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Petsakou A, Liu Y, Liu Y, Comjean A, Hu Y, Perrimon N. Epithelial Ca 2+ waves triggered by enteric neurons heal the gut. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.14.553227. [PMID: 37645990 PMCID: PMC10461974 DOI: 10.1101/2023.08.14.553227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/01/2023]
Abstract
A fundamental and unresolved question in regenerative biology is how tissues return to homeostasis after injury. Answering this question is essential for understanding the etiology of chronic disorders such as inflammatory bowel diseases and cancer. We used the Drosophila midgut to investigate this question and discovered that during regeneration a subpopulation of cholinergic enteric neurons triggers Ca2+ currents among enterocytes to promote return of the epithelium to homeostasis. Specifically, we found that down-regulation of the cholinergic enzyme Acetylcholinesterase in the epithelium enables acetylcholine from defined enteric neurons, referred as ARCENs, to activate nicotinic receptors in enterocytes found near ARCEN-innervations. This activation triggers high Ca2+ influx that spreads in the epithelium through Inx2/Inx7 gap junctions promoting enterocyte maturation followed by reduction of proliferation and inflammation. Disrupting this process causes chronic injury consisting of ion imbalance, Yki activation and increase of inflammatory cytokines together with hyperplasia, reminiscent of inflammatory bowel diseases. Altogether, we found that during gut regeneration the conserved cholinergic pathway facilitates epithelial Ca2+ waves that heal the intestinal epithelium. Our findings demonstrate nerve- and bioelectric-dependent intestinal regeneration which advance the current understanding of how a tissue returns to its homeostatic state after injury and could ultimately help existing therapeutics.
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Affiliation(s)
| | - Yifang Liu
- Department of Genetics, Harvard Medical School, Boston, USA
| | - Ying Liu
- Department of Genetics, Harvard Medical School, Boston, USA
| | - Aram Comjean
- Department of Genetics, Harvard Medical School, Boston, USA
| | - Yanhui Hu
- Department of Genetics, Harvard Medical School, Boston, USA
| | - Norbert Perrimon
- Department of Genetics, Harvard Medical School, Boston, USA
- Howard Hughes Medical Institute, Boston, USA
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2
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Si S, Zhao X, Su F, Lu H, Zhang D, Sun L, Wang F, Xu L. New advances in clinical application of neostigmine: no longer focusing solely on increasing skeletal muscle strength. Front Pharmacol 2023; 14:1227496. [PMID: 37601044 PMCID: PMC10436336 DOI: 10.3389/fphar.2023.1227496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 07/28/2023] [Indexed: 08/22/2023] Open
Abstract
Neostigmine is a clinical cholinesterase inhibitor, that is, commonly used to enhance the function of the cholinergic neuromuscular junction. Recent studies have shown that neostigmine regulates the immune-inflammatory response through the cholinergic anti-inflammatory pathway, affecting perioperative neurocognitive function. This article reviews the relevant research evidence over the past 20 years, intending to provide new perspectives and strategies for the clinical application of neostigmine.
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Affiliation(s)
- Shangkun Si
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Xiaohu Zhao
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Fan Su
- Department of Anesthesiology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Hongxiu Lu
- Department of Anesthesiology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Dongbin Zhang
- Department of Anesthesiology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Li Sun
- Department of Anesthesiology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Fulei Wang
- Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Li Xu
- Shandong University of Traditional Chinese Medicine, Jinan, China
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3
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Keever KR, Yakubenko VP, Hoover DB. Neuroimmune nexus in the pathophysiology and therapy of inflammatory disorders: role of α7 nicotinic acetylcholine receptors. Pharmacol Res 2023; 191:106758. [PMID: 37028776 DOI: 10.1016/j.phrs.2023.106758] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 03/30/2023] [Accepted: 04/02/2023] [Indexed: 04/08/2023]
Abstract
The α7-nicotinic acetylcholine receptor (α7nAChR) is a key protein in the cholinergic anti-inflammatory pathway (CAP) that links the nervous and immune systems. Initially, the pathway was discovered based on the observation that vagal nerve stimulation (VNS) reduced the systemic inflammatory response in septic animals. Subsequent studies form a foundation for the leading hypothesis about the central role of the spleen in CAP activation. VNS evokes noradrenergic stimulation of ACh release from T cells in the spleen, which in turn activates α7nAChRs on the surface of macrophages. α7nAChR-mediated signaling in macrophages reduces inflammatory cytokine secretion and modifies apoptosis, proliferation, and macrophage polarization, eventually reducing the systemic inflammatory response. A protective role of the CAP has been demonstrated in preclinical studies for multiple diseases including sepsis, metabolic disease, cardiovascular diseases, arthritis, Crohn's disease, ulcerative colitis, endometriosis, and potentially COVID-19, sparking interest in using bioelectronic and pharmacological approaches to target α7nAChRs for treating inflammatory conditions in patients. Despite a keen interest, many aspects of the cholinergic pathway are still unknown. α7nAChRs are expressed on many other subsets of immune cells that can affect the development of inflammation differently. There are also other sources of ACh that modify immune cell functions. How the interplay of ACh and α7nAChR on different cells and in various tissues contributes to the anti-inflammatory responses requires additional study. This review provides an update on basic and translational studies of the CAP in inflammatory diseases, the relevant pharmacology of α7nAChR-activated drugs and raises some questions that require further investigation.
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4
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Oshaghi M, Kourosh-Arami M, Roozbehkia M. Role of neurotransmitters in immune-mediated inflammatory disorders: a crosstalk between the nervous and immune systems. Neurol Sci 2023; 44:99-113. [PMID: 36169755 DOI: 10.1007/s10072-022-06413-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 09/14/2022] [Indexed: 02/07/2023]
Abstract
Immune-mediated inflammatory diseases (IMIDs) are a group of common heterogeneous disorders, characterized by an alteration of cellular homeostasis. Primarily, it has been shown that the release and diffusion of neurotransmitters from nervous tissue could result in signaling through lymphocyte cell-surface receptors and the modulation of immune function. This finding led to the idea that the neurotransmitters could serve as immunomodulators. It is now manifested that neurotransmitters can also be released from leukocytes and act as autocrine or paracrine modulators. Increasing data indicate that there is a crosstalk between inflammation and alterations in neurotransmission. The primary goal of this review is to demonstrate how these two pathways may converge at the level of the neuron and glia to involve in IMID. We review the role of neurotransmitters in IMID. The different effects that these compounds exert on a variety of immune cells are also reviewed. Current and future developments in understanding the cross-talk between the immune and nervous systems will undoubtedly identify new ways for treating immune-mediated diseases utilizing agonists or antagonists of neurotransmitter receptors.
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Affiliation(s)
- Mojgan Oshaghi
- Department of Medical Laboratory Science, Faculty of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran
| | - Masoumeh Kourosh-Arami
- Department of Neuroscience, School of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.
| | - Maryam Roozbehkia
- Department of Medical Laboratory Science, Faculty of Allied Medical Sciences, Iran University of Medical Sciences, Tehran, Iran.
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5
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Yasmin F, Sahito AM, Mir SL, Khatri G, Shaikh S, Gul A, Hassan SA, Koritala T, Surani S. Electrical neuromodulation therapy for inflammatory bowel disease. World J Gastrointest Pathophysiol 2022; 13:128-142. [PMID: 36187600 PMCID: PMC9516456 DOI: 10.4291/wjgp.v13.i5.128] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2021] [Revised: 02/19/2022] [Accepted: 07/18/2022] [Indexed: 02/08/2023] Open
Abstract
Inflammatory bowel disease (IBD) is an inflammatory disease of the gastrointestinal (GI) tract. It has financial and quality of life impact on patients. Although there has been a significant advancement in treatments, a considerable number of patients do not respond to it or have severe side effects. Therapeutic approaches such as electrical neuromodulation are being investigated to provide alternate options. Although bioelectric neuromodulation technology has evolved significantly in the last decade, sacral nerve stimulation (SNS) for fecal incontinence remains the only neuromodulation protocol commonly utilized use for GI disease. For IBD treatment, several electrical neuromodulation techniques have been studied, such as vagus NS, SNS, and tibial NS. Several animal and clinical experiments were conducted to study the effectiveness, with encouraging results. The precise underlying mechanisms of action for electrical neuromodulation are unclear, but this modality appears to be promising. Randomized control trials are required to investigate the efficacy of intrinsic processes. In this review, we will discuss the electrical modulation therapy for the IBD and the data pertaining to it.
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Affiliation(s)
- Farah Yasmin
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Abdul Moiz Sahito
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Syeda Lamiya Mir
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Govinda Khatri
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Somina Shaikh
- Department of Medicine, Dow University of Health Sciences, Karachi 74200, Pakistan
| | - Ambresha Gul
- Department of Medicine, People’s University of Medical and Health Sciences, Nawabshah 67480, Pakistan
| | - Syed Adeel Hassan
- Department of Medicine, University of Louisville, Louiseville, KY 40292, United States
| | - Thoyaja Koritala
- Department of Medicine, Mayo Clinic, Rochester, NY 55902, United States
| | - Salim Surani
- Department of Medicine, Texas A&M University, College Station, TX 77843, United States
- Department of Anesthesiology, Mayo Clinic, Rochester, MN 55902, United States
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6
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Goggins E, Mitani S, Tanaka S. Clinical perspectives on vagus nerve stimulation: present and future. Clin Sci (Lond) 2022; 136:695-709. [PMID: 35536161 PMCID: PMC9093220 DOI: 10.1042/cs20210507] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 04/15/2022] [Accepted: 04/22/2022] [Indexed: 12/30/2022]
Abstract
The vagus nerve, the great wanderer, is involved in numerous processes throughout the body and vagus nerve stimulation (VNS) has the potential to modulate many of these functions. This wide-reaching capability has generated much interest across a range of disciplines resulting in several clinical trials and studies into the mechanistic basis of VNS. This review discusses current preclinical and clinical evidence supporting the efficacy of VNS in different diseases and highlights recent advancements. Studies that provide insights into the mechanism of VNS are considered.
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Affiliation(s)
- Eibhlin Goggins
- Division of Nephrology and Center for Immunity, Inflammation, and Regenerative Medicine, University of Virginia, Charlottesville, VA, U.S.A
| | - Shuhei Mitani
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Shinji Tanaka
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
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7
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Metz CN, Pavlov VA. Treating disorders across the lifespan by modulating cholinergic signaling with galantamine. J Neurochem 2021; 158:1359-1380. [PMID: 33219523 PMCID: PMC10049459 DOI: 10.1111/jnc.15243] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 11/15/2020] [Accepted: 11/16/2020] [Indexed: 02/06/2023]
Abstract
Advances in understanding the regulatory functions of the nervous system have revealed neural cholinergic signaling as a key regulator of cytokine responses and inflammation. Cholinergic drugs, including the centrally acting acetylcholinesterase inhibitor, galantamine, which are in clinical use for the treatment of Alzheimer's disease and other neurodegenerative and neuropsychiatric disorders, have been rediscovered as anti-inflammatory agents. Here, we provide a timely update on this active research and clinical developments. We summarize the involvement of cholinergic mechanisms and inflammation in the pathobiology of Alzheimer's disease, Parkinson's disease, and schizophrenia, and the effectiveness of galantamine treatment. We also highlight recent findings demonstrating the effects of galantamine in preclinical and clinical settings of numerous conditions and diseases across the lifespan that are characterized by immunological, neurological, and metabolic dysfunction.
