title: Effect of methylguanidine in a model of septic shock induced by LPS.
abstract: Septic shock, a severe form of sepsis, is characterized by cardiovascular collapse following microbial invasion of the body. The progressive hypotension, hyporeactivity to vasopressor agents and vascular leak leads to circulatory failure with multiple organ dysfunction and death. Many inflammatory mediators (e.g. TNF-alpha, IL-1 and IL-6) are involved in the pathogenesis of shock and, among them, nitric oxide (NO). The overproduction of NO during septic shock has been demonstrated to contribute to circulatory failure, myocardial dysfunction, organ injury and multiple organ failure. We have previously demonstrated with in vitro and in vivo studies that methylguanidine (MG), a guanidine compound deriving from protein catabolism, significantly inhibits iNOS activity, TNF-alpha release and carrageenan-induced acute inflammation in rats. The aim of the present study was to evaluate the possible anti-inflammatory activity of MG in a model of septic shock induced by lipopolysaccharide (LPS) in mice. MG was administered intraperitoneally (i.p.) at the dose of 30 mg/kg 1 h before and at 1 and 6 h after LPS-induced shock. LPS injection (10 mg/kg in 0.9% NaCl; 0.1 ml/mouse; i.p.) in mouse developed a shock syndrome with enhanced NO release and liver, kidney and pancreatic damage 18 h later. NOx levels, evaluated as nitrite/nitrate serum levels, was significantly reduced in MG-treated rats (78.6%, p < 0.0001; n = 10). Immunohistochemistry revealed, in the lung tissue of LPS-treated group, a positive staining for nitrotyrosine and poly(adenosine diphosphate [ADP] ribose) synthase, both of which were reduced in MG-treated mice. Furthermore, enzymatic evaluation revealed a significant reduction in liver, renal and pancreatic tissue damage and MG treatment also improved significantly the survival rate. This study provides evidence that MG attenuates the degree of inflammation and tissue damage associated with endotoxic shock in mice. The mechanisms of the anti-inflammatory effect of MG is, at least in part, dependent on the inhibition of NO formation.
authors.affiliation: Department of Pharmaceutical Sciences, University of Salerno, Via Ponte Don Melillo 11/c, 84084 Fisciano-Salerno, Italy. salvator@unime.it
authors.forename: Stefania
authors.initials: S
authors.lastname: Marzocco
authors.forename: Rosanna
authors.initials: R
authors.lastname: Di Paola
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Ribecco
authors.forename: Raffaella
authors.initials: R
authors.lastname: Sorrentino
authors.forename: Britti
authors.initials: B
authors.lastname: Domenico
authors.forename: Massimini
authors.initials: M
authors.lastname: Genesio
authors.forename: Aldo
authors.initials: A
authors.lastname: Pinto
authors.forename: Giuseppina
authors.initials: G
authors.lastname: Autore
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
mesh_terms: D000818:Animals; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008760:Methylguanidine / Q000494:pharmacology*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D012772:Shock, Septic / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D015996:Survival Rate; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000378:metabolism
chemical_list: D008070:Lipopolysaccharides; D016328:NF-kappa B; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D008760:Methylguanidine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse