title: Activation of central muscarinic receptor type 1 prevents development of endotoxin tolerance in rat liver.
abstract: Endotoxin tolerance is a mechanism in which cells receiving low doses of endotoxin, enter a transient phase with less inflammatory response to the next endotoxin challenges. Central nervous system is known to modulate systemic inflammation through activation of the cholinergic system; however, the role of central anti-inflammatory pathway in pathophysiology of hepatic endotoxin tolerance is unknown. Our study was designed to assess the effect central muscarinic type 1 receptor (M1) activation on development of endotoxin tolerance in rat liver. Endotoxin tolerance was induced by daily intraperitoneal injection of endotoxin (1 mg/kg) for 5 days. Animals were randomly divided into two groups which received intracerebroventricular injection of either MCNA-343 (an M1 agonist, 5 ng/kg) or saline 1h after intraperitoneal injection of saline or endotoxin. The responsiveness to endotoxin was assessed by measuring hepatic MCP-1 (monocyte chemotactic protein-1), iNOS (inducible nitric oxide synthase) and TNF-α (tumor necrosis-α) mRNA expression 3h after intraperitoneal administration of endotoxin using quantitative RT-PCR. A significant reduction in hepatic expression of MCP-1, iNOS and TNF-α was observed in rats with 5 days endotoxin challenge in comparison with rats given a single dose of endotoxin. There was no significant difference in hepatic expression of MCP-1, iNOS or TNF-α between acute and chronic LPS-treated groups in rats given MCNA-343. Central MCNA-343 stimulation could prevent the induction of hepatic endotoxin tolerance in animals receiving repeated doses of endotoxin. This indicates that M1 cholinergic receptor activation in the central nervous system can modulate endotoxin tolerance in rat liver.
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: Golnar
authors.initials: G
authors.lastname: Eftekhari
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: Khalil
authors.initials: K
authors.lastname: Hajiasgharzadeh
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: S Mohammad
authors.initials: SM
authors.lastname: Ahmadi-Soleimani
authors.affiliation: Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Ahmad R
authors.initials: AR
authors.lastname: Dehpour
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
authors.forename: Saeed
authors.initials: S
authors.lastname: Semnanian
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: mani@modares.ac.ir.
authors.forename: Ali R
authors.initials: AR
authors.lastname: Mani
mesh_terms: D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000494:pharmacology*; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D018932:Chemokine CCL2 / Q000235:genetics; D004361:Drug Tolerance / Q000502:physiology*; D015870:Gene Expression; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D043643:Receptor, Muscarinic M1 / Q000819:agonists* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: C491766:Ccl2 protein, rat; D018932:Chemokine CCL2; D008070:Lipopolysaccharides; D018721:Muscarinic Agonists; D012333:RNA, Messenger; D043643:Receptor, Muscarinic M1; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase
keywords: Endotoxin tolerance; Inflammation; Liver; Muscarinic type 1 receptor