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Affiliation(s)
- Christine N. Metz
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
| | - Valentin A. Pavlov
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, USA
- Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
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8
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Duan H, Cai X, Luan Y, Yang S, Yang J, Dong H, Zeng H, Shao L. Regulation of the Autonomic Nervous System on Intestine. Front Physiol 2021; 12:700129. [PMID: 34335306 PMCID: PMC8317205 DOI: 10.3389/fphys.2021.700129] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Accepted: 06/22/2021] [Indexed: 12/12/2022] Open
Abstract
Intestine is composed of various types of cells including absorptive epithelial cells, goblet cells, endocrine cells, Paneth cells, immunological cells, and so on, which play digestion, absorption, neuroendocrine, immunological function. Intestine is innervated with extrinsic autonomic nerves and intrinsic enteric nerves. The neurotransmitters and counterpart receptors are widely distributed in the different intestinal cells. Intestinal autonomic nerve system includes sympathetic and parasympathetic nervous systems, which regulate cellular proliferation and function in intestine under physiological and pathophysiological conditions. Presently, distribution and functional characteristics of autonomic nervous system in intestine were reviewed. How autonomic nervous system regulates intestinal cell proliferation was discussed. Function of autonomic nervous system on intestinal diseases was extensively reviewed. It might be helpful to properly manipulate autonomic nervous system during treating different intestinal diseases.
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Affiliation(s)
- Hongyi Duan
- Medical College of Nanchang University, Nanchang, China
| | - Xueqin Cai
- Medical College of Nanchang University, Nanchang, China
| | - Yingying Luan
- Medical College of Nanchang University, Nanchang, China
| | - Shuo Yang
- Medical College of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China
| | - Juan Yang
- Medical College of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China
| | - Hui Dong
- Medical College of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Interdisciplinary Science, Nanchang University, Nanchang, China
| | - Huihong Zeng
- Medical College of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Interdisciplinary Science, Nanchang University, Nanchang, China
| | - Lijian Shao
- Medical College of Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China.,Jiangxi Provincial Key Laboratory of Interdisciplinary Science, Nanchang University, Nanchang, China
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9
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Stakenborg N, Boeckxstaens GE. Bioelectronics in the brain-gut axis: focus on inflammatory bowel disease (IBD). Int Immunol 2021; 33:337-348. [PMID: 33788920 PMCID: PMC8183669 DOI: 10.1093/intimm/dxab014] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Accepted: 03/30/2021] [Indexed: 12/17/2022] Open
Abstract
Accumulating evidence shows that intestinal homeostasis is mediated by cross-talk between the nervous system, enteric neurons and immune cells, together forming specialized neuroimmune units at distinct anatomical locations within the gut. In this review, we will particularly discuss how the intrinsic and extrinsic neuronal circuitry regulates macrophage function and phenotype in the gut during homeostasis and aberrant inflammation, such as observed in inflammatory bowel disease (IBD). Furthermore, we will provide an overview of basic and translational IBD research using these neuronal circuits as a novel therapeutic tool. Finally, we will highlight the different challenges ahead to make bioelectronic neuromodulation a standard treatment for intestinal immune-mediated diseases.
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Affiliation(s)
- Nathalie Stakenborg
- Center of Intestinal Neuro-immune Interaction, Translational Research Center for GI Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, University of Leuven, Herestraat 49, O&N1 bus 701, Leuven 3000, Belgium
| | - Guy E Boeckxstaens
- Center of Intestinal Neuro-immune Interaction, Translational Research Center for GI Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing, University of Leuven, Herestraat 49, O&N1 bus 701, Leuven 3000, Belgium
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10
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Bricher Choque PN, Vieira RP, Ulloa L, Grabulosa C, Irigoyen MC, De Angelis K, Ligeiro De Oliveira AP, Tracey KJ, Pavlov VA, Consolim-Colombo FM. The Cholinergic Drug Pyridostigmine Alleviates Inflammation During LPS-Induced Acute Respiratory Distress Syndrome. Front Pharmacol 2021; 12:624895. [PMID: 34017249 PMCID: PMC8129580 DOI: 10.3389/fphar.2021.624895] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 04/13/2021] [Indexed: 01/12/2023] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a critical illness complication that is associated with high mortality. ARDS is documented in severe cases of COVID-19. No effective pharmacological treatments for ARDS are currently available. Dysfunctional immune responses and pulmonary and systemic inflammation are characteristic features of ARDS pathogenesis. Recent advances in our understanding of the regulation of inflammation point to an important role of the vagus-nerve-mediated inflammatory reflex and neural cholinergic signaling. We examined whether pharmacological cholinergic activation using a clinically approved (for myasthenia gravis) cholinergic drug, the acetylcholinesterase inhibitor pyridostigmine alters pulmonary and systemic inflammation in mice with lipopolysaccharide (LPS)-induced ARDS. Male C57Bl/6 mice received one intratracheal instillation of LPS or were sham manipulated (control). Both groups were treated with either vehicle or pyridostigmine (1.5 mg/kg twice daily, 3 mg/day) administered by oral gavage starting at 1 h post-LPS and euthanized 24 h after LPS administration. Other groups were either sham manipulated or received LPS for 3 days and were treated with vehicle or pyridostigmine and euthanized at 72 h. Pyridostigmine treatment reduced the increased total number of cells and neutrophils in the bronchoalveolar lavage fluid (BALF) in mice with ARDS at 24 and 72 h. Pyridostigmine also reduced the number of macrophages and lymphocytes at 72 h. In addition, pyridostigmine suppressed the levels of TNF, IL-1β, IL-6, and IFN-γ in BALF and plasma at 24 and 72 h. However, this cholinergic agent did not significantly altered BALF and plasma levels of the anti-inflammatory cytokine IL-10. Neither LPS nor pyridostigmine affected BALF IFN-γ and IL-10 levels at 24 h post-LPS. In conclusion, treatments with the cholinergic agent pyridostigmine ameliorate pulmonary and systemic inflammatory responses in mice with endotoxin-induced ARDS. Considering that pyridostigmine is a clinically approved drug, these findings are of substantial interest for implementing pyridostigmine in therapeutic strategies for ARDS.
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Affiliation(s)
- Pamela Nithzi Bricher Choque
- Laboratory of Pulmonary Immunology, Postgraduate Program in Medicine, Universidade Nove de Julho (UNINOVE), São Paulo, Brazil
| | - Rodolfo P. Vieira
- Post-graduation Program in Bioengineering and in Biomedical Engineering, Universidade Brasil, São Paulo, Brazil
- Brazilian Institute of Teaching and Research in Pulmonary and Exercise Immunology (IBEPIPE), São Paulo, Brazil
- Federal University of São Paulo (UNIFESP), Post-graduation Program in Sciences of Human Movement and Rehabilitation, São Paulo, Brazil
- Departament of Physiology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Luis Ulloa
- Department of Anesthesiology, Duke University Medical Center, Durham, NC, United States
| | - Caren Grabulosa
- Laboratory of Pulmonary Immunology, Postgraduate Program in Medicine, Universidade Nove de Julho (UNINOVE), São Paulo, Brazil
| | - Maria Claudia Irigoyen
- Hypertension Unit, Heart Institute (INCOR), Medical School of University of São Paulo, São Paulo, Brazil
| | - Katia De Angelis
- Departament of Physiology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Ana Paula Ligeiro De Oliveira
- Laboratory of Pulmonary Immunology, Postgraduate Program in Medicine, Universidade Nove de Julho (UNINOVE), São Paulo, Brazil
| | - Kevin J. Tracey
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Valentin A. Pavlov
- The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, NY, United States
| | - Fernanda Marciano Consolim-Colombo
- Laboratory of Pulmonary Immunology, Postgraduate Program in Medicine, Universidade Nove de Julho (UNINOVE), São Paulo, Brazil
- Hypertension Unit, Heart Institute (INCOR), Medical School of University of São Paulo, São Paulo, Brazil
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11
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Bonaz B, Sinniger V, Pellissier S. Therapeutic Potential of Vagus Nerve Stimulation for Inflammatory Bowel Diseases. Front Neurosci 2021; 15:650971. [PMID: 33828455 PMCID: PMC8019822 DOI: 10.3389/fnins.2021.650971] [Citation(s) in RCA: 81] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Accepted: 03/01/2021] [Indexed: 12/12/2022] Open
Abstract
The vagus nerve is a mixed nerve, comprising 80% afferent fibers and 20% efferent fibers. It allows a bidirectional communication between the central nervous system and the digestive tract. It has a dual anti-inflammatory properties via activation of the hypothalamic pituitary adrenal axis, by its afferents, but also through a vago-vagal inflammatory reflex involving an afferent (vagal) and an efferent (vagal) arm, called the cholinergic anti-inflammatory pathway. Indeed, the release of acetylcholine at the end of its efferent fibers is able to inhibit the release of tumor necrosis factor (TNF) alpha by macrophages via an interneuron of the enteric nervous system synapsing between the efferent vagal endings and the macrophages and releasing acetylcholine. The vagus nerve also synapses with the splenic sympathetic nerve to inhibit the release of TNF-alpha by splenic macrophages. It can also activate the spinal sympathetic system after central integration of its afferents. This anti-TNF-alpha effect of the vagus nerve can be used in the treatment of chronic inflammatory bowel diseases, represented by Crohn’s disease and ulcerative colitis where this cytokine plays a key role. Bioelectronic medicine, via vagus nerve stimulation, may have an interest in this non-drug therapeutic approach as an alternative to conventional anti-TNF-alpha drugs, which are not devoid of side effects feared by patients.
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Affiliation(s)
- Bruno Bonaz
- Division of Hepato-Gastroenterology, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France.,Grenoble Institute of Neurosciences, Inserm U1216, University Grenoble Alpes, Grenoble, France
| | - Valérie Sinniger
- Division of Hepato-Gastroenterology, Centre Hospitalier Universitaire Grenoble Alpes, Grenoble, France.,Grenoble Institute of Neurosciences, Inserm U1216, University Grenoble Alpes, Grenoble, France
| | - Sonia Pellissier
- Laboratoire Inter-Universitaire de Psychologie Personnalité, Cognition, Changement Social, University Grenoble Alpes, University Savoie Mont Blanc, Grenoble, France
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12
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Cheng J, Shen H, Chowdhury R, Abdi T, Selaru F, Chen JDZ. Potential of Electrical Neuromodulation for Inflammatory Bowel Disease. Inflamm Bowel Dis 2020; 26:1119-1130. [PMID: 31782957 DOI: 10.1093/ibd/izz289] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Indexed: 12/12/2022]
Abstract
Inflammatory bowel disease (IBD) is a common chronic inflammatory disease of the digestive tract that is often debilitating. It affects patients' quality of life and imposes a financial burden. Despite advances in treatment with medications such as biologics, a large proportion of patients do not respond to medical therapy or develop adverse events. Therefore, alternative treatment options such as electrical neuromodulation are currently being investigated. Electrical neuromodulation, also called bioelectronic medicine, is emerging as a potential new treatment for IBD. Over the past decade, advancements have been made in electrical neuromodulation. A number of electrical neuromodulation methods, such as vagus nerve stimulation, sacral nerve stimulation, and tibial nerve stimulation, have been tested to treat IBD. A series of animal and clinical trials have been performed to evaluate efficacy with promising results. Although the exact underlying mechanisms of action for electrical neuromodulation remain to be explored, this modality is promising. Further randomized controlled trials and basic experiments are needed to investigate efficacy and clarify intrinsic mechanisms.
