Protective role of M 3 muscarinic acetylcholine receptor in indomethacin-induced small intestinal injury
EP prostanoid receptor (EP R) contributes to the intestinal epithelial Cl secretion, and inhibition of prostaglandin E (PGE) production by non-steroidal anti-inflammatory drugs (NSAIDs) plays a central role in NSAID-induced enteropathy. Although M muscarinic acetylcholine receptor (M R) also contrib...
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| Veröffentlicht in: | Journal of molecular medicine (Berlin, Germany) Germany), 2024-09, Vol.102 (9), p.1175 |
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| container_title | Journal of molecular medicine (Berlin, Germany) |
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| creator | Igarashi-Hisayoshi, Yoko Ihara, Eikichi Bai, Xiaopeng Tanaka, Yoshimasa Ogino, Haruei Chinen, Takatoshi Taguchi, Yasushi Ogawa, Yoshihiro |
| description | EP
prostanoid receptor (EP
R) contributes to the intestinal epithelial Cl
secretion, and inhibition of prostaglandin E (PGE) production by non-steroidal anti-inflammatory drugs (NSAIDs) plays a central role in NSAID-induced enteropathy. Although M
muscarinic acetylcholine receptor (M
R) also contributes to the intestinal epithelial Cl
secretion, it remains unclear whether M
R is involved in NSAID-induced enteropathy due to a lack of selective agents. The present study explored how M
R is involved in the regulation of the intestinal epithelial Cl
secretion and its pathophysiological role in NSAID-induced enteropathy. Using the novel highly-selective M
positive allosteric modulator PAM-369 that we recently developed, we evaluated the role of M
R in the intestinal epithelial secretion ex vivo by measuring the short circuit current (Isc) of intestinal epithelium with a Ussing chamber system and examined whether or not M
R protects against small intestinal injury in indomethacin-treated mice. Both the PGE
derivative misoprostol and carbachol similarly increased the Isc in a concentration-dependent manner. The Isc increases were abolished either by receptor antagonists (an EP
R antagonist and a M
R antagonist, respectively) or by removal of extracellular Cl
. PAM-369 enhanced the carbachol-induced Isc by potentiating M
R, which could contribute to enhanced intestinal epithelial secretion. Treatment with PAM-369 ameliorated small intestinal injury in indomethacin-treated mice. Importantly, the M
R expression was significantly up-regulated, and PAM-369 potentiation of M
R was augmented in indomethacin-treated mice compared to untreated mice. These findings show that M
R plays a role in maintaining the intestinal epithelial secretion, which could contribute to protection against indomethacin-induced small intestinal injury. M
R is a promising target for treating or preventing NSAID-induced enteropathy. KEY MESSAGES: PAM-369, the M
positive allosteric modulator, was used to potentiate M
R. PAM-369 enhanced carbachol-induced Isc in mouse ileum. PAM-369 ameliorated small intestinal injury in indomethacin-treated mice. M
R is a promising target for treating or preventing NSAID-induced enteropathy. |
| doi_str_mv | 10.1007/s00109-024-02474-0 |
| format | Article |
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prostanoid receptor (EP
R) contributes to the intestinal epithelial Cl
secretion, and inhibition of prostaglandin E (PGE) production by non-steroidal anti-inflammatory drugs (NSAIDs) plays a central role in NSAID-induced enteropathy. Although M
muscarinic acetylcholine receptor (M
R) also contributes to the intestinal epithelial Cl
secretion, it remains unclear whether M
R is involved in NSAID-induced enteropathy due to a lack of selective agents. The present study explored how M
R is involved in the regulation of the intestinal epithelial Cl
secretion and its pathophysiological role in NSAID-induced enteropathy. Using the novel highly-selective M
positive allosteric modulator PAM-369 that we recently developed, we evaluated the role of M
R in the intestinal epithelial secretion ex vivo by measuring the short circuit current (Isc) of intestinal epithelium with a Ussing chamber system and examined whether or not M
