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      Anti-Inflammation of Spirocyclopiperazinium Salt Compound LXM-10 Targeting α7 nAChR and M4 mAChR and Inhibiting JAK2/STAT3 Pathway in Rats

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          Abstract

          The present study aims to investigate the therapeutic effects of LXM-10 by intragastric administration in both acute and chronic inflammatory models, and to explore the underlying molecular mechanisms. The results showed that LXM-10 produced significant anti-inflammatory effects on carrageenan induced paw edema and complete Freund's adjuvant (CFA) induced arthritis, in which LXM-10 inhibited paw swelling in a dose- and time-dependent manner. ELISA analysis showed the production of pro-inflammatory cytokines including TNF-α and IL-6 was decreased by LXM-10. Western blot analysis showed that LXM-10 significantly reduced phosphorylation of Janus kinase 2 (JAK2) and further blunted phosphorylation of signal transducer and activator of transcription-3 (STAT3). The effects that LXM-10 had shown were attenuated by methyllycaconitine citrate (an α7 nicotinic acetylcholine receptor antagonist) or tropicamide (an M4 muscarinic acetylcholine receptor antagonist) in vivo. In conclusion, the studies showed that intragastric administration of LXM-10 exerted significant anti-inflammation effects in acute and chronic models, which may be attribute to the activation of α7 nicotinic acetylcholine receptor and M4 muscarinic acetylcholine receptor, thereby inhibiting the JAK2/STAT3 signal pathway, and ultimately reducing the production of pro-inflammatory cytokines of TNF-α and IL-6.

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          Most cited references28

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          Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation.

          Hong. Wang, Man Yu, Mahendar Ochani … (2003)
          Excessive inflammation and tumour-necrosis factor (TNF) synthesis cause morbidity and mortality in diverse human diseases including endotoxaemia, sepsis, rheumatoid arthritis and inflammatory bowel disease. Highly conserved, endogenous mechanisms normally regulate the magnitude of innate immune responses and prevent excessive inflammation. The nervous system, through the vagus nerve, can inhibit significantly and rapidly the release of macrophage TNF, and attenuate systemic inflammatory responses. This physiological mechanism, termed the 'cholinergic anti-inflammatory pathway' has major implications in immunology and in therapeutics; however, the identity of the essential macrophage acetylcholine-mediated (cholinergic) receptor that responds to vagus nerve signals was previously unknown. Here we report that the nicotinic acetylcholine receptor alpha7 subunit is required for acetylcholine inhibition of macrophage TNF release. Electrical stimulation of the vagus nerve inhibits TNF synthesis in wild-type mice, but fails to inhibit TNF synthesis in alpha7-deficient mice. Thus, the nicotinic acetylcholine receptor alpha7 subunit is essential for inhibiting cytokine synthesis by the cholinergic anti-inflammatory pathway.
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            Points of control in inflammation.

            Carl Nathan (2002)
            Inflammation is a complex set of interactions among soluble factors and cells that can arise in any tissue in response to traumatic, infectious, post-ischaemic, toxic or autoimmune injury. The process normally leads to recovery from infection and to healing, However, if targeted destruction and assisted repair are not properly phased, inflammation can lead to persistent tissue damage by leukocytes, lymphocytes or collagen. Inflammation may be considered in terms of its checkpoints, where binary or higher-order signals drive each commitment to escalate, go signals trigger stop signals, and molecules responsible for mediating the inflammatory response also suppress it, depending on timing and context. The non-inflammatory state does not arise passively from an absence of inflammatory stimuli; rather, maintenance of health requires the positive actions of specific gene products to suppress reactions to potentially inflammatory stimuli that do not warrant a full response.
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              Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis.

              Hong. Wang, Hong Liao, Mahendar Ochani … (2004)
              Physiological anti-inflammatory mechanisms can potentially be exploited for the treatment of inflammatory disorders. Here we report that the neurotransmitter acetylcholine inhibits HMGB1 release from human macrophages by signaling through a nicotinic acetylcholine receptor. Nicotine, a selective cholinergic agonist, is more efficient than acetylcholine and inhibits HMGB1 release induced by either endotoxin or tumor necrosis factor-alpha (TNF-alpha). Nicotinic stimulation prevents activation of the NF-kappaB pathway and inhibits HMGB1 secretion through a specific 'nicotinic anti-inflammatory pathway' that requires the alpha7 nicotinic acetylcholine receptor (alpha7nAChR). In vivo, treatment with nicotine attenuates serum HMGB1 levels and improves survival in experimental models of sepsis, even when treatment is started after the onset of the disease. These results reveal acetylcholine as the first known physiological inhibitor of HMGB1 release from human macrophages and suggest that selective nicotinic agonists for the alpha7nAChR might have therapeutic potential for the treatment of sepsis.
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                Author and article information

                Contributors
                Min Wu: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2013
                Publication date (Electronic): 28 June 2013
                Volume: 8
                Issue: 6
                Electronic Location Identifier: e66895
                Affiliations
                [1 ]State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing, China
                [2 ]Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University, Beijing, China
                [3 ]Department of Chemical Biology, School of Pharmaceutical Sciences, Peking University, Beijing, China
                [4 ]Medical and Healthy Analysis Center, Peking University, Beijing, China
                University of North Dakota, United States of America
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: JY. Performed the experiments: WZ XG YJ JY. Analyzed the data: WZ. Contributed reagents/materials/analysis tools: QS RL. Wrote the paper: JY WZ.

                Article
                Publisher ID: PONE-D-13-07620
                DOI: 10.1371/journal.pone.0066895
                PMC ID: 3695990
                PubMed ID: 23840548
                SO-VID: 19a0c87e-b56f-46dc-9782-71e59aace5cd
                Copyright statement: Copyright @ 2013
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 20 February 2013
                Date accepted : 13 May 2013
                Page count
                Pages: 8
                Funding
                The work was supported by the funds of National Science Foundation of China (NSFC 20772009,URL: http://www.nsfc.gov.cn/Portal0/default152.htm), and the Beijing Municipal Natural Science Foundation (7122097,URL: http://www.bjnsf.org/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology
                Subject: Anatomy and Physiology
                Subject: Immune Physiology
                Subject: Cytokines
                Subject: Biochemistry
                Subject: Proteins
                Subject: Acetylcholine Receptors
                Subject: Muscarinic Acetylcholine Receptors
                Subject: Nicotinic Acetylcholine Receptors
                Subject: Drug Discovery
                Subject: Immunology
                Subject: Immune System
                Subject: Cytokines
                Subject: Immunity
                Subject: Inflammation
                Subject: Microbiology
                Subject: Immunity
                Subject: Inflammation
                Subject: Model Organisms
                Subject: Animal Models
                Subject: Rat
                Subject: Molecular Cell Biology
                Subject: Signal Transduction
                Subject: Signaling in Cellular Processes
                Subject: STAT signaling family
                Subject: Chemistry
                Subject: Chemical Biology

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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