Hutchinson MR, Lewis SS, Coats BD, Skyba DA, Crysdale NY, Berkelhammer DL, Brzeski A, Northcutt A, Vietz CM, Judd CM, Maier SF, Watkins LR, Johnson KW. Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast). Brain Behav Immun 2009; 23:240-50. [PMID: 18938237 PMCID: PMC2662518 DOI: 10.1016/j.bbi.2008.09.012] [Citation(s) in RCA: 202] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/16/2008] [Revised: 09/18/2008] [Accepted: 09/28/2008] [Indexed: 12/26/2022] Open
Abstract
Morphine-induced glial proinflammatory responses have been documented to contribute to tolerance to opioid analgesia. Here, we examined whether drugs previously shown to suppress glial proinflammatory responses can alter other clinically relevant opioid effects; namely, withdrawal or acute analgesia. AV411 (ibudilast) and minocycline, drugs with distinct mechanisms of action that result in attenuation of glial proinflammatory responses, each reduced naloxone-precipitated withdrawal. Analysis of brain nuclei associated with opioid withdrawal revealed that morphine altered expression of glial activation markers, cytokines, chemokines, and a neurotrophic factor. AV411 attenuated many of these morphine-induced effects. AV411 also protected against spontaneous withdrawal-induced hyperactivity and weight loss recorded across a 12-day timecourse. Notably, in the spontaneous withdrawal study, AV411 treatment was delayed relative to the start of the morphine regimen so to also test whether AV411 could still be effective in the face of established morphine dependence, which it was. AV411 did not simply attenuate all opioid effects, as co-administering AV411 with morphine or oxycodone caused three-to-five-fold increases in acute analgesic potency, as revealed by leftward shifts in the analgesic dose response curves. Timecourse analyses revealed that plasma morphine levels were not altered by AV411, suggestive that potentiated analgesia was not simply due to prolongation of morphine exposure or increased plasma concentrations. These data support and extend similar potentiation of acute opioid analgesia by minocycline, again providing converging lines of evidence of glial involvement. Hence, suppression of glial proinflammatory responses can significantly reduce opioid withdrawal, while improving analgesia.
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Affiliation(s)
- Mark R. Hutchinson
- Department of Psychology and the Center for Neuroscience, University of Colorado at Boulder, Boulder, CO, USA,Discipline of Pharmacology, School of Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia
| | - Susannah S. Lewis
- Department of Psychology and the Center for Neuroscience, University of Colorado at Boulder, Boulder, CO, USA
| | - Benjamen D. Coats
- Department of Psychology and the Center for Neuroscience, University of Colorado at Boulder, Boulder, CO, USA
| | - David A. Skyba
- Department of Basic Sciences, College of Osteopathic Medicine, Touro University Nevada, Henderson, NV, USA
| | - Nicole Y. Crysdale
- Department of Psychology and the Center for Neuroscience, University of Colorado at Boulder, Boulder, CO, USA
| | - Debra L. Berkelhammer
- Department of Psychology and the Center for Neuroscience, University of Colorado at Boulder, Boulder, CO, USA
| | - Anita Brzeski
- Department of Psychology and the Center for Neuroscience, University of Colorado at Boulder, Boulder, CO, USA
| | - Alexis Northcutt
- Department of Psychology and the Center for Neuroscience, University of Colorado at Boulder, Boulder, CO, USA
| | | | - Charles M. Judd
- Department of Psychology and the Center for Neuroscience, University of Colorado at Boulder, Boulder, CO, USA
| | - Steven F. Maier
- Department of Psychology and the Center for Neuroscience, University of Colorado at Boulder, Boulder, CO, USA
| | - Linda R. Watkins
- Department of Psychology and the Center for Neuroscience, University of Colorado at Boulder, Boulder, CO, USA,Corresponding author: Linda R. Watkins, Department of Psychology, Campus Box 345, University of Colorado at Boulder, Boulder, Colorado, USA 80309-0345, , Fax: 303 492 2967, Ph: 303 492-7034
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Takei Y, Laskey R. Interpreting crosstalk between TNF-alpha and NGF: potential implications for disease. Trends Mol Med 2008; 14:381-8. [PMID: 18693138 DOI: 10.1016/j.molmed.2008.07.002] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2008] [Revised: 07/04/2008] [Accepted: 07/04/2008] [Indexed: 12/19/2022]
Abstract
Tumour necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine, whereas nerve growth factor (NGF) is a neurotrophin that can promote neural cell survival, differentiation and maturation. However, recent papers indicate that TNF-alpha has a pivotal role in fate decisions of neural cells in normal noninflammatory conditions, whereas NGF contributes to maintenance of inflammation. Although these observations suggest a close relationship between NGF and TNF-alpha signalling, crosstalk between these factors is not fully understood. In this Opinion article, we review recent reports regarding possible crosstalk between NGF and TNF-alpha and we propose a positive-feedback loop of their expression. We discuss the possible mechanisms by which disturbance of the crosstalk could contribute to diseases such as cancer and Alzheimer's disease.