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Affiliation(s)
- Jiafei Cheng
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.,Division of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Hong Shen
- Division of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
| | - Reezwana Chowdhury
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Tsion Abdi
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Florin Selaru
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
| | - Jiande D Z Chen
- Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
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13
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Cox MA, Bassi C, Saunders ME, Nechanitzky R, Morgado-Palacin I, Zheng C, Mak TW. Beyond neurotransmission: acetylcholine in immunity and inflammation. J Intern Med 2020; 287:120-133. [PMID: 31710126 DOI: 10.1111/joim.13006] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Revised: 08/24/2019] [Accepted: 09/10/2019] [Indexed: 12/21/2022]
Abstract
Acetylcholine (ACh) is best known as a neurotransmitter and was the first such molecule identified. ACh signalling in the neuronal cholinergic system has long been known to regulate numerous biological processes (reviewed by Beckmann and Lips). In actuality, ACh is a ubiquitous signalling molecule that is produced by numerous non-neuronal cell types and even by some single-celled organisms. Within multicellular organisms, a non-neuronal cholinergic system that includes the immune system functions in parallel with the neuronal cholinergic system. Several immune cell types both respond to ACh signals and can directly produce ACh. Recent work from our laboratory has demonstrated that the capacity to produce ACh is an intrinsic property of T cells responding to viral infection, and that this ability to produce ACh is dependent upon IL-21 signalling to the T cells. Furthermore, during infection this immune-derived ACh is necessary for the T cells to migrate into infected tissues. In this review, we will discuss the various sources of ACh that are relevant during immune responses and describe how ACh acts on immune cells to influence their functions. We will also address the clinical implications of this fascinating aspect of immunity, focusing on ACh's role in the migration of T cells during infection and cancer.
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Affiliation(s)
- M A Cox
- The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - C Bassi
- The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - M E Saunders
- The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - R Nechanitzky
- The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - I Morgado-Palacin
- The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - C Zheng
- The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
| | - T W Mak
- The Campbell Family Institute for Breast Cancer Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.,Ontario Institute for Cancer Research, Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.,Department of Immunology, University of Toronto, Toronto, ON, Canada.,Department of Pathology, University of Hong Kong, Hong Kong, Hong Kong
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14
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Meroni E, Stakenborg N, Viola MF, Boeckxstaens GE. Intestinal macrophages and their interaction with the enteric nervous system in health and inflammatory bowel disease. Acta Physiol (Oxf) 2019; 225:e13163. [PMID: 29998613 PMCID: PMC6519157 DOI: 10.1111/apha.13163] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 07/07/2018] [Accepted: 07/09/2018] [Indexed: 12/19/2022]
Abstract
Over the past decades, there has been an increasing understanding of cellular and molecular mechanisms that mediate modulation of the immune system by the autonomic nervous system. The discovery that vagal nerve stimulation (VNS) attenuates endotoxin-induced experimental sepsis paved the way for further studies investigating neuro-immune interaction. In particular, great attention is now given to intestinal macrophages: several studies report the existence of both intrinsic and extrinsic neural mechanisms by which intestinal immune homoeostasis can be regulated in different layers of the intestine, mainly by affecting macrophage activation through neurotransmitter release. Given the important role of inflammation in numerous disease processes, such as inflammatory bowel disease (IBD), cholinergic anti-inflammatory mechanisms are under intense investigation both from a basic and clinical science perspective in immune-mediated diseases such as IBD. This review discusses recent insights on the cross-talk between enteric neurons and the immune system, especially focusing on macrophages, and provides an overview of basic and translational aspects of the cholinergic anti-inflammatory response as therapeutic alternative to reinstall immune homoeostasis in intestinal chronic inflammation.
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Affiliation(s)
- Elisa Meroni
- Department of Chronic Diseases, Metabolism and AgeingTranslational Research Center for Gastrointestinal Disorders (TARGID)KU Leuven—University of LeuvenLeuvenBelgium
| | - Nathalie Stakenborg
- Department of Chronic Diseases, Metabolism and AgeingTranslational Research Center for Gastrointestinal Disorders (TARGID)KU Leuven—University of LeuvenLeuvenBelgium
| | - Maria Francesca Viola
- Department of Chronic Diseases, Metabolism and AgeingTranslational Research Center for Gastrointestinal Disorders (TARGID)KU Leuven—University of LeuvenLeuvenBelgium
| | - Guy E. Boeckxstaens
- Department of Chronic Diseases, Metabolism and AgeingTranslational Research Center for Gastrointestinal Disorders (TARGID)KU Leuven—University of LeuvenLeuvenBelgium
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15
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Metz CN, Pavlov VA. Vagus nerve cholinergic circuitry to the liver and the gastrointestinal tract in the neuroimmune communicatome. Am J Physiol Gastrointest Liver Physiol 2018; 315:G651-G658. [PMID: 30001146 PMCID: PMC6293249 DOI: 10.1152/ajpgi.00195.2018] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Improved understanding of neuroimmune communication and the neural regulation of immunity and inflammation has recently led to proposing the concept of the "neuroimmune communicatome." This advance is based on experimental evidence for an organized and brain-integrated reflex-like relationship and dialogue between the nervous and the immune systems. A key circuitry in this communicatome is provided by efferent vagus nerve fibers and cholinergic signaling. Inflammation and metabolic alterations coexist in many disorders affecting the liver and the gastrointestinal (GI) tract, including obesity, metabolic syndrome, fatty liver disease, liver injury, and liver failure, as well as inflammatory bowel disease. Here, we outline mechanistic insights regarding the role of the vagus nerve and cholinergic signaling in the regulation of inflammation linked to metabolic derangements and the pathogenesis of these disorders in preclinical settings. Recent clinical advances using this knowledge in novel therapeutic neuromodulatory approaches within the field of bioelectronic medicine are also briefly summarized.
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Affiliation(s)
- Christine N. Metz
- 1Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York,2Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York
| | - Valentin A. Pavlov
- 1Center for Biomedical Science and Bioelectronic Medicine, The Feinstein Institute for Medical Research, Northwell Health, Manhasset, New York,2Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York
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16
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Zila I, Mokra D, Kopincova J, Kolomaznik M, Javorka M, Calkovska A. Vagal-immune interactions involved in cholinergic anti-inflammatory pathway. Physiol Res 2018; 66:S139-S145. [PMID: 28937230 DOI: 10.33549/physiolres.933671] [Citation(s) in RCA: 42] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Inflammation and other immune responses are involved in the variety of diseases and disorders. The acute response to endotoxemia includes activation of innate immune mechanisms as well as changes in autonomic nervous activity. The autonomic nervous system and the inflammatory response are intimately linked and sympathetic and vagal nerves are thought to have anti-inflammation functions. The basic functional circuit between vagus nerve and inflammatory response was identified and the neuroimmunomodulation loop was called cholinergic anti-inflammatory pathway. Unique function of vagus nerve in the anti-inflammatory reflex arc was found in many experimental and pre-clinical studies. They brought evidence on the cholinergic signaling interacting with systemic and local inflammation, particularly suppressing immune cells function. Pharmacological/electrical modulation of vagal activity suppressed TNF-alpha and other proinflammatory cytokines production and had beneficial therapeutic effects. Many questions related to mapping, linking and targeting of vagal-immune interactions have been elucidated and brought understanding of its basic physiology and provided the initial support for development of Tracey´s inflammatory reflex. This review summarizes and critically assesses the current knowledge defining cholinergic anti-inflammatory pathway with main focus on studies employing an experimental approach and emphasizes the potential of modulation of vagally-mediated anti-inflammatory pathway in the treatment strategies.
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Affiliation(s)
- I Zila
- Department of Physiology and Biomedical Center Martin, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin, Slovakia.
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17
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Bonaz B. Is-there a place for vagus nerve stimulation in inflammatory bowel diseases? Bioelectron Med 2018; 4:4. [PMID: 32232080 PMCID: PMC7098256 DOI: 10.1186/s42234-018-0004-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Accepted: 02/27/2018] [Indexed: 12/11/2022] Open
Abstract
The vagus nerve (VN), the longest nerve of the organism that innervates the gastrointestinal tract, is a mixed nerve composed of 80% of afferent and 20% of efferent fibers. The VN has anti-inflammatory properties, in particular an anti-TNFα effect through the cholinergic anti-inflammatory pathway. The VN is a key component of the autonomic nervous system, i.e. the parasympathetic nervous system. An imbalance of the autonomic nervous system, as represented by a low vagal tone, is described in many diseases and has a pro-inflammatory role. Inflammatory bowel diseases (IBD) are chronic disorders of the gastro-intestinal tract where TNFα is a key cytokine. VN stimulation (VNS), classically used for the treatment of drug resistant epilepsy and depression, would be of interest in the treatment of IBD. We have recently reported in a 6 month follow-up pilot study that VNS improves active Crohn’s disease. Preliminary data of another pilot study confirm this interest. Similarly, VNS has recently been reported to improve rheumatoid arthritis, another TNFα mediated disease. Bioelectronic Medicine, as represented by VNS, opens new therapeutic avenues in the treatment of such chronic inflammatory disorders. In the present manuscript, we will focus on the interest of VNS in IBD.
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Affiliation(s)
- Bruno Bonaz
- 1Division of Hepato-Gastroenterology, University Hospital, Alpes, F-38000 Grenoble, France.,University Grenoble Alpes, Grenoble Institute of Neurosciences, GIN, Inserm U1216, F-38000 Grenoble, France.,3Division of Hepato-Gastroenterology, CHU Grenoble Alpes, -10217, 38043 Grenoble Cedex 09, CS France
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18
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Wazea SA, Wadie W, Bahgat AK, El-Abhar HS. Galantamine anti-colitic effect: Role of alpha-7 nicotinic acetylcholine receptor in modulating Jak/STAT3, NF-κB/HMGB1/RAGE and p-AKT/Bcl-2 pathways. Sci Rep 2018; 8:5110. [PMID: 29572553 PMCID: PMC5865178 DOI: 10.1038/s41598-018-23359-6] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Accepted: 03/12/2018] [Indexed: 12/30/2022] Open
Abstract
Vagal stimulation controls systemic inflammation and modulates the immune response in different inflammatory conditions, including inflammatory bowel diseases (IBD). The released acetylcholine binds to alpha-7 nicotinic acetylcholine receptor (α7 nAChR) to suppress pro-inflammatory cytokines. This provides a new range of potential therapeutic approaches for controlling inflammatory responses. The present study aimed to assess whether galantamine (Galan) anti-inflammatory action involves α7 nAChR in a 2,4,6-trinitrobenzene sulfonic acid (TNBS) model of colitis and to estimate its possible molecular pathways. Rats were assigned into normal, TNBS, sulfasalazine (Sulfz), Galan treated (10 mg/kg), methyllycaconitine (MLA; 5.6 mg/kg), and MLA + Galan groups. Drugs were administered orally once per day (11 days) and colitis was induced on the 8th day. Galan reduced the TNBS-induced ulceration, colon mass index, colonic MDA, neutrophils adhesion and infiltration (ICAM-1/MPO), inflammatory mediators (NF-κB, TNF-α, HMGB1, and RAGE), while increased the anti-apoptotic pathway (p-Akt/Bcl-2). Mechanistic study revealed that Galan increased the anti-inflammatory cytokine IL-10, phosphorylated Jak2, while reduced the inflammation controller SOCS3. However, combining MLA with Galan abrogated the beneficial anti-inflammatory/anti-apoptotic signals. The results of the present study indicate that Galan anti-inflammatory/-apoptotic/ -oxidant effects originate from the stimulation of the peripheral α7 nAChR, with the involvement of the Jak2/SOCS3 signaling pathway.
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Affiliation(s)
- Shakeeb A Wazea
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Walaa Wadie
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
| | - Ashraf K Bahgat
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
| | - Hanan S El-Abhar
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt.,Department of Pharmacology & Toxicology, Faculty of Pharmacy, Future University in Egypt, Cairo, Egypt
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19
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Bonaz B, Sinniger V, Pellissier S. The Vagus Nerve in the Neuro-Immune Axis: Implications in the Pathology of the Gastrointestinal Tract. Front Immunol 2017; 8:1452. [PMID: 29163522 PMCID: PMC5673632 DOI: 10.3389/fimmu.2017.01452] [Citation(s) in RCA: 225] [Impact Index Per Article: 28.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2017] [Accepted: 10/17/2017] [Indexed: 12/12/2022] Open
Abstract
The vagus nerve (VN) is the longest nerve of the organism and a major component of the parasympathetic nervous system which constitutes the autonomic nervous system (ANS), with the sympathetic nervous system. There is classically an equilibrium between the sympathetic and parasympathetic nervous systems which is responsible for the maintenance of homeostasis. An imbalance of the ANS is observed in various pathologic conditions. The VN, a mixed nerve with 4/5 afferent and 1/5 efferent fibers, is a key component of the neuro-immune and brain-gut axes through a bidirectional communication between the brain and the gastrointestinal (GI) tract. A dual anti-inflammatory role of the VN is observed using either vagal afferents, targeting the hypothalamic–pituitary–adrenal axis, or vagal efferents, targeting the cholinergic anti-inflammatory pathway. The sympathetic nervous system and the VN act in synergy, through the splenic nerve, to inhibit the release of tumor necrosis factor-alpha (TNFα) by macrophages of the peripheral tissues and the spleen. Because of its anti-inflammatory effect, the VN is a therapeutic target in the treatment of chronic inflammatory disorders where TNFα is a key component. In this review, we will focus on the anti-inflammatory role of the VN in inflammatory bowel diseases (IBD). The anti-inflammatory properties of the VN could be targeted pharmacologically, with enteral nutrition, by VN stimulation (VNS), with complementary medicines or by physical exercise. VNS is one of the alternative treatments for drug resistant epilepsy and depression and one might think that VNS could be used as a non-drug therapy to treat inflammatory disorders of the GI tract, such as IBD, irritable bowel syndrome, and postoperative ileus, which are all characterized by a blunted autonomic balance with a decreased vagal tone.
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Affiliation(s)
- Bruno Bonaz
- Division of Hepato-Gastroenterology, Grenoble University Hospital, Grenoble, Alpes, France.,U1216, INSERM, GIN, Grenoble Institute of Neurosciences, University Grenoble Alpes, Grenoble, France
| | - Valérie Sinniger
- Division of Hepato-Gastroenterology, Grenoble University Hospital, Grenoble, Alpes, France.,U1216, INSERM, GIN, Grenoble Institute of Neurosciences, University Grenoble Alpes, Grenoble, France
| | - Sonia Pellissier
- Laboratoire Inter-Universitaire de Psychologie, Personnalité, Cognition et Changement Social LIP/PC2S-EA4145, University Savoie Mont Blanc, Chambéry, France
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20
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Bonaz B, Sinniger V, Pellissier S. Vagus nerve stimulation: a new promising therapeutic tool in inflammatory bowel disease. J Intern Med 2017; 282:46-63. [PMID: 28421634 DOI: 10.1111/joim.12611] [Citation(s) in RCA: 116] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Inflammatory bowel disease (IBD), that is Crohn's disease (CD) and ulcerative colitis, affects about 1.5 million persons in the USA and 2.2 million in Europe. The pathophysiology of IBD involves immunological, genetic and environmental factors. The treatment is medico-surgical but suspensive. Anti-TNFα agents have revolutionized the treatment of IBD but have side effects. In addition, a non-negligible percentage of patients with IBD stop or take episodically their treatment. Consequently, a nondrug therapy targeting TNFα through a physiological pathway, devoid of major side effects and with a good cost-effectiveness ratio, would be of interest. The vagus nerve has dual anti-inflammatory properties through its afferent (i.e. hypothalamic-pituitary-adrenal axis) and efferent (i.e. the anti-TNFα effect of the cholinergic anti-inflammatory pathway) fibres. We have shown that there is an inverse relationship between vagal tone and plasma TNFα level in patients with CD, and have reported, for the first time, that chronic vagus nerve stimulation has anti-inflammatory properties in a rat model of colitis and in a pilot study performed in seven patients with moderate CD. Two of these patients failed to improve after 3 months of vagus nerve stimulation but five were in deep remission (clinical, biological and endoscopic) at 6 months of follow-up and vagal tone was restored. No major side effects were observed. Thus, vagus nerve stimulation provides a new therapeutic option in the treatment of CD.
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Affiliation(s)
- B Bonaz
- University Clinic of Hepato-Gastroenterology, University Hospital, Grenoble, France.,University Grenoble Alpes, Grenoble Institute of Neurosciences (GIN), Inserm (U1216), Grenoble, France
| | - V Sinniger
- University Clinic of Hepato-Gastroenterology, University Hospital, Grenoble, France.,University Grenoble Alpes, Grenoble Institute of Neurosciences (GIN), Inserm (U1216), Grenoble, France
| | - S Pellissier
- University Clinic of Hepato-Gastroenterology, University Hospital, Grenoble, France.,Laboratoire Inter-Universitaire de Psychologie, Personnalité, Cognition et Changement Social (LIP/PC2S), University Savoie Mont-Blanc, Chambéry, France
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21
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Hoover DB. Cholinergic modulation of the immune system presents new approaches for treating inflammation. Pharmacol Ther 2017; 179:1-16. [PMID: 28529069 DOI: 10.1016/j.pharmthera.2017.05.002] [Citation(s) in RCA: 207] [Impact Index Per Article: 25.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The nervous system and immune system have broad and overlapping distributions in the body, and interactions of these ubiquitous systems are central to the field of neuroimmunology. Over the past two decades, there has been explosive growth in our understanding of neuroanatomical, cellular, and molecular mechanisms that mediate central modulation of immune functions through the autonomic nervous system. A major catalyst for growth in this field was the discovery that vagal nerve stimulation (VNS) caused a prominent attenuation of the systemic inflammatory response evoked by endotoxin in experimental animals. This effect was mediated by acetylcholine (ACh) stimulation of nicotinic receptors on splenic macrophages. Hence, the circuit was dubbed the "cholinergic anti-inflammatory pathway". Subsequent work identified the α7 nicotinic ACh receptor (α7nAChR) as the crucial target for attenuation of pro-inflammatory cytokine release from macrophages and dendritic cells. Further investigation made the important discovery that cholinergic T cells within the spleen and not cholinergic nerve cells were the source of ACh that stimulated α7 receptors on splenic macrophages. Given the important role that inflammation plays in numerous disease processes, cholinergic anti-inflammatory mechanisms are under intensive investigation from a basic science perspective and in translational studies of animal models of diseases such as inflammatory bowel disease and rheumatoid arthritis. This basic work has already fostered several clinical trials examining the efficacy of VNS and cholinergic therapeutics in human inflammatory diseases. This review provides an overview of basic and translational aspects of the cholinergic anti-inflammatory response and relevant pharmacology of drugs acting at the α7nAChR.
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Affiliation(s)
- Donald B Hoover
- Department of Biomedical Sciences and Center of Excellence in Inflammation, Infectious Disease and Immunity, Quillen College of Medicine, East Tennessee State University, Johnson City, TN 37614, USA.
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22
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Finkin-Groner E, Finkin S, Zeeli S, Weinstock M. Indoline derivatives mitigate liver damage in a mouse model of acute liver injury. Pharmacol Rep 2017. [PMID: 28628850 DOI: 10.1016/j.pharep.2017.03.025] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND Exposure of mice to D-galactosamine (GalN) and lipopolysaccharide (LPS) induces acute liver failure through elevation of TNF-α, which causes liver damage resembling that in humans. The current study evaluated in this model the effect of two indoline derivatives, which have anti-inflammatory activity in macrophages. METHODS AN1297 and AN1284 (0.025-0.75mg/kg) or dexamethasone (3mg/kg), were injected subcutaneously, 15min before intraperitoneal injection of GalN (800mg) plus LPS (50μg) in male Balb/C mice. After 6h, their livers were evaluated histologically by staining with hematoxylin and eosin for tissue damage and by cleaved caspase 3 for apoptosis. Activity of liver enzymes, alanine transaminase (ALT) and aspartate aminotransferase (AST) and levels of TNF-α and IL-6 were measured in plasma, and those of TNF-α and IL-6, in the liver. RESULTS AN1297 (0.075-0.75mg/kg) and AN1284 (0.25-0.75mg/kg) maximally reduced ALT by 51% and 80%, respectively. Only AN1284 (0.25 and 0.75mg/kg) reduced AST by 41% and 48%. AN1297 and AN1284 (0.25mg/kg) decreased activation of caspase 3 (a sign of apoptosis) by 80% and plasma TNF-α by 75%. AN1297 and AN1284 (0.075mg/kg) prevented the rise in TNF-α and IL-6 in the liver. AN1284 (0.25mg/kg) reduced mortality from 90% to 20% (p<0.01) and AN1297, to 60% (p=0.121). Both indoline derivatives inhibited the phosphorylation of MAPK p38 and DNA binding of the transcription factor, AP-1. CONCLUSION While both compounds are highly potent anti-inflammatory agents, AN1284 is more effective in mitigating the underlying causes of GalN/LPS-induced acute liver failure in mice.
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Affiliation(s)
- Efrat Finkin-Groner
- Institute of Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Shlomi Finkin
- Department of Immunology and Cancer Research, Institute for Medical Research Israel Canada, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Shani Zeeli
- Department of Chemistry, Bar Ilan University, Ramat Gan, Israel
| | - Marta Weinstock
- Institute of Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, Jerusalem, Israel.
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23
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Shifrin H, Mouhadeb O, Gluck N, Varol C, Weinstock M. Cholinergic Anti-Inflammatory Pathway Does Not Contribute to Prevention of Ulcerative Colitis by Novel Indoline Carbamates. J Neuroimmune Pharmacol 2017; 12:484-491. [PMID: 28271317 DOI: 10.1007/s11481-017-9735-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2016] [Accepted: 02/28/2017] [Indexed: 12/27/2022]
Abstract
Indoline carbamates, AN680 and AN917 decrease cytokines, TNF-α and IL-6 in peritoneal macrophages activated by lipopolysaccharide (LPS) and in mouse tissues after LPS injection. They prevent nuclear translocation of nuclear factor κB (NF-κB) and activator protein 1. Only AN917 inhibits cholinesterase (ChE) at relevant concentrations. ChE inhibitors decrease NF-κB by activating α7 nicotinic acetylcholine receptors (α7nAChR). The current study compared the effect of rivastigmine, a ChE inhibitor, AN680 and AN917 on ulcerative colitis induced in mice by ingestion of dextran sodium sulfate (4.5%) solution. Rivastigmine (1 mg/kg), AN680 (2.5-10 mg/kg) and AN917 (2-5 mg/kg) were injected subcutaneously once daily for 8 days. Disease severity was assessed by disease activity index (DAI), colonoscopy, colon length and body weight loss, colonic levels of TNF-α, IL-6, IL-1β and myeloid peroxidase (MPO) activity. AN680 (5 mg/kg) reduced DAI, colon shrinkage, weight loss, histopathological signs of colon damage, MPO activity, TNF-α, IL-1β and IL-6 levels without inhibiting ChE. AN917 (5 mg/kg) and rivastigmine (1 mg/kg) inhibited ChE in plasma and colon by 65%, reduced DAI, MPO activity and IL-6, but not TNF-α or IL-1β. AN917 did not prevent weight loss or colon shrinkage. Mecamylamine abolished the reduction of DAI, MPO activity and IL-6 by AN917 and rivastigmine, indicating they were mediated by α7nAChR. CONCLUSIONS AN680 is very effective in preventing DSS-induced UC in mice and may therefore have potential therapeutic application in humans. Addition of ChE inhibition and indirect activation of α7nAChR lessens the efficacy of AN917 in this model.
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Affiliation(s)
- Helena Shifrin
- Institute of Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Odelia Mouhadeb
- Research Centre for Digestive Tract and Liver Diseases, Tel Aviv-Sourasky Medical Centre and Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Nathan Gluck
- Research Centre for Digestive Tract and Liver Diseases, Tel Aviv-Sourasky Medical Centre and Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Chen Varol
- Research Centre for Digestive Tract and Liver Diseases, Tel Aviv-Sourasky Medical Centre and Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Marta Weinstock
- Institute of Drug Research, The Hebrew University of Jerusalem, Jerusalem, Israel.
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24
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Liu GX, Gan HT. Effect of enteric nervous system on intestinal epithelial barrier in inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2017; 25:107-113. [DOI: 10.11569/wcjd.v25.i2.107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Both enteric nervous system and intestinal epithelial barrier are vital components to ensure gut homeostasis. Recent studies have shown the implications of their close relationship for gut health and disease. By secreting neurotransmitters, the enteric nervous system plays an important role in regulating the epithelial barrier function. Meanwhile, communicating largely through the vagal nerve, the central nervous system could also interact with the intestinal epithelium through the enteric nervous system. Although the etiology and pathogenesis of inflammatory bowel disease remain elusive, increasing evidence has shown that the dysregulation of enteric nervous system affects both epithelial integrity and barrier function, which contributes to the occurrence and development of inflammatory bowel disease. This review will summarize the current knowledge regarding the effect of enteric nervous system on intestinal epithelial barrier and its implication in the development of inflammatory bowel disease.
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25
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Abstract
Research during the last decade has significantly advanced our understanding of the molecular mechanisms at the interface between the nervous system and the immune system. Insight into bidirectional neuro-immune communication has characterized the nervous system as an important partner of the immune system in the regulation of inflammation. Neuronal pathways, including the vagus nerve-based inflammatory reflex, are physiological regulators of immune function and inflammation. In parallel, neuronal function is altered in conditions characterized by immune dysregulation and inflammation. Here, we review these regulatory mechanisms and describe the neural circuitry modulating immunity. Understanding these mechanisms reveals possibilities to use targeted neuromodulation as a therapeutic approach for inflammatory and autoimmune disorders. These findings and current clinical exploration of neuromodulation in the treatment of inflammatory diseases define the emerging field of Bioelectronic Medicine.
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Affiliation(s)
- Valentin A Pavlov
- Center for Biomedical Science, The Feinstein Institute for Medical Research, 350 Community Dr, Manhasset, NY, 11030, USA.
| | - Kevin J Tracey
- Center for Biomedical Science, The Feinstein Institute for Medical Research, 350 Community Dr, Manhasset, NY, 11030, USA.
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26
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Goverse G, Stakenborg M, Matteoli G. The intestinal cholinergic anti-inflammatory pathway. J Physiol 2016; 594:5771-5780. [PMID: 26959627 DOI: 10.1113/jp271537] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Accepted: 03/02/2016] [Indexed: 01/10/2023] Open
Abstract
The main task of the immune system is to distinguish and respond accordingly to 'danger' or 'non-danger' signals. This is of critical importance in the gastrointestinal tract in which immune cells are constantly in contact with food antigens, symbiotic microflora and potential pathogens. This complex mixture of food antigens and symbionts are essential for providing vital nutrients, so they must be tolerated by the intestinal immune system to prevent aberrant inflammation. Therefore, in the gut the balance between immune activation and tolerance should be tightly regulated to maintain intestinal homeostasis and to prevent hypersensitivity to harmless luminal antigens. Loss of this delicate equilibrium can lead to abnormal activation of the intestinal immune system resulting in devastating gastrointestinal disorders such as inflammatory bowel disease (IBD). Recent evidence supports the idea that the central nervous system interacts dynamically via the vagus nerve with the intestinal immune system to modulate inflammation through humoral and neural pathways, using a mechanism also referred to as the intestinal cholinergic anti-inflammatory pathway. In this review, we will focus on the current understanding of the mechanisms and neuronal circuits involved in the intestinal cholinergic anti-inflammatory pathway. Further investigation on the crosstalk between the nervous and intestinal immune system will hopefully provide new insights leading to the identification of innovative therapeutic approaches to treat intestinal inflammatory diseases.
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Affiliation(s)
- Gera Goverse
- Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Michelle Stakenborg
- Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium
| | - Gianluca Matteoli
- Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium.
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27
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Bertrand D, Lee CHL, Flood D, Marger F, Donnelly-Roberts D. Therapeutic Potential of α7 Nicotinic Acetylcholine Receptors. Pharmacol Rev 2015; 67:1025-73. [DOI: 10.1124/pr.113.008581] [Citation(s) in RCA: 108] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
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28
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Alterations in the distal colon innervation in Winnie mouse model of spontaneous chronic colitis. Cell Tissue Res 2015; 362:497-512. [PMID: 26227258 DOI: 10.1007/s00441-015-2251-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2015] [Accepted: 06/29/2015] [Indexed: 12/19/2022]
Abstract
The gastrointestinal tract is innervated by extrinsic sympathetic, parasympathetic and sensory nerve fibers as well as by intrinsic fibers from the neurons in myenteric and submucosal ganglia embedded into the gastrointestinal wall. Morphological and functional studies of intestinal innervation in animal models are important for understanding the pathophysiology of inflammatory bowel disease (IBD). The recently established Winnie mouse model of spontaneous chronic colitis caused by a point mutation in the Muc2 mucin gene develops inflammation due to a primary epithelial defect. Winnie mice display symptoms of diarrhea, ulcerations and rectal bleeding similar to those in IBD. In this study, we investigated myenteric neurons, noradrenergic, cholinergic and sensory nerve fibers in the distal colon of Winnie (Win/Win) mice compared to C57/BL6 and heterozygote littermates (Win/Wt) using histological and immunohistochemical methods. All Win/Win mice used in this study had inflammation with signs of mucosal damage, goblet cell loss, thickening of muscle and mucosal layers, and increased CD45-immunoreactivity in the distal colon. The density of sensory, cholinergic and noradrenergic fibers innervating the myenteric plexus, muscle and mucosa significantly decreased in the distal colon of Win/Win mice compared to C57/BL6 and Win/Wt mice, while the total number of myenteric neurons as well as subpopulations of cholinergic and nitrergic neurons remained unchanged. In conclusion, changes in the colon morphology and innervation found in Winnie mice have multiple similarities with changes observed in patients with ulcerative colitis.
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Li MJ, Niu JK, Miao YL. Relationship between brain-gut axis and inflammatory bowel disease. Shijie Huaren Xiaohua Zazhi 2015; 23:1097-1103. [DOI: 10.11569/wcjd.v23.i7.1097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is a chronic relapsing inflammatory disease affecting the gastrointestinal tract. The incidence of IBD has increased dramatically year by year in China. Currently, the IBD research is focused on genetically predisposed factors, immune response, environmental triggers and infections. However, the etiology of IBD is still unclear. Recently, more attention has been paid to the research of neural regulation affecting the progression of IBD. Previous research has revealed that psycho-neuro-endocrine-immune modulation through the brain-gut axis plays a crucial role in the pathogenesis of IBD. It is important to explore other psychotherapies applied to adjutant therapy in IBD. This review reviews the recent advances in understanding the relationship between the brain-gut axis and inflammatory bowel disease.
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Viana-Cardoso KV, Silva MTB, Peixoto-Junior AA, Marinho LS, Matias NS, Soares PMG, Santos AA, Brito GAC, Rola FH, Gondim FDAA. Sensory and inflammatory colonic changes induced by vincristine in distinct rat models of colitis. ACTA ACUST UNITED AC 2015; 34:27-34. [DOI: 10.1111/aap.12020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Revised: 06/15/2012] [Accepted: 09/01/2012] [Indexed: 12/30/2022]
Affiliation(s)
- K. V. Viana-Cardoso
- Curso de Fisioterapia; Universidade Federal do Ceará; 949 Alexandre Baraúna street, Rodolfo Teófilo 60430-160 Fortaleza Ceará Brasil
| | - M. T. B. Silva
- Departamento de Fisiologia e Farmacologia; Faculdade de Medicina; Universidade Federal do Ceará; 1127, Cel. Nunes de Melo street, Rodolfo Teófilo 60430-270 Fortaleza Ceará Brasil
| | - A. A. Peixoto-Junior
- Departamento de Fisiologia e Farmacologia; Faculdade de Medicina; Universidade Federal do Ceará; 1127, Cel. Nunes de Melo street, Rodolfo Teófilo 60430-270 Fortaleza Ceará Brasil
- Hospital Universitário Walter Cantídio; Universidade Federal do Ceará; 1290, Capitão Francisco Pedro street, Rodolfo Teófilo 60430-370 Fortaleza Ceará Brasil
| | - L. S. Marinho
- Departamento de Fisiologia e Farmacologia; Faculdade de Medicina; Universidade Federal do Ceará; 1127, Cel. Nunes de Melo street, Rodolfo Teófilo 60430-270 Fortaleza Ceará Brasil
| | - N. S. Matias
- Departamento de Fisiologia e Farmacologia; Faculdade de Medicina; Universidade Federal do Ceará; 1127, Cel. Nunes de Melo street, Rodolfo Teófilo 60430-270 Fortaleza Ceará Brasil
| | - P. M. G. Soares
- Departamento de Morfologia; Faculdade de Medicina; Universidade Federal do Ceará; Delmiro de Farias street, Rodolfo Teófilo 60416-030 Fortaleza Ceará Brasil
| | - A. A. Santos
- Departamento de Fisiologia e Farmacologia; Faculdade de Medicina; Universidade Federal do Ceará; 1127, Cel. Nunes de Melo street, Rodolfo Teófilo 60430-270 Fortaleza Ceará Brasil
| | - G. A. C. Brito
- Departamento de Morfologia; Faculdade de Medicina; Universidade Federal do Ceará; Delmiro de Farias street, Rodolfo Teófilo 60416-030 Fortaleza Ceará Brasil
| | - F. H. Rola
- Departamento de Fisiologia e Farmacologia; Faculdade de Medicina; Universidade Federal do Ceará; 1127, Cel. Nunes de Melo street, Rodolfo Teófilo 60430-270 Fortaleza Ceará Brasil
| | - F. de A. A. Gondim
- Departamento de Medicina Clínica; Divisão de Neurologia; Faculdade de Medicina; Universidade Federal do Ceará; 1608, Prof. Costa Mendstreet 4th Floor, Rodolfo Teófilo 60430-140 Fortaleza Ceará Brasil
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Levine YA, Koopman F, Faltys M, Zitnik R, Tak PP. Neurostimulation of the Cholinergic Antiinflammatory Pathway in Rheumatoid Arthritis and Inflammatory Bowel Disease. Bioelectron Med 2014. [DOI: 10.15424/bioelectronmed.2014.00008] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
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Özyurt H, Özden AS, Çevik Ö, Özgen Z, Cadirci S, Elmas MA, Ercan F, Şener G, Gören MZ. Investigation into the role of the cholinergic system in radiation-induced damage in the rat liver and ileum. JOURNAL OF RADIATION RESEARCH 2014; 55:866-75. [PMID: 24914105 PMCID: PMC4202297 DOI: 10.1093/jrr/rru039] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
It has been previously shown that acetylcholine (ACh) may affect pro-inflammatory and anti-inflammatory cytokines. The role of the cholinergic system in radiation-induced inflammatory responses and tissue damage remains unclear. Therefore, the present study was designed to determine the radio-protective properties of the cholinergic system in the ileum and the liver of rats. Rats were exposed to 8-Gy single-fraction whole-abdominal irradiation and were then decapitated at either 36 h or 10 d post-irradiation. The rats were treated either with intraperitoneal physiological saline (1 ml/kg), physostigmine (80 µg/kg) or atropine (50 μg/kg) twice daily for 36 h or 10 d. Cardiac blood samples and liver and ileal tissues were obtained in which TNF-α, IL-1β and IL-10 levels were assayed using ELISA. In the liver and ileal homogenates, caspase-3 immunoblots were performed and myeloperoxidase (MPO) activity was analyzed. Plasma levels of IL-1β and TNF-α increased significantly following radiation (P < 0.01 and P < 0.001, respectively) as compared with non-irradiated controls, and physostigmine treatment prevented the increase in the pro-inflammatory cytokines (P < 0.01 and P < 0.001, respectively). Plasma IL-10 levels were not found to be significantly changed following radiation, whereas physostigmine augmented IL-10 levels during the late phase (P < 0.01). In the liver and ileum homogenates, IL-1β and TNF-α levels were also elevated following radiation, and this effect was inhibited by physostigmine treatment but not by atropine. Similarly, physostigmine also reversed the changes in MPO activity and in the caspase-3 levels in the liver and ileum. Histological examination revealed related changes. Physostigmine experiments suggested that ACh has a radio-protective effect not involving the muscarinic receptors.
