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Updated: Aug 20, 2026
Lipopolysaccharide Infusion as a Porcine Endotoxemic Shock Model
Published on: December 8, 2023
Effect of methylguanidine in a model of septic shock induced by LPS
Stefania Marzocco1, Rosanna Di Paola, Maria Teresa Ribecco
1Department of Pharmaceutical Sciences, University of Salerno, Via Ponte Don Melillo 11/c, 84084 Fisciano-Salerno, Italy. salvator@unime.it
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.
Insights
Methylguanidine (MG) reduces inflammation and tissue damage in a mouse model of septic shock. This study shows MG inhibits nitric oxide (NO) formation, a key factor in septic shock progression.
Area of Science:
- Biomedical Science
- Pharmacology
- Immunology
Background:
- Septic shock involves cardiovascular collapse and organ damage due to microbial invasion.
- Overproduction of nitric oxide (NO) exacerbates septic shock, leading to circulatory failure and organ injury.
- Methylguanidine (MG), a protein catabolism product, has shown anti-inflammatory properties by inhibiting iNOS activity and TNF-alpha release.
Purpose of the Study:
- To investigate the anti-inflammatory effects of methylguanidine (MG) in a lipopolysaccharide (LPS)-induced mouse model of septic shock.
- To determine if MG can mitigate the NO overproduction and subsequent tissue damage characteristic of endotoxic shock.
Main Methods:
- Septic shock was induced in mice using intraperitoneal injection of lipopolysaccharide (LPS).
- Methylguanidine (MG) was administered at 30 mg/kg before and after LPS challenge.
- Nitrite/nitrate serum levels, nitrotyrosine and poly(ADP-ribose) synthase expression in lung tissue, and liver, kidney, and pancreatic tissue damage were assessed.
Main Results:
- MG treatment significantly reduced serum nitrite/nitrate levels by 78.6% (p < 0.0001).
- Immunohistochemistry showed reduced nitrotyrosine and poly(ADP-ribose) synthase staining in lung tissue of MG-treated mice.
- MG significantly reduced liver, kidney, and pancreatic tissue damage and improved the survival rate.
Conclusions:
- Methylguanidine (MG) demonstrates significant anti-inflammatory and protective effects in a mouse model of endotoxic shock.
- MG's therapeutic benefits are, at least partially, attributed to the inhibition of nitric oxide (NO) formation.
- These findings suggest MG as a potential therapeutic agent for managing septic shock and its associated complications.