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Affiliation(s)
- Yoshinori Takei
- Medical Research Council (MRC) Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road Cambridge CB2 0XZ, UK.
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19
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Henkel AW, Sperling W, Rotter A, Reulbach U, Reichardt C, Bönsch D, Maler JM, Kornhuber J, Wiltfang J. Antidepressant drugs modulate growth factors in cultured cells. BMC Pharmacol 2008; 8:6. [PMID: 18318898 PMCID: PMC2275236 DOI: 10.1186/1471-2210-8-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2007] [Accepted: 03/04/2008] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Different classes of antidepressant drugs are used as a treatment for depression by activating the catecholinergic system. In addition, depression has been associated with decrease of growth factors, which causes insufficient axonal sprouting and reduced neuronal damage repair. In this study, antidepressant treatments are analyzed in a cell culture system, to study the modulation of growth factors. RESULTS We quantified the transcription of several growth factors in three cell lines after application of antidepressant drugs by real time polymerase chain reaction. Antidepressant drugs counteracted against phorbolester-induced deregulation of growth factors in PMA-differentiated neuronal SY5Y cells. We also found indications in a pilot experiment that magnetic stimulation could possibly modify BDNF in the cell culture system. CONCLUSION The antidepressant effects antidepressant drugs might be explained by selective modulation of growth factors, which subsequently affects neuronal plasticity.
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Affiliation(s)
- Andreas W Henkel
- Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany
| | - Wolfgang Sperling
- Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany
| | - Andrea Rotter
- Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany
| | - Udo Reulbach
- Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany
| | - Cornelia Reichardt
- Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany
| | - Dominikus Bönsch
- Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany
| | - Juan M Maler
- Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany
| | - Johannes Kornhuber
- Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany
| | - Jens Wiltfang
- Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany
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Neuroinflammation and disruption in working memory in aged mice after acute stimulation of the peripheral innate immune system. Brain Behav Immun 2008; 22:301-11. [PMID: 17951027 PMCID: PMC2374919 DOI: 10.1016/j.bbi.2007.08.014] [Citation(s) in RCA: 320] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2007] [Revised: 07/24/2007] [Accepted: 08/27/2007] [Indexed: 11/23/2022] Open
Abstract
Acute cognitive disorders are common in elderly patients with peripheral infections but it is not clear why. Here, we injected old and young mice with Escherichia coli lipopolysaccharide (LPS) to mimic an acute peripheral infection and separated the hippocampal neuronal cell layers from the surrounding hippocampal tissue by laser capture microdissection and measured mRNA for several inflammatory cytokines (IL-1 beta, IL-6, and TNFalpha) that are known to disrupt cognition. The results showed that old mice had an increased inflammatory response in the hippocampus after LPS compared to younger cohorts. Immunohistochemistry further showed more microglial cells in the hippocampus of old mice compared to young adults, and that more IL-1 beta-positive cells were present in the dentate gyrus and in the CA1, CA2, and CA3 regions of LPS-treated old mice compared to young adults. In a test of cognition that required animals to effectively integrate new information with a preexisting schema to complete a spatial task, we found that hippocampal processing is more easily disrupted in old animals than in younger ones when the peripheral innate immune system is stimulated. Collectively, the results suggest that aging can facilitate neurobehavioral complications associated with peripheral infections probably by allowing the over expression of inflammatory cytokines in brain areas that mediate cognitive processing.