R protects against small intestinal injury in indomethacin-treated mice. Both the PGE
derivative misoprostol and carbachol similarly increased the Isc in a concentration-dependent manner. The Isc increases were abolished either by receptor antagonists (an EP
R antagonist and a M
R antagonist, respectively) or by removal of extracellular Cl
. PAM-369 enhanced the carbachol-induced Isc by potentiating M
R, which could contribute to enhanced intestinal epithelial secretion. Treatment with PAM-369 ameliorated small intestinal injury in indomethacin-treated mice. Importantly, the M
R expression was significantly up-regulated, and PAM-369 potentiation of M
R was augmented in indomethacin-treated mice compared to untreated mice. These findings show that M
R plays a role in maintaining the intestinal epithelial secretion, which could contribute to protection against indomethacin-induced small intestinal injury. M
R is a promising target for treating or preventing NSAID-induced enteropathy. KEY MESSAGES: PAM-369, the M
positive allosteric modulator, was used to potentiate M
R. PAM-369 enhanced carbachol-induced Isc in mouse ileum. PAM-369 ameliorated small intestinal injury in indomethacin-treated mice. M
R is a promising target for treating or preventing NSAID-induced enteropathy.</description><identifier>EISSN: 1432-1440</identifier><identifier>DOI: 10.1007/s00109-024-02474-0</identifier><identifier>PMID: 39172154</identifier><language>eng</language><publisher>Germany</publisher><subject>Animals ; Anti-Inflammatory Agents, Non-Steroidal - adverse effects ; Anti-Inflammatory Agents, Non-Steroidal - pharmacology ; Carbachol - pharmacology ; Indomethacin - adverse effects ; Intestinal Mucosa - drug effects ; Intestinal Mucosa - metabolism ; Intestinal Mucosa - pathology ; Intestine, Small - drug effects ; Intestine, Small - injuries ; Intestine, Small - metabolism ; Intestine, Small - pathology ; Male ; Mice ; Mice, Inbred C57BL ; Misoprostol - pharmacology ; Receptor, Muscarinic M3 - metabolism</subject><ispartof>Journal of molecular medicine (Berlin, Germany), 2024-09, Vol.102 (9), p.1175</ispartof><rights>2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0002-8553-5084</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39172154$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Igarashi-Hisayoshi, Yoko</creatorcontrib><creatorcontrib>Ihara, Eikichi</creatorcontrib><creatorcontrib>Bai, Xiaopeng</creatorcontrib><creatorcontrib>Tanaka, Yoshimasa</creatorcontrib><creatorcontrib>Ogino, Haruei</creatorcontrib><creatorcontrib>Chinen, Takatoshi</creatorcontrib><creatorcontrib>Taguchi, Yasushi</creatorcontrib><creatorcontrib>Ogawa, Yoshihiro</creatorcontrib><title>Protective role of M 3 muscarinic acetylcholine receptor in indomethacin-induced small intestinal injury</title><title>Journal of molecular medicine (Berlin, Germany)</title><addtitle>J Mol Med (Berl)</addtitle><description>EP
prostanoid receptor (EP
R) contributes to the intestinal epithelial Cl
secretion, and inhibition of prostaglandin E (PGE) production by non-steroidal anti-inflammatory drugs (NSAIDs) plays a central role in NSAID-induced enteropathy. Although M
muscarinic acetylcholine receptor (M
R) also contributes to the intestinal epithelial Cl
secretion, it remains unclear whether M
R is involved in NSAID-induced enteropathy due to a lack of selective agents. The present study explored how M
R is involved in the regulation of the intestinal epithelial Cl
secretion and its pathophysiological role in NSAID-induced enteropathy. Using the novel highly-selective M
positive allosteric modulator PAM-369 that we recently developed, we evaluated the role of M
R in the intestinal epithelial secretion ex vivo by measuring the short circuit current (Isc) of intestinal epithelium with a Ussing chamber system and examined whether or not M
R protects against small intestinal injury in indomethacin-treated mice. Both the PGE