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Affiliation(s)
- Hazan Özyurt
- Dr Lutfi Kirdar Kartal Training and Research Hospital, Radiation Oncology, 34865 Istanbul, Turkey
| | - A Sevgi Özden
- Dr Lutfi Kirdar Kartal Training and Research Hospital, Radiation Oncology, 34865 Istanbul, Turkey
| | - Özge Çevik
- Cumhuriyet University School of Pharmacy, Department of Biochemistry, 58140 Sivas, Turkey
| | - Zerrin Özgen
- Marmara University Pendik Training and Research Hospital, Radiation Oncology, Üst Kaynarca, Istanbul, Turkey
| | - Selin Cadirci
- Marmara University School of Pharmacy, Pharmacology, 34668 Istanbul, Turkey
| | - Merve Açıkel Elmas
- Marmara University School of Medicine, Department of Histology and Embryology, Başıbüyük Health Campus, Basic Medical Sciences Building, Başıbüyük, Maltepe, 34854 Istanbul, Turkey
| | - Feriha Ercan
- Marmara University School of Medicine, Department of Histology and Embryology, Başıbüyük Health Campus, Basic Medical Sciences Building, Başıbüyük, Maltepe, 34854 Istanbul, Turkey
| | - Göksel Şener
- Marmara University School of Pharmacy, Pharmacology, 34668 Istanbul, Turkey
| | - M Z Gören
- Marmara University School of Medicine, Department of Medical Pharmacology, Başıbüyük Health Campus, Basic Medical Sciences Building, Başıbüyük, Maltepe, 34854 Istanbul, Turkey
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Central cholinergic activation of a vagus nerve-to-spleen circuit alleviates experimental colitis. Mucosal Immunol 2014; 7:335-47. [PMID: 23881354 PMCID: PMC3859808 DOI: 10.1038/mi.2013.52] [Citation(s) in RCA: 144] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Accepted: 06/20/2013] [Indexed: 02/04/2023]
Abstract
The cholinergic anti-inflammatory pathway is an efferent vagus nerve-based mechanism that regulates immune responses and cytokine production through α7 nicotinic acetylcholine receptor (α7nAChR) signaling. Decreased efferent vagus nerve activity is observed in inflammatory bowel disease. We determined whether central activation of this pathway alters inflammation in mice with colitis and the mediating role of a vagus nerve-to-spleen circuit and α7nAChR signaling. Two experimental models of colitis were used in C57BL/6 mice. Central cholinergic activation induced by the acetylcholinesterase inhibitor galantamine or a muscarinic acetylcholine receptor agonist treatments resulted in reduced mucosal inflammation associated with decreased major histocompatibility complex II level and pro-inflammatory cytokine secretion by splenic CD11c⁺ cells mediated by α7nAChR signaling. The cholinergic anti-inflammatory efficacy was abolished in mice with vagotomy, splenic neurectomy, or splenectomy. In conclusion, central cholinergic activation of a vagus nerve-to-spleen circuit controls intestinal inflammation and this regulation can be explored to develop novel therapeutic strategies.
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Fichna J, Lapointe T, Chapman K, Janecka A, Vergnolle N, Altier C, Storr MA. New neostigmine-based behavioral mouse model of abdominal pain. Pharmacol Rep 2013; 64:1146-54. [PMID: 23238471 DOI: 10.1016/s1734-1140(12)70911-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2011] [Revised: 05/11/2012] [Indexed: 11/29/2022]
Abstract
BACKGROUND Animal models of visceral pain have gained much attention as an important tool to elucidate the possible mechanisms underlying functional gastrointestinal (GI) disorders. Here we report the development of a new, minimally invasive behavioral model of abdominal pain induced by ip administration of neostigmine in mice. METHODS Spontaneous behavioral responses evoked by ip injection of neostigmine were compared to pain-related behaviors induced by acetic acid solution (ip), mustard oil (MO) and capsaicin (both ic). Pain behaviors were quantified by assessment of defined postures (licking of the abdomen, stretching, squashing of the abdomen and abdominal contractions). Neuronal activation of spinal cord was measured by determining the number of c-Fos-positive cells. RESULTS Neostigmine (2.5 μg/kg, ip), acetic acid solution (ip), MO and capsaicin (both ic) induced spontaneous behavioral responses in mice, which were blocked by morphine (3 mg/kg, ip), suggesting the involvement of pain signaling pathways. Injection of neostigmine enhanced c-Fos expression in spinal cord neurons. CONCLUSION The neostigmine model represents a new minimally invasive mouse model to study visceral pain. Based on the neuronal activation pattern in the spinal cord we suggest that this model may be used to study abdominal pain signaling pathways in the GI tract.
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Affiliation(s)
- Jakub Fichna
- Snyder Institute for Chronic Diseases, Division of Gastroenterology, Department of Medicine, University of Calgary, Calgary, AB, Canada
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Abstract
The central nervous system interacts dynamically with the immune system to modulate inflammation through humoral and neural pathways. Recently, in animal models of sepsis, the vagus nerve (VN) has been proposed to play a crucial role in the regulation of the immune response, also referred to as the cholinergic anti-inflammatory pathway. The VN, through release of acetylcholine, dampens immune cell activation by interacting with α-7 nicotinic acetylcholine receptors. Recent evidence suggests that the vagal innervation of the gastrointestinal tract also plays a major role controlling intestinal immune activation. Indeed, VN electrical stimulation potently reduces intestinal inflammation restoring intestinal homeostasis, whereas vagotomy has the reverse effect. In this review, we will discuss the current understanding concerning the mechanisms and effects involved in the cholinergic anti-inflammatory pathway in the gastrointestinal tract. Deeper investigation on this counter-regulatory neuroimmune mechanism will provide new insights in the cross-talk between the nervous and immune system leading to the identification of new therapeutic targets to treat intestinal immune disease.
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Affiliation(s)
- Gianluca Matteoli
- Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Herestraat 49, Leuven 3000, Belgium.
| | - Guy E Boeckxstaens
- Department of Clinical and Experimental Medicine, Translational Research Center for Gastrointestinal Disorders (TARGID), University of Leuven, Leuven, Belgium,Department of Clinical and Experimental Medicine, University Hospital Leuven, University of Leuven, Leuven, Belgium
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Bonaz B, Picq C, Sinniger V, Mayol JF, Clarençon D. Vagus nerve stimulation: from epilepsy to the cholinergic anti-inflammatory pathway. Neurogastroenterol Motil 2013; 25:208-21. [PMID: 23360102 DOI: 10.1111/nmo.12076] [Citation(s) in RCA: 210] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND The brain and the gut communicate bidirectionally through the autonomic nervous system (ANS). The vagus nerve (VN), a major component of the ANS, plays a key role in the neuro-endocrine-immune axis to maintain homeostasia through its afferents (through the activation of the hypothalamic pituitary adrenal axis and the central ANS) and through its efferents (i.e. the cholinergic anti-inflammatory pathway; CAP). The CAP has an anti-TNF effect both through the release of acetylcholine at the distal VN acting on macrophages and through the connection of the VN with the spleen through the splenic sympathetic nerve. Vagus nerve stimulation (VNS) of vagal afferents at high frequency (20-30 Hz) is used for the treatment of drug-resistant epilepsy and depression. Low-frequency (5 Hz) VNS of vagal efferents activates the CAP for an anti-inflammatory effect that is as an anti-TNF therapy in inflammatory diseases were TNF is a key cytokine as represented by experimental sepsis, postoperative ileus, burn-induced intestinal barrier injury, colitis. However, both vagal afferents and efferents are activated by VNS. PURPOSE The objective of this review was to explore the following: (i) the supporting evidence for the importance of VNS in epilepsy (and depression) and its mechanisms of action, (ii) the anti-inflammatory characteristics of the VN, (iii) the experimental evidence that VNS impact on inflammatory disorders focusing on the digestive tract, and (iv) how VNS could potentially be harnessed therapeutically in human inflammatory disorders such as inflammatory bowel diseases, irritable bowel syndrome, postoperative ileus, rheumatoid arthritis as an anti-inflammatory therapy.
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Affiliation(s)
- B Bonaz
- Clinique Universitaire d'Hépato-Gastroentérologie, CHU de Grenoble, Grenoble Cedex, France.