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Abstract
Cytokine activation or dysregulation is implied in a variety of painful disease states. Numerous experimental studies provide evidence that proinflammatory cytokines induce or facilitate neuropathic pain. Cytokine levels are rapidly and markedly upregulated in the peripheral nerves, dorsal root ganglia, spinal cord and in particular regions of the brain, after peripheral nerve injuries. Direct receptor-mediated actions on afferent nerve fibers as well as cytokine effects involving further mediators have been reported. Whereas direct application of exogenous proinflammatory cytokines induces pain, blockade of these cytokines or application of anti-inflammatory cytokines reduces pain behavior in most experimental paradigms. Cytokine measurements may identify patients at risk of developing chronic pain associated with their neuropathic conditions, as in the examples of peripheral neuropathies and postherpetic neuralgia. Anticytokine agents currently on the market are effective for the treatment of mostly inflammatory pain conditions, and are starting to be introduced for neuropathic pain states; however, their use is limited by potential life-threatening complications. Owing to the pleiotropy and redundancy of the cytokine system, the successful approach may not be inhibition of one particular cytokine but strategies shifting the balance between pro- and anti-inflammatory cytokines in properly selected patients. Agents that specifically target downstream signaling molecules may provide hope for safer and more specific therapies.
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Affiliation(s)
- Maria Schäfers
- Department of Neurology, University of Duisburg-Essen, Hufelandstr. 55,45147 Essen, Germany.
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Cytokines in Synaptic Function. ACTA ACUST UNITED AC 2008. [DOI: 10.1016/s1567-7443(07)10007-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register]
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Takei Y, Laskey R. Tumor necrosis factor alpha regulates responses to nerve growth factor, promoting neural cell survival but suppressing differentiation of neuroblastoma cells. Mol Biol Cell 2007; 19:855-64. [PMID: 18094051 DOI: 10.1091/mbc.e07-06-0624] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Although nerve growth factor (NGF) promotes survival of neurons, tumor necrosis factor alpha (TNF-alpha) contributes to cell death triggered by NGF depletion, through TNF-alpha receptor (TNFR) 1. In contrast to this effect, TNF-alpha can promote neural cell survival via TNF-alpha receptor TNFR2. Although these findings demonstrate pivotal roles of TNF-alpha and NGF in cell fate decisions, cross-talk between these signaling pathways has not been clarified. We find that NGF can induce TNF-alpha synthesis through the nuclear factor-kappaB transcription factor. This provides a new basis for examining the cross-talk between NGF and TNF-alpha. Inhibition of TNFR2 shows opposite effects on two downstream kinases of NGF, extracellular signal-regulated kinase (Erk) and Akt. It increases Erk activation by NGF, and this increased activation induces differentiation of neuroblastoma cell lines. Reciprocally, inhibition of TNFR2 decreases Akt activation by NGF. Consistent with an essential role of Akt in survival signaling, inhibition of TNF-alpha signaling decreases NGF-dependent survival of neurons from rat dorsal root ganglia. Thus, NGF and NGF-induced TNF-alpha cooperate to activate Akt, promoting survival of normal neural cells. However, the NGF-induced TNF-alpha suppresses Erk activation by NGF, blocking NGF-induced differentiation of neuroblastoma cells. TNFR2 signaling could be a novel target to modulate cell responses to NGF.
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Affiliation(s)
- Yoshinori Takei
- MRC Cancer Cell Unit, Hutchison/MRC Research Centre, Cambridge CB2 0XZ, United Kingdom.