derivative misoprostol and carbachol similarly increased the Isc in a concentration-dependent manner. The Isc increases were abolished either by receptor antagonists (an EP
R antagonist and a M
R antagonist, respectively) or by removal of extracellular Cl
. PAM-369 enhanced the carbachol-induced Isc by potentiating M
R, which could contribute to enhanced intestinal epithelial secretion. Treatment with PAM-369 ameliorated small intestinal injury in indomethacin-treated mice. Importantly, the M
R expression was significantly up-regulated, and PAM-369 potentiation of M
R was augmented in indomethacin-treated mice compared to untreated mice. These findings show that M
R plays a role in maintaining the intestinal epithelial secretion, which could contribute to protection against indomethacin-induced small intestinal injury. M
R is a promising target for treating or preventing NSAID-induced enteropathy. KEY MESSAGES: PAM-369, the M
positive allosteric modulator, was used to potentiate M
R. PAM-369 enhanced carbachol-induced Isc in mouse ileum. PAM-369 ameliorated small intestinal injury in indomethacin-treated mice. M
R is a promising target for treating or preventing NSAID-induced enteropathy.</description><subject>Animals</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - adverse effects</subject><subject>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</subject><subject>Carbachol - pharmacology</subject><subject>Indomethacin - adverse effects</subject><subject>Intestinal Mucosa - drug effects</subject><subject>Intestinal Mucosa - metabolism</subject><subject>Intestinal Mucosa - pathology</subject><subject>Intestine, Small - drug effects</subject><subject>Intestine, Small - injuries</subject><subject>Intestine, Small - metabolism</subject><subject>Intestine, Small - pathology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Misoprostol - pharmacology</subject><subject>Receptor, Muscarinic M3 - metabolism</subject><issn>1432-1440</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFjs0KwjAQhIMg_r-AB8kLVJMmUnoWxYvgwXuJ6Zam5KckqdC3N4Kehd2ZWeY7LEJbSvaUkOIQCKGkzEjOP1sknaAF5SzPKOdkjpYhdAkpjiWfoTkraZHTI1-g9u5dBBnVC7B3GrBr8A0zbIYghVdWSSwkxFHL1mllEwQS-ug8VjZN7QzEVkhls3QMEmocjNA6VRFCVFZ8Yjf4cY2mjdABNl9fod3l_Dhds354Gqir3isj_Fj9XmN_gTe4H0ta</recordid><startdate>202409</startdate><enddate>202409</enddate><creator>Igarashi-Hisayoshi, Yoko</creator><creator>Ihara, Eikichi</creator><creator>Bai, Xiaopeng</creator><creator>Tanaka, Yoshimasa</creator><creator>Ogino, Haruei</creator><creator>Chinen, Takatoshi</creator><creator>Taguchi, Yasushi</creator><creator>Ogawa, Yoshihiro</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><orcidid>https://orcid.org/0000-0002-8553-5084</orcidid></search><sort><creationdate>202409</creationdate><title>Protective role of M 3 muscarinic acetylcholine receptor in indomethacin-induced small intestinal injury</title><author>Igarashi-Hisayoshi, Yoko ; Ihara, Eikichi ; Bai, Xiaopeng ; Tanaka, Yoshimasa ; Ogino, Haruei ; Chinen, Takatoshi ; Taguchi, Yasushi ; Ogawa, Yoshihiro</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmed_primary_391721543</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - adverse effects</topic><topic>Anti-Inflammatory Agents, Non-Steroidal - pharmacology</topic><topic>Carbachol - pharmacology</topic><topic>Indomethacin - adverse effects</topic><topic>Intestinal Mucosa - drug effects</topic><topic>Intestinal Mucosa - metabolism</topic><topic>Intestinal Mucosa - pathology</topic><topic>Intestine, Small - drug effects</topic><topic>Intestine, Small - injuries</topic><topic>Intestine, Small - metabolism</topic><topic>Intestine, Small - pathology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Misoprostol - pharmacology</topic><topic>Receptor, Muscarinic M3 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Igarashi-Hisayoshi, Yoko</creatorcontrib><creatorcontrib>Ihara, Eikichi</creatorcontrib><creatorcontrib>Bai, Xiaopeng</creatorcontrib><creatorcontrib>Tanaka, Yoshimasa</creatorcontrib><creatorcontrib>Ogino, Haruei</creatorcontrib><creatorcontrib>Chinen, Takatoshi</creatorcontrib><creatorcontrib>Taguchi, Yasushi</creatorcontrib><creatorcontrib>Ogawa, Yoshihiro</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>Journal of molecular medicine (Berlin, Germany)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Igarashi-Hisayoshi, Yoko</au><au>Ihara, Eikichi</au><au>Bai, Xiaopeng</au><au>Tanaka, Yoshimasa</au><au>Ogino, Haruei</au><au>Chinen, Takatoshi</au><au>Taguchi, Yasushi</au><au>Ogawa, Yoshihiro</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Protective role of M 3 muscarinic acetylcholine receptor in indomethacin-induced small intestinal injury</atitle><jtitle>Journal of molecular medicine (Berlin, Germany)</jtitle><addtitle>J Mol Med (Berl)</addtitle><date>2024-09</date><risdate>2024</risdate><volume>102</volume><issue>9</issue><spage>1175</spage><pages>1175-</pages><eissn>1432-1440</eissn><abstract>EP
prostanoid receptor (EP
R) contributes to the intestinal epithelial Cl
secretion, and inhibition of prostaglandin E (PGE) production by non-steroidal anti-inflammatory drugs (NSAIDs) plays a central role in NSAID-induced enteropathy. Although M
muscarinic acetylcholine receptor (M
R) also contributes to the intestinal epithelial Cl
secretion, it remains unclear whether M
R is involved in NSAID-induced enteropathy due to a lack of selective agents. The present study explored how M
R is involved in the regulation of the intestinal epithelial Cl
secretion and its pathophysiological role in NSAID-induced enteropathy. Using the novel highly-selective M
positive allosteric modulator PAM-369 that we recently developed, we evaluated the role of M
R in the intestinal epithelial secretion ex vivo by measuring the short circuit current (Isc) of intestinal epithelium with a Ussing chamber system and examined whether or not M
R protects against small intestinal injury in indomethacin-treated mice. Both the PGE
derivative misoprostol and carbachol similarly increased the Isc in a concentration-dependent manner. The Isc increases were abolished either by receptor antagonists (an EP
R antagonist and a M
R antagonist, respectively) or by removal of extracellular Cl
. PAM-369 enhanced the carbachol-induced Isc by potentiating M
R, which could contribute to enhanced intestinal epithelial secretion. Treatment with PAM-369 ameliorated small intestinal injury in indomethacin-treated mice. Importantly, the M
R expression was significantly up-regulated, and PAM-369 potentiation of M
R was augmented in indomethacin-treated mice compared to untreated mice. These findings show that M
R plays a role in maintaining the intestinal epithelial secretion, which could contribute to protection against indomethacin-induced small intestinal injury. M
R is a promising target for treating or preventing NSAID-induced enteropathy. KEY MESSAGES: PAM-369, the M
positive allosteric modulator, was used to potentiate M
R. PAM-369 enhanced carbachol-induced Isc in mouse ileum. PAM-369 ameliorated small intestinal injury in indomethacin-treated mice. M
R is a promising target for treating or preventing NSAID-induced enteropathy.</abstract><cop>Germany</cop><pmid>39172154</pmid><doi>10.1007/s00109-024-02474-0</doi><orcidid>https://orcid.org/0000-0002-8553-5084</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | EISSN: 1432-1440 |
| ispartof | Journal of molecular medicine (Berlin, Germany), 2024-09, Vol.102 (9), p.1175 |
| issn | 1432-1440 |
| language | eng |
| recordid | cdi_pubmed_primary_39172154 |
| source | MEDLINE; SpringerLink (Online service) |
| subjects | Animals Anti-Inflammatory Agents, Non-Steroidal - adverse effects Anti-Inflammatory Agents, Non-Steroidal - pharmacology Carbachol - pharmacology Indomethacin - adverse effects Intestinal Mucosa - drug effects Intestinal Mucosa - metabolism Intestinal Mucosa - pathology Intestine, Small - drug effects Intestine, Small - injuries Intestine, Small - metabolism Intestine, Small - pathology Male Mice Mice, Inbred C57BL Misoprostol - pharmacology Receptor, Muscarinic M3 - metabolism |
| title | Protective role of M 3 muscarinic acetylcholine receptor in indomethacin-induced small intestinal injury |
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