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Rivastigmine alleviates experimentally induced colitis in mice and rats by acting at central and peripheral sites to modulate immune responses. PLoS One 2013; 8:e57668. [PMID: 23469045 PMCID: PMC3585220 DOI: 10.1371/journal.pone.0057668] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2012] [Accepted: 01/24/2013] [Indexed: 01/14/2023] Open
Abstract
The cholinergic anti-inflammatory system and α7 nicotinic receptors in macrophages have been proposed to play a role in neuroimmunomodulation and in the etiology of ulcerative colitis. We investigated the ability of a cholinesterase (ChE) inhibitor rivastigmine, to improve the pathology of ulcerative colitis by increasing the concentration of extracellular acetylcholine in the brain and periphery. In combination with carbachol (10 µM), rivastigmine (1 µM) significantly decreased the release of nitric oxide, TNF-α, IL-1β and IL-6 from lipopolysaccharide-activated RAW 264.7 macrophages and this effect was abolished by α7 nicotinic receptor blockade by bungarotoxin. Rivastigmine (1 mg/kg) but not (0.5 mg/kg), injected subcutaneously once daily in BALB/c mice with colitis induced by 4% dextran sodium sulphate (DSS), reduced the disease activity index (DAI) by 60% and damage to colon structure. Rivastigmine (1 mg/kg) also reduced myeloperoxidase activity and IL-6 by >60%, and the infiltration of CD11b expressing cells by 80%. These effects were accompanied by significantly greater ChE inhibition in cortex, brain stem, plasma and colon than that after 0.5 mg/kg. Co-administration of rivastigmine (1 mg/kg) with the muscarinic antagonist scopolamine significantly increased the number of CD11b expressing cells in the colon but did not change DAI compared to those treated with rivastigmine alone. Rivastigmine 1 and 2 mg given rectally to rats with colitis induced by rectal administration of 30 mg dintrobezene sulfonic acid (DNBS) also caused a dose related reduction in ChE activity in blood and colon, the number of ulcers and area of ulceration, levels of TNF-α and in MPO activity. The study revealed that the ChE inhibitor rivastigmine is able to reduce gastro-intestinal inflammation by actions at various sites at which it preserves ACh. These include ACh released from vagal nerve endings that activates alpha7 nicotinic receptors on circulating macrophages and in brainstem neurons.
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Boeckxstaens G. The clinical importance of the anti-inflammatory vagovagal reflex. HANDBOOK OF CLINICAL NEUROLOGY 2013; 117:119-34. [PMID: 24095121 DOI: 10.1016/b978-0-444-53491-0.00011-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Excessive activation of the immune system is prevented by anti-inflammatory mediators such as corticosteroids and anti-inflammatory cytokines. Recently, it became clear that the brain not only senses peripheral inflammation through vagal afferent nerve fibers, but also provides an integrated response dampening the immune system through vagal efferents. This so-called anti-inflammatory pathway has been introduced as a third system by which the immune system is modulated. In sepsis, the anti-inflammatory effect is mediated by modulation of splenic macrophages, whereas in the gut, vagal nerve fibers synapse with enteric cholinergic neurons interacting with resident intestinal macrophages. In this chapter, the preclinical data underscoring the importance of this pathway are summarized, and its clinical significance is reviewed. Finally, the current data supporting its relevance to human disease and its therapeutic potential will be discussed. Insight in the mechanisms underlying these crucial properties will lead to better understanding of immune-mediated diseases and ultimately to improved anti-inflammatory therapies.
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Affiliation(s)
- G Boeckxstaens
- Department of Gastroenterology, University Hospital Leuven, University of Leuven, Leuven, Belgium.
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Katiraei P, Bultron G. Need for a comprehensive medical approach to the neuro-immuno-gastroenterology of irritable bowel syndrome. World J Gastroenterol 2011; 17:2791-800. [PMID: 21734786 PMCID: PMC3120938 DOI: 10.3748/wjg.v17.i23.2791] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2010] [Revised: 03/08/2011] [Accepted: 03/15/2011] [Indexed: 02/06/2023] Open
Abstract
Irritable bowel syndrome (IBS) is defined by the Rome III criteria as symptoms of recurrent abdominal pain or discomfort with the onset of a marked change in bowel habits with no evidence of an inflammatory, anatomic, metabolic, or neoplastic process. As such, many clinicians regard IBS as a central nervous system problem of altered pain perception. Here, we review the recent literature and discuss the evidence that supports an organic based model, which views IBS as a complex, heterogeneous, inter-dependent, and multi-variable inflammatory process along the neuronal-gut axis. We delineate the organic pathophysiology of IBS, demonstrate the role of inflammation in IBS, review the possible differences between adult and pediatric IBS, discuss the merits of a comprehensive treatment model as taught by the Institute of Functional Medicine, and describe the potential for future research for this syndrome.
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Meregnani J, Clarençon D, Vivier M, Peinnequin A, Mouret C, Sinniger V, Picq C, Job A, Canini F, Jacquier-Sarlin M, Bonaz B. Anti-inflammatory effect of vagus nerve stimulation in a rat model of inflammatory bowel disease. Auton Neurosci 2010; 160:82-9. [PMID: 21071287 DOI: 10.1016/j.autneu.2010.10.007] [Citation(s) in RCA: 215] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2010] [Revised: 10/07/2010] [Accepted: 10/15/2010] [Indexed: 01/26/2023]
Abstract
Vagus nerve stimulation of afferents is used as an adjunctive treatment for drug-resistant epilepsy and depression. In addition, anti-inflammatory properties of vagus nerve stimulation have been reported in various experimental models of inflammation but not in colitis. These effects are thought to be mediated via peripheral release of acetylcholine from the vagus and subsequent activation of macrophages. Our aim was to evaluate in rats the anti-inflammatory effects of chronic vagus nerve stimulation on colonic inflammation. Colitis was induced by intracolonic instillation of trinitrobenzene sulfonic acid. Vagus nerve stimulation (left cervical) was performed in freely moving animals 3 h per day for five consecutive days. Assessment of colonic inflammation was obtained using physiological (e.g. body weight, temperature and locomotor activity) parameters, macroscopical (area of lesions), histological, and biological parameters (e.g. myeloperoxidase activity, cytokine and cytokine-related mRNAs), both at the level of the damaged colon and the colon immediately above. A global multivariate index of colitis was then generated for a better characterization of colonic inflammation. Vagus nerve stimulation reduced the degree of body weight loss and inflammatory markers as observed above the lesion by histological score and myeloperoxidase quantification. This anti-inflammatory effect was also demonstrated by the improvement of the multivariate index of colitis. These data argue for an anti-inflammatory role of vagus nerve stimulation chronically performed in freely moving rats with colitis and provide potential therapeutic applications for patients with inflammatory bowel diseases.
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Affiliation(s)
- J Meregnani
- Stress et Interactions Neuro-Digestives, Grenoble Institut des Neurosciences, INSERM U UJF-CEA-CHU, Université Joseph Fourier, France
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Bencherif M, Lippiello PM, Lucas R, Marrero MB. Alpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases. Cell Mol Life Sci 2010; 68:931-49. [PMID: 20953658 DOI: 10.1007/s00018-010-0525-1] [Citation(s) in RCA: 150] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2010] [Revised: 08/24/2010] [Accepted: 08/30/2010] [Indexed: 12/19/2022]
Abstract
In recent years the etiopathology of a number of debilitating diseases such as type 2 diabetes, arthritis, atherosclerosis, psoriasis, asthma, cystic fibrosis, sepsis, and ulcerative colitis has increasingly been linked to runaway cytokine-mediated inflammation. Cytokine-based therapeutic agents play a major role in the treatment of these diseases. However, the temporospatial changes in various cytokines are still poorly understood and attempts to date have focused on the inhibition of specific cytokines such as TNF-α. As an alternative approach, a number of preclinical studies have confirmed the therapeutic potential of targeting alpha7 nicotinic acetylcholine receptor-mediated anti-inflammatory effects through modulation of proinflammatory cytokines. This "cholinergic anti-inflammatory pathway" modulates the immune system through cholinergic mechanisms that act on alpha7 receptors expressed on macrophages and immune cells. If the preclinical findings translate into human efficacy this approach could potentially provide new therapies for treating a broad array of intractable diseases and conditions with inflammatory components.
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Abstract
OBJECTIVE Lethal sepsis occurs when an excessive inflammatory response evolves that cannot be controlled by physiologic anti-inflammatory mechanisms, such as the recently described cholinergic anti-inflammatory pathway. Here we studied whether the cholinergic anti-inflammatory pathway can be activated by pharmacologic cholinesterase inhibition in vivo. DESIGN Prospective, randomized laboratory investigation that used an established murine sepsis model. SETTING Research laboratory in a university hospital. SUBJECTS Female C57BL/6 mice. INTERVENTIONS Sepsis in mice was induced by cecal ligation and puncture. Animals were treated immediately with intraperitoneal injections of nicotine (400 microg/kg), physostigmine (80 microg/kg), neostigmine (80 microg/kg), or solvent three times daily for 3 days. MEASUREMENTS AND MAIN RESULTS Treatment with physostigmine significantly reduced lethality (p < or = .01) as efficiently as direct stimulation of the cholinergic anti-inflammatory pathway with nicotine (p < or = .05). Administration of cholinesterase inhibitors significantly down-regulated the binding activity of nuclear factor-kappaB (p < or = .05) and significantly reduced the concentration of circulating proinflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and interleukin-6 (p < or = .001), and pulmonary neutrophil invasion (p < or = .05). Animals treated with the peripheral cholinesterase inhibitor neostigmine showed no difference compared with physostigmine-treated animals. CONCLUSIONS Our results demonstrate that cholinesterase inhibitors can be used successfully in the treatment of sepsis in a murine model and may be of interest for clinical use.
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Bai A, Guo Y, Lu N. The effect of the cholinergic anti-inflammatory pathway on experimental colitis. Scand J Immunol 2007; 66:538-45. [PMID: 17953529 DOI: 10.1111/j.1365-3083.2007.02011.x] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Inflammatory bowel diseases (IBD) are characterized by proinflammatory cytokines, tissue damage and loss of neuron in inflamed mucosa, which implies the cholinergic anti-inflammatory pathway may be destroyed during the process of inflammatory response. In the study, we identified the effect of cholinergic agonist as anabaseine (AN) and nicotinic receptor antagonist as chlorisondamine diiodide (CHD) on trinitrobenzene sulfonic acid (TNBS)-induced colitis, to investigate the potential therapeutic effect of the cholinergic anti-inflammatory pathway on IBD. Experimental colitis was induced by TNBS at day 1, 10 mug AN or 1.5 mug CHD was injected i.p. to mouse right after the induction of colitis, and repeated on interval day till the mice were sacrificed at day 8. Colonic inflammation was examined by histological analysis, myeloperoxidase (MPO) activity, and the production of tumour necrosis factor (TNF)-alpha in tissue. Lamina propria mononuclear cells (LPMC) were isolated, and NF-kappaB activation was detected by western blot. The mice with colitis treated by AN showed less tissue damage, less MPO activity, less TNF-alpha production in colon, and inhibited NF-kappaB activation in LPMC, compared with those mice with colitis untreated, whereas the mice with colitis treated by CHD showed the worst tissue damage, the highest MPO activity, the highest TNF-alpha level, and enlarged NF-kappaB activation in LPMC. Agonist of the cholinergic anti-inflammatory pathway inhibits colonic inflammatory response by downregulating the production of TNF-alpha, and inhibiting NF-kappaB activation, which suggests that modulating the cholinergic anti-inflammatory pathway may be a new potential management for IBD.