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Spengler RN, Sud R, Knight PR, Ignatowski TA. Antinociception mediated by alpha(2)-adrenergic activation involves increasing tumor necrosis factor alpha (TNFalpha) expression and restoring TNFalpha and alpha(2)-adrenergic inhibition of norepinephrine release. Neuropharmacology 2007; 52:576-89. [PMID: 17055005 PMCID: PMC1839855 DOI: 10.1016/j.neuropharm.2006.08.027] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2006] [Revised: 07/26/2006] [Accepted: 08/21/2006] [Indexed: 02/07/2023]
Abstract
The central component that establishes chronic pain from peripheral nerve injury is associated with increased tumor necrosis factor-alpha (TNFalpha) production in the brain. This study examined TNFalpha and its reciprocally permissive role with alpha(2)-adrenergic activation during peak and progressive decline of thermal hyperalgesia in sciatic nerve chronic constriction injury (CCI). Accumulation of TNFalpha mRNA (in situ hybridization) increases in the hippocampus and locus coeruleus during the onset of neuropathic pain and persists as hyperalgesia abates. Activation of alpha(2)-adrenergic receptors in control rats decreases TNFalpha mRNA accumulation in these brain regions. In contrast, during hyperalgesia, alpha(2)-adrenergic activation enhances TNFalpha mRNA accumulation. Whether this enhanced TNFalpha production is associated with changes in the regulation of norepinephrine (NE) release was tested. Hippocampal slices were electrically depolarized to evaluate alpha(2)-adrenergic and TNFalpha regulation of NE release. While inhibition of NE release by TNFalpha is maximal during peak hyperalgesia, it subsequently transforms to facilitate NE release. In addition, alpha(2)-adrenergic receptor activation with clonidine (0.2mg/kg, i.p.) in CCI rats experiencing hyperalgesia restores TNFalpha and alpha(2)-adrenergic inhibition of NE release. While TNFalpha directs the development of hyperalgesia, it also directs its resolution. Transformed sensitivity to alpha(2)-adrenergic agonists during hyperalgesia demonstrates a mechanism for therapy.
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Affiliation(s)
- Robert N. Spengler
- Department of Pathology and Anatomical Sciences, University at Buffalo, The State University of New York, 3435 Main Street, Buffalo, NY 14214
- Department of Anesthesiology, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 3435 Main Street, Buffalo, NY 14214
| | - Reeteka Sud
- Department of Pathology and Anatomical Sciences, University at Buffalo, The State University of New York, 3435 Main Street, Buffalo, NY 14214
| | - Paul R. Knight
- Department of Anesthesiology, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 3435 Main Street, Buffalo, NY 14214
| | - Tracey A. Ignatowski
- Department of Pathology and Anatomical Sciences, University at Buffalo, The State University of New York, 3435 Main Street, Buffalo, NY 14214
- Department of Anesthesiology, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 3435 Main Street, Buffalo, NY 14214
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Sud R, Ignatowski TA, Lo CPK, Spengler RN. Uncovering molecular elements of brain-body communication during development and treatment of neuropathic pain. Brain Behav Immun 2007; 21:112-24. [PMID: 16859892 DOI: 10.1016/j.bbi.2006.06.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2006] [Revised: 05/22/2006] [Accepted: 06/01/2006] [Indexed: 02/07/2023] Open
Abstract
Integral to neuropathic pain is a reciprocal interaction between tumor necrosis factor-alpha (TNF) production and the alpha(2)-adrenergic receptor response, offering an attractive therapeutic target. The effects of varying levels of brain TNF on alpha(2)-adrenergic regulation of cyclic AMP (cAMP) production in the hippocampus and sciatic nerve were investigated during the development and amitriptyline treatment of chronic pain. Increased levels of TNF during the development of chronic pain transform alpha(2)-adrenergic inhibition of cAMP production in the brain to potentiation. While alpha(2)-adrenergic receptors regulate TNF production, they also affect descending noradrenergic pathways. Increases in levels of TNF in the brain deeply impact peripheral inflammation through regulating alpha(2)-adrenergic receptors, offering insight into brain-body interactions during neuropathic pain. Amitriptyline as an analgesic inhibits pain-induced increases in brain-associated TNF and transforms peripheral alpha(2)-adrenergic receptors. The dynamic equilibrium between TNF levels and alpha(2)-adrenergic functioning is uniquely altered during development and treatment of neuropathic pain. Proper manipulations of this interaction offer efficacious treatment of neuropathic pain.
