Galantamine ameliorates experimental pancreatitis
Abstract Background Acute pancreatitis is a common and serious inflammatory condition currently lacking disease modifying therapy. The cholinergic anti-inflammatory pathway (CAP) is a potent protective anti-inflammatory response activated by vagus nerve-dependent α7 nicotinic acetylcholine receptor...
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| Format: | Article |
| Language: | English |
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BMC
2023-10-01
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| Series: | Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s10020-023-00746-y |
| _version_ | 1797219736107352064 |
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| author | Dane A. Thompson Tea Tsaava Arvind Rishi Sam J. George Tyler D. Hepler Daniel Hide Valentin A. Pavlov Michael Brines Sangeeta S. Chavan Kevin J. Tracey |
| author_facet | Dane A. Thompson Tea Tsaava Arvind Rishi Sam J. George Tyler D. Hepler Daniel Hide Valentin A. Pavlov Michael Brines Sangeeta S. Chavan Kevin J. Tracey |
| author_sort | Dane A. Thompson |
| collection | DOAJ |
| description | Abstract Background Acute pancreatitis is a common and serious inflammatory condition currently lacking disease modifying therapy. The cholinergic anti-inflammatory pathway (CAP) is a potent protective anti-inflammatory response activated by vagus nerve-dependent α7 nicotinic acetylcholine receptor (α7nAChR) signaling using splenic CD4+ T cells as an intermediate. Activating the CAP ameliorates experimental acute pancreatitis. Galantamine is an acetylcholinesterase inhibitor (AChEI) which amplifies the CAP via modulation of central muscarinic ACh receptors (mAChRs). However, as mAChRs also activate pancreatitis, it is currently unknown whether galantamine would be beneficial in acute pancreatitis. Methods The effect of galantamine (1–6 mg/kg-body weight) on caerulein-induced acute pancreatitis was evaluated in mice. Two hours following 6 hourly doses of caerulein (50 µg/kg-body weight), organ and serum analyses were performed with accompanying pancreatic histology. Experiments utilizing vagotomy, gene knock out (KO) technology and the use of nAChR antagonists were also performed. Results Galantamine attenuated pancreatic histologic injury which was mirrored by a reduction in serum amylase and pancreatic inflammatory cytokines and an increase the anti-inflammatory cytokine IL-10 in the serum. These beneficial effects were not altered by bilateral subdiaphragmatic vagotomy, KO of either choline acetyltransferase+ T cells or α7nAChR, or administration of the nAChR ganglionic blocker mecamylamine or the more selective α7nAChR antagonist methyllycaconitine. Conclusion Galantamine improves acute pancreatitis via a mechanism which does not involve previously established physiological and molecular components of the CAP. As galantamine is an approved drug in widespread clinical use with an excellent safety record, our findings are of interest for further evaluating the potential benefits of this drug in patients with acute pancreatitis. |
| first_indexed | 2024-03-11T12:40:39Z |
| format | Article |
| id | doaj.art-637ce3daf8364f509c994bd8ab365cf4 |
| institution | Directory Open Access Journal |
| issn | 1528-3658 |
| language | English |
| last_indexed | 2024-04-24T12:38:23Z |
| publishDate | 2023-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Medicine |
| spelling | doaj.art-637ce3daf8364f509c994bd8ab365cf42024-04-07T11:21:53ZengBMCMolecular Medicine1528-36582023-10-0129111010.1186/s10020-023-00746-yGalantamine ameliorates experimental pancreatitisDane A. Thompson0Tea Tsaava1Arvind Rishi2Sam J. George3Tyler D. Hepler4Daniel Hide5Valentin A. Pavlov6Michael Brines7Sangeeta S. Chavan8Kevin J. Tracey9Laboratory of Biomedical Sciences, Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell HealthLaboratory of Biomedical Sciences, Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell HealthDepartment of Pathology and Laboratory Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/NorthwellLaboratory of Biomedical Sciences, Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell HealthLaboratory of Biomedical Sciences, Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell HealthLaboratory of Biomedical Sciences, Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell HealthLaboratory of Biomedical Sciences, Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell HealthLaboratory of Biomedical Sciences, Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell HealthLaboratory of Biomedical Sciences, Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell HealthLaboratory of Biomedical Sciences, Institute for Bioelectronic Medicine, Feinstein Institutes for Medical Research, Northwell HealthAbstract Background Acute pancreatitis is a common and serious inflammatory condition currently lacking disease modifying therapy. The cholinergic anti-inflammatory pathway (CAP) is a potent protective anti-inflammatory response activated by vagus nerve-dependent α7 nicotinic acetylcholine receptor (α7nAChR) signaling using splenic CD4+ T cells as an intermediate. Activating the CAP ameliorates experimental acute pancreatitis. Galantamine is an acetylcholinesterase inhibitor (AChEI) which amplifies the CAP via modulation of central muscarinic ACh receptors (mAChRs). However, as mAChRs also activate pancreatitis, it is currently unknown whether galantamine would be beneficial in acute pancreatitis. Methods The effect of galantamine (1–6 mg/kg-body weight) on caerulein-induced acute pancreatitis was evaluated in mice. Two hours following 6 hourly doses of caerulein (50 µg/kg-body weight), organ and serum analyses were performed with accompanying pancreatic histology. Experiments utilizing vagotomy, gene knock out (KO) technology and the use of nAChR antagonists were also performed. Results Galantamine attenuated pancreatic histologic injury which was mirrored by a reduction in serum amylase and pancreatic inflammatory cytokines and an increase the anti-inflammatory cytokine IL-10 in the serum. These beneficial effects were not altered by bilateral subdiaphragmatic vagotomy, KO of either choline acetyltransferase+ T cells or α7nAChR, or administration of the nAChR ganglionic blocker mecamylamine or the more selective α7nAChR antagonist methyllycaconitine. Conclusion Galantamine improves acute pancreatitis via a mechanism which does not involve previously established physiological and molecular components of the CAP. As galantamine is an approved drug in widespread clinical use with an excellent safety record, our findings are of interest for further evaluating the potential benefits of this drug in patients with acute pancreatitis.https://doi.org/10.1186/s10020-023-00746-yPancreatitisGalantamineVagus nerveInflammationCytokinesCholinergic anti-inflammatory pathway |
| spellingShingle | Dane A. Thompson Tea Tsaava Arvind Rishi Sam J. George Tyler D. Hepler Daniel Hide Valentin A. Pavlov Michael Brines Sangeeta S. Chavan Kevin J. Tracey Galantamine ameliorates experimental pancreatitis Molecular Medicine Pancreatitis Galantamine Vagus nerve Inflammation Cytokines Cholinergic anti-inflammatory pathway |
| title | Galantamine ameliorates experimental pancreatitis |
| title_full | Galantamine ameliorates experimental pancreatitis |
| title_fullStr | Galantamine ameliorates experimental pancreatitis |
| title_full_unstemmed | Galantamine ameliorates experimental pancreatitis |
| title_short | Galantamine ameliorates experimental pancreatitis |
| title_sort | galantamine ameliorates experimental pancreatitis |
| topic | Pancreatitis Galantamine Vagus nerve Inflammation Cytokines Cholinergic anti-inflammatory pathway |
| url | https://doi.org/10.1186/s10020-023-00746-y |
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