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Affiliation(s)
- A Bai
- Department of Gastroenterology, the First Affiliated Hospital, Nanchang University, Nanchang City, China
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Coruzzi P, Castiglioni P, Parati G, Brambilla V, Brambilla L, Gualerzi M, Cademartiri F, Franzè A, De Angelis G, Di Rienzo M, Di Mario F. Autonomic cardiovascular regulation in quiescent ulcerative colitis and Crohn's disease. Eur J Clin Invest 2007; 37:964-70. [PMID: 18036030 DOI: 10.1111/j.1365-2362.2007.01887.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND In inflammatory bowel diseases, changes in autonomic enteric regulation may also affect neural cardiovascular control. However, while cardiac autonomic modulation has been shown to be impaired in active ulcerative colitis, the occurrence of cardiovascular autonomic alterations, also in the quiescent phase of inflammatory bowel diseases, is still a matter of debate. The aim of our study was thus to explore the features of cardiovascular autonomic regulation in ulcerative colitis and Crohn's disease during their remission phase. MATERIALS AND METHODS Autonomic cardiovascular control was evaluated by time- and frequency-domain indexes of spontaneous heart rate and blood pressure variability and by assessing the baroreflex heart rate control (sequence technique) in 26 patients with ulcerative colitis, in 26 patients with Crohn's disease and in 23 healthy controls. RESULTS The groups were matched for age, gender and body mass index. They had similar blood pressure mean levels and variability. By contrast, mean heart rate, its overall variability (standard deviation), and baroreflex sensitivity were lower in ulcerative colitis patients than in controls. Moreover, all indexes related to cardiac vagal control were significantly lower in ulcerative colitis patients with respect not only to controls but also to Crohn's disease patients. CONCLUSIONS Cardiac vagal control is impaired in quiescent ulcerative colitis only, and not in Crohn's disease, while in both bowel diseases vascular control appears preserved. Since cardiovagal modulation seems related to anti-inflammatory mechanisms, the reduced parasympathetic cardiac regulation in apparently quiescent ulcerative colitis suggests that such systemic derangement is accompanied by local subclinical inflammations, even in the absence of clinically active inflammatory processes.
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Affiliation(s)
- P Coruzzi
- University of Parma, Department of Radiology, Azienda Ospedaliero-Universitaria Parma, Italy.
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Taylor CT, Keely SJ. The autonomic nervous system and inflammatory bowel disease. Auton Neurosci 2007; 133:104-14. [PMID: 17234460 DOI: 10.1016/j.autneu.2006.11.005] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2006] [Revised: 10/19/2006] [Indexed: 12/22/2022]
Abstract
Crohn's disease and ulcerative colitis, collectively known as inflammatory bowel disease (IBD), are chronic, recurring, inflammatory conditions of the intestine. The precise mechanisms underlying the pathogenesis of IBD are not yet clear but they are believed to involve a number of precipitating factors, most notably genetic susceptibility and environmental influences. The autonomic nervous system (ANS) has long been known as a critical regulator of intestinal function and much evidence now exists to suggest that it also plays an important role in the development of IBD. Dramatic changes in the ANS in IBD are apparent from the cellular to the molecular level ultimately leading to altered communication between the ANS and effector cells of the intestine. This review aims to synthesize the current understanding of the pathogenesis of IBD with a particular emphasis on the role that the ANS plays in the progression of these diseases.
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Affiliation(s)
- Cormac T Taylor
- School of Medicine and Medical Science, UCD Conway Institute, University College Dublin, Ireland
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Pavlov VA, Ochani M, Gallowitsch-Puerta M, Ochani K, Huston JM, Czura CJ, Al-Abed Y, Tracey KJ. Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia. Proc Natl Acad Sci U S A 2006; 103:5219-23. [PMID: 16549778 PMCID: PMC1405626 DOI: 10.1073/pnas.0600506103] [Citation(s) in RCA: 238] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2005] [Indexed: 01/04/2023] Open
Abstract
TNF has a critical mediator role in inflammation and is an important therapeutic target. We recently discovered that TNF production is regulated by neural signals through the vagus nerve. Activation of this "cholinergic antiinflammatory pathway" inhibits the production of TNF and other cytokines and protects animals from the inflammatory damage caused by endotoxemia and severe sepsis. Here, we describe a role for central muscarinic acetylcholine receptors in the activation of the cholinergic antiinflammatory pathway. Central muscarinic cholinergic activation by muscarine, the M1 receptor agonist McN-A-343, and the M2 receptor antagonist methoctramine inhibited serum TNF levels significantly during endotoxemia. Centrally administered methoctramine stimulated vagus-nerve activity measured by changes in instantaneous heart-rate variability. Blockade of peripheral muscarinic receptors did not abolish antiinflammatory signaling through the vagus nerve, indicating that peripheral muscarinic receptors on immune cells are not required for the cytokine-regulating activities of the cholinergic antiinflammatory pathway. The role of central muscarinic receptors in activating the cholinergic antiinflammatory pathway is of interest for the use of centrally acting muscarinic cholinergic enhancers as antiinflammatory agents.
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Affiliation(s)
- Valentin A Pavlov
- Laboratory of Biomedical Science, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY 11030, USA.
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Saunders PR, Miceli P, Vallance BA, Wang L, Pinto S, Tougas G, Kamath M, Jacobson K. Noradrenergic and cholinergic neural pathways mediate stress-induced reactivation of colitis in the rat. Auton Neurosci 2006; 124:56-68. [PMID: 16464645 DOI: 10.1016/j.autneu.2005.12.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2005] [Revised: 11/10/2005] [Accepted: 12/05/2005] [Indexed: 11/20/2022]
Abstract
Evidence to date suggests that stress-induced exacerbation or relapse of intestinal inflammation in inflammatory bowel disease requires both activation of the autonomic nervous system and the activation of the immune system by the presence of previously encountered luminal antigens. The aim of the present study was to further explore these associations and to determine the role of the autonomic nervous in modulating the intestinal inflammatory response to stress. Rats healed from an initial dinitrobenzene sulfonic acid-induced colitis were given a non-colitic dose of dinitrobenzene sulfonic acid (dissolved in saline) or 0.9% saline intra-rectally and then subjected to restraint stress. Cardiac sympathovagal balance was assessed by power spectral analysis of heart rate variability data collected from telemetric electrocardiogram recordings before, during and post stress. Only rats that were stressed and received dinitrobenzene sulfonic acid showed an inflammatory relapse characterized by significant macroscopic damage and elevated myeloperoxidase activity associated with a significant infiltration of mucosal and submucosal T lymphocytes. No difference in inflammatory markers was observed in animals that received intra-rectal saline and restraint stress. Rats subjected to stress and intra-rectal dinitrobenzene sulfonic acid demonstrated an increase in sympathetic activity with a nearly four fold increase in LF:HF ratio during stress and a significant increase in heart rate. Shortly after cessation of stress, the LF:HF ratio decreased significantly, returning to baseline levels, however the heart rate remained significantly elevated over baseline levels following stress, but decreased to a level that was significantly lower than during stress. The stress/dinitrobenzene sulfonic acid-induced relapses were preventable by pre-treating rats with hexamethonium (a nicotinic cholinergic ganglion blocking agent) or the co-administration of atropine (a muscarinic cholinoceptor antagonist) and bretylium (a noradrenergic ganglion blocking agent), but was not prevented when either atropine or bretylium were administered alone. This study utilizes an established model of chemically induced colitis that when integrated with stress results in relapsing inflammatory bowel disease. Moreover, this study demonstrates that noradrenergic and cholinergic neural pathways mediate the stress response critical for the relapse of colitis.
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Affiliation(s)
- Paul R Saunders
- Intestinal Disease Research Program, McMaster University, Hamilton, Ontario, Canada
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Akinci SB, Ulu N, Yondem OZ, Firat P, Guc MO, Kanbak M, Aypar U. Effect of neostigmine on organ injury in murine endotoxemia: missing facts about the cholinergic antiinflammatory pathway. World J Surg 2006; 29:1483-9. [PMID: 16222449 DOI: 10.1007/s00268-005-0073-2] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
Electrical and pharmacologic stimulation of the efferent cholinergic antiinflammatory pathway suppress the systemic inflammatory response and can prevent lethal endotoxemia. Neostigmine, a cholinergic agent, has not been tested to determine if it can prevent histopathologic organ injury in endotoxemia. In the present study, the effects of neostigmine treatment on the histopathologic organ injury inflicted by Escherichia coli endotoxin in a mouse model of septic shock was investigated. Endotoxemia in mice caused weight loss and increased spleen, liver, and lung weight. When the organs were examined for histopathologic injury, endotoxemia increased interstitial inflammation in the lungs, liver injury, and organ injury in general terms; neostigmine, at a dose of 0.1 mg/kg, failed to attenuate these effects. Although the simultaneous administration of neostigmine at a dose of 0.3 mg/kg and endotoxin decreased interstitial inflammation in the lungs, vacuolar degeneration in the liver, and total liver injury, mortality was increased with this dose in the presence of endotoxemia. We conclude that neostigmine at a dose of 0.1 mg/kg was not protective against histopathologic organ injury in mice with endotoxemia, and a higher dose (0.3 mg/kg) was not tolerated probably owing to nonspecific parasympathetic action including cardiovascular effects. Further studies are required to determine the contribution of sites in the cholinergic antiinflammatory pathway.
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Affiliation(s)
- Seda B Akinci
- Department of Anaesthesiology and Reanimation, Hacettepe University Faculty of Medicine, Sihhiye, Ankara 06100, Turkey.
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Lourenssen S, Wells RW, Blennerhassett MG. Differential responses of intrinsic and extrinsic innervation of smooth muscle cells in rat colitis. Exp Neurol 2005; 195:497-507. [PMID: 16098965 DOI: 10.1016/j.expneurol.2005.06.012] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2005] [Revised: 06/02/2005] [Accepted: 06/19/2005] [Indexed: 12/31/2022]
Abstract
Intestinal smooth muscle cells receive neural input from axons that originate within the intestine, as well as from axons of extrinsic origin. In the inflamed intestine, altered motility may arise from damage to the axon/smooth muscle cell relationship, but the extent of change is unknown. Western blotting, histology and immunocytochemistry were used in the TNBS model of colitis in the rat to evaluate intrinsic and extrinsic axon numbers, which were then correlated with circular smooth muscle cell (CSMC) number during the time course from the acute onset of colitis to apparent recovery, at Day 35 post TNBS. Total axon profiles in the circular smooth muscle layer were reduced by nearly 50% on Day 4 of colitis, to 428 +/- 82 axons/section from 757 +/- 125 in control (n = 8-14 animals). The intrinsic innervation density (axon number per CSMC) dropped sharply by Day 2 to less than 30% of control. Although CSMC number nearly tripled during colitis, innervation density was restored to control levels by Day 6 due to a coordinated three-fold increase in axon number. The subpopulation of extrinsic axons expressing tyrosine hydroxylase showed a unique pattern during colitis, with no initial decrease in axon number, followed by axonal proliferation between Days 6 and 16 post-TNBS. We conclude that loss of intrinsic axons is an early event in colitis, and although reversed by axonal proliferation, transient denervation may promote CSMC hyperplasia as seen in earlier work in vitro. Axonal proliferation of both intrinsic and extrinsic axons is identified as a major homeostatic mechanism, with distinct patterns of damage and repair suggesting a structural basis for the altered motility seen in the inflamed colon.
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Affiliation(s)
- Sandra Lourenssen
- Gastrointestinal Diseases Research Unit, Queens University, Hotel Dieu Hospital, 166 Brock Street, Kingston, Ontario, Canada K7L 5G2
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