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Affiliation(s)
- Reeteka Sud
- Department of Pathology and Anatomical Sciences, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, 3435 Main Street, Buffalo, NY 14214, USA
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Reynolds JL, Ignatowski TA, Sud R, Spengler RN. An antidepressant mechanism of desipramine is to decrease tumor necrosis factor-alpha production culminating in increases in noradrenergic neurotransmission. Neuroscience 2005; 133:519-31. [PMID: 15878644 DOI: 10.1016/j.neuroscience.2005.02.023] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2004] [Revised: 02/11/2005] [Accepted: 02/12/2005] [Indexed: 02/07/2023]
Abstract
The monoamine theory of depression proposes decreased bioavailability of monoamines, such as norepinephrine (NE), as the underlying cause of depression. Thus, the antidepressant efficacy of NE-reuptake inhibitors such as desipramine is attributed to increases in synaptic concentrations of NE. The time difference between inhibition of reuptake and therapeutic efficacy, however, argues against this being the primary mechanism. If desipramine elicits its therapeutic efficacy by increasing NE release, in turn, increasing activation of the alpha(2)-adrenergic autoinhibitory receptor, then mimicking this increase with an exogenous agonist (clonidine) should support or even enhance the efficacy of the antidepressant. Intriguingly, simultaneous administration of clonidine with desipramine prevented the cellular and behavioral effects elicited by desipramine alone, in both acute and chronic administration paradigms. These results suggest the involvement of additional factor(s) in the mechanism of antidepressant action of this drug. Desipramine administration results in a virtual ablation of neuron-derived tumor necrosis factor-alpha (TNF), thus implicating an essential role of TNF in the therapeutic efficacy of this antidepressant. Additionally, following chronic administration of desipramine, TNF-regulation of NE release is transformed, from inhibition to facilitation. Here, we demonstrate that a transformation in TNF-regulation of NE release in the brain is a key element in the efficacy of this antidepressant. Interestingly, an increase in neurotransmission prior to the antidepressant's effect on TNF production prevents the efficacy of the antidepressant drug. Thus, the efficacy of desipramine is due to decreased levels of TNF in the brain induced by this drug, ultimately modifying noradrenergic neurotransmission.
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Affiliation(s)
- J L Reynolds
- Department of Pathology and Anatomical Sciences, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA
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Reynolds JL, Ignatowski TA, Spengler RN. Effect of tumor necrosis factor-alpha on the reciprocal G-protein-induced regulation of norepinephrine release by the alpha2-adrenergic receptor. J Neurosci Res 2005; 79:779-87. [PMID: 15672410 DOI: 10.1002/jnr.20407] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Alpha2-adrenergic receptors control norepinephrine (NE) release and tumor necrosis factor-alpha (TNF) production from neurons. TNF regulates NE release, depending on alpha2-adrenergic receptor functioning. The relationship between TNF production in the brain and alpha2-adrenergic receptor activation could have profound control over NE release. TNF and alpha2-adrenergic regulation of NE release was investigated in rat hippocampal slices incubated with pertussis toxin (PTX). The alpha2-adrenergic receptor couples to Galpha(i/o)-proteins to inhibit NE release; however, in slices preexposed to PTX, alpha2-adrenergic receptor activation facilitates NE release. TNF exposure subsequent to PTX restores alpha2-adrenergic inhibition of NE release. PTX exposure of hippocampal slices prevents agonist-induced increases in Galpha(i/o) labeling with a GTP analog; after subsequent TNF exposure, agonist-induced increases in Galpha(i/o) labeling are restored. TNF regulation of NE release transforms from inhibition to facilitation depending on alpha2-adrenergic receptor activation following PTX exposure. Therefore, TNF directs the coupling of the alpha2-adrenergic receptor, ultimately affecting NE release.
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Affiliation(s)
- Jessica L Reynolds
- Department of Pathology and Anatomical Sciences, School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY 14214, USA
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Tuppo EE, Arias HR. The role of inflammation in Alzheimer's disease. Int J Biochem Cell Biol 2005; 37:289-305. [PMID: 15474976 DOI: 10.1016/j.biocel.2004.07.009] [Citation(s) in RCA: 481] [Impact Index Per Article: 24.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/09/2004] [Indexed: 11/17/2022]
Abstract
Considerable evidence gained over the past decade has supported the conclusion that neuroinflammation is associated with Alzheimer's disease (AD) pathology. Inflammatory components related to AD neuroinflammation include brain cells such as microglia and astrocytes, the classic and alternate pathways of the complement system, the pentraxin acute-phase proteins, neuronal-type nicotinic acetylcholine receptors (AChRs), peroxisomal proliferators-activated receptors (PPARs), as well as cytokines and chemokines. Both the microglia and astrocytes have been shown to generate beta-amyloid protein (Abeta), one of the main pathologic features of AD. Abeta itself has been shown to act as a pro-inflammatory agent causing the activation of many of the inflammatory components. Further substantiation for the role of neuroinflammation in AD has come from studies that demonstrate patients who took non-steroidal anti-inflammatory drugs had a lower risk of AD than those who did not. These same results have led to increased interest in pursuing anti-inflammatory therapy for AD but with poor results. On the other hand, increasing amount of data suggest that AChRs and PPARs are involved in AD-induced neuroinflammation and in this regard, future therapy may focus on their specific targeting in the AD brain.
