title: The Effects of Sub-Chronic Treatment with Pioglitazone on the Septic Mice Mortality in the Model of Cecal Ligation and Puncture: Involvement of Nitric Oxide Pathway.
abstract: Sepsis is a systemic inflammatory response syndrome caused by an infection and remains as a major challenge in health care. Many studies have reported that pioglitazone may display anti-inflammatory effects. This study was designed to evaluate the effect of subchronic treatment with pioglitazone on high-grade septic mice survival and nitrergic system involvement. Diffused sepsis was induced by cecal ligation and puncture (CLP) surgery in male NMRI mice (20-30 g). Pioglitazone (5,10 and 20 mg/kg) was administered by gavage daily for 5 days prior to surgery. Nitric oxide involvement was assessed by sub-chronic administration of a non-selective nitric oxide synthase inhibitor, L-NAME and a selective inducible nitric oxide synthase inhibitor, aminoguanidine. TNF-α  and IL-1β plasma levels were measured by ELISA. Pioglitazone (10 and 20 mg/kg) significantly improved survival rate in septic mice. The chronic intraperitoneally co-administration of L-NAME (0.5 mg/kg, daily) or aminoguanidine (1 mg/kg, daily) with a daily dose of pioglitazone, 5 mg/kg, significantly increased the survival rate. This survival improving effect was accompanied by a significant reduction in pro-inflammatory cytokines TNF-α and IL-1β plasma levels. In conclusion, sub-chronic pioglitazone treatment can improve survival in mouse sepsis model by CLP. Inhibition of nitric oxide release, probably through inducible nitric oxide synthase at least in part is responsible for this effect. Suppression of TNF-α and IL-1β could be another mechanism in pioglitazone-induced survival improving effect in septic mice.
authors.affiliation: Department of Pharmacology and Toxicology, Pharmaceutical Sciences Branch and Pharmaceutical Sciences Research Center, Islamic Azad University, Tehran, Iran.
authors.forename: Hamed
authors.initials: H
authors.lastname: Shafaroodi
authors.affiliation: Department of Pharmacology and Toxicology, Pharmaceutical Sciences Branch and Pharmaceutical Sciences Research Center, Islamic Azad University, Tehran, Iran. AND Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. AND Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Mahsa
authors.initials: M
authors.lastname: Hassanipour
authors.affiliation: Department of Pharmacology and Toxicology, Pharmaceutical Sciences Branch and Pharmaceutical Sciences Research Center, Islamic Azad University, Tehran, Iran.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Mousavi
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. AND Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Nastaran
authors.initials: N
authors.lastname: Rahimi
authors.affiliation: Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. AND Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Ahmad Reza
authors.initials: AR
authors.lastname: Dehpour
mesh_terms: D000818:Animals; D002432:Cecum; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006146:Guanidines / Q000494:pharmacology; D008026:Ligation; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism*; D000077205:Pioglitazone; D018805:Sepsis / Q000188:drug therapy*; D015398:Signal Transduction; D045162:Thiazolidinediones / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D006146:Guanidines; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; C004479:pimagedine; D000077205:Pioglitazone
keywords: Cecal ligation and puncture; Cytokines; Mice; Nitric oxide; Pioglitazone; Sepsis