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Affiliation(s)
- Ehab E Tuppo
- Center for Aging, University of Medicine and Dentistry of New Jersey-School of Osteopathic Medicine, Stratford, NJ 08084, USA.
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Renauld AE, Ignatowski TA, Spengler RN. Alpha 2-adrenergic receptor inhibition of cAMP accumulation is transformed to facilitation by tumor necrosis factor-alpha. Brain Res 2004; 1004:212-6. [PMID: 15033439 DOI: 10.1016/j.brainres.2004.01.029] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/02/2004] [Indexed: 11/26/2022]
Abstract
Activation of the alpha(2)-adrenergic receptor on neurons regulates the activity of neurons. Inhibition of forskolin-stimulated cAMP accumulation induced by alpha(2)-adrenergic receptor activation is altered following exposure of the neuron SH-SY5Y cell line to tumor necrosis factor-alpha (TNF). Acute (5 and 15 min) exposure to TNF induces a transformation in alpha(2)-adrenergic regulation of cAMP accumulation from inhibition to facilitation. These findings support an autocrine role for the regulation of TNF production from neurons.
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Affiliation(s)
- Amy E Renauld
- Department of Pathology and Anatomical Sciences, School of Medicine and Biomedical Sciences, SUNY at Buffalo, 206 Farber Hall, 3435 Main Street, Buffalo, NY 14214, USA
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Wenk GL, McGann K, Hauss-Wegrzyniak B, Rosi S. The toxicity of tumor necrosis factor-alpha upon cholinergic neurons within the nucleus basalis and the role of norepinephrine in the regulation of inflammation: implications for Alzheimer's disease. Neuroscience 2004; 121:719-29. [PMID: 14568031 DOI: 10.1016/s0306-4522(03)00545-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Inflammation and reduced forebrain norepinephrine are features of Alzheimer's disease that may interact to contribute to the degeneration of specific neural systems. We reproduced these conditions within the basal forebrain cholinergic system, a region that is vulnerable to degeneration in Alzheimer's disease. Tumor necrosis factor-alpha was infused into the basal forebrain of young mice pretreated with a norepinephrine neuronal toxin, N-(2-chloroethyl)-N-ethyl-2 bromobenzylamine (DSP4), with the expectation that the loss of noradrenergic input would enhance the loss of cholinergic neurons. The results indicate that chronic infusion of tumor necrosis factor-alpha alone significantly decreased cortical choline acetyltransferase activity and increased the number of activated microglia and astrocytes within the basal forebrain. The loss of forebrain norepinephrine following systemic treatment with DSP4 did not alter the level of cortical choline acetyltransferase activity or activate microglia but significantly activated astrocytes within the basal forebrain. Infusion of tumor necrosis factor-alpha into DSP4-pretreated mice also reduced cortical choline acetyltransferase activity on the side of the infusion; however, the decline was not significantly greater than that produced by the infusion of tumor necrosis factor-alpha alone. The neurodegeneration seen may be indirect since a double-immunofluorescence investigation did not find evidence for the co-existence of tumor necrosis factor-alpha type I receptors on choline acetyltransferase-positive cells in the basal forebrain. The results suggest that noradrenergic cell loss in Alzheimer's disease does not augment the consequences of the chronic neuroinflammation and does not enhance neurodegeneration of forebrain cholinergic neurons.
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Affiliation(s)
- G L Wenk
- Arizona Research Laboratories, Division of Neural Systems, Memory and Aging, University of Arizona, Tucson, AZ 85724, USA.
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