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Updated: Aug 24, 2026
Use of Animal Model of Sepsis to Evaluate Novel Herbal Therapies
Published on: April 11, 2012
A2A adenosine receptor activation improves survival in mouse models of endotoxemia and sepsis
Gail W Sullivan1, Guodong Fang, Joel Linden
1Department of Internal Medicine, University of Virginia, Charlottesville, Virginia, USA. gws3u@virginia.edu
Background:
Sepsis is currently treated with antibiotics and various adjunctive therapies that are not very effective.
Methods:
Mouse survival (4-5 days) and peritoneal and blood bacteria counts were determined after challenge with intraperitoneal lipopolysaccharide (LPS) or live Escherichia coli.
Results:
The A(2A) adenosine receptor (AR) agonist 4-[3-[6-amino-9-(5-ethylcarbamoyl-3, 4-dihydroxy-tetrahydro-furan-2-yl)-9H-purin-2-yl]-prop-2-ynyl]-cyclohexanecarboxylic acid methyl ester (ATL146e; 0.05-50 mu g/kg) protected mice from challenge with LPS, and protection occurred when treatment was delayed up to 24 h after challenge. Deletion of the A (2A) AR gene, Adora2a, inhibited protection by ATL146e. A putative A (3)AR agonist, N(6)-3-iodobenzyladenosine-5'-N-methyluronamide (IB-MECA; 500 mu g/kg but not 5 or 50 mu g/kg) protected mice from challenge with LPS. The protective effects of both ATL146e and IB-MECA were counteracted by the A(2A) AR selective antagonist 4-(2-[7-amino-2-[2-furyl][1,2,4]triazolo[2,3-a][1,3,5]triazin-5-yl-amino]ethyl)-phenol. In the live E. coli model, treatment with ATL146e (50 mu g/kg initiated 8 h after infection) increased survival in mice treated with ceftriaxone (5 days) from 40% to 100%. Treatment with ATL146e did not affect peritoneal numbers of live E. coli at the time of death or 120 h after infection but did increase numbers of peritoneal neutrophils and decreased the number of live E. coli in blood.
Conclusions:
AR agonists increase mouse survival in endotoxemia and sepsis via A(2A) AR-mediated mechanisms and reduce the number of live bacteria in blood.
Insights
Adenosine receptor (AR) agonists, specifically targeting the A(2A) AR, significantly improved mouse survival in sepsis models. These AR agonists reduced live bacteria in the bloodstream, offering a promising new therapeutic avenue.
Area of Science:
- Pharmacology
- Immunology
- Infectious Diseases
Background:
- Sepsis treatment remains challenging with current antibiotics and adjunctive therapies showing limited efficacy.
- Exploring novel therapeutic targets is crucial for improving sepsis outcomes.
Purpose of the Study:
- To investigate the efficacy of adenosine receptor (AR) agonists in preclinical models of sepsis and endotoxemia.
- To elucidate the role of A(2A) and A(3) ARs in sepsis-induced mortality and bacterial dissemination.
Main Methods:
- Mice were challenged with lipopolysaccharide (LPS) or live Escherichia coli to induce sepsis models.
- Survival rates, bacterial counts in peritoneal fluid and blood, and neutrophil infiltration were assessed.
- Pharmacological modulation using AR agonists (ATL146e, IB-MECA) and antagonists was employed.
Main Results:
- The A(2A) AR agonist ATL146e demonstrated significant protection against LPS challenge, even when treatment was delayed up to 24 hours.
- A(3) AR agonist IB-MECA also showed protective effects against LPS, which were blocked by an A(2A) AR antagonist.
- In a live E. coli sepsis model, ATL146e combined with ceftriaxone increased survival from 40% to 100%, reduced blood bacteria, and increased peritoneal neutrophils.
Conclusions:
- Adenosine receptor agonists, particularly those acting via A(2A) AR, enhance survival in sepsis and endotoxemia.
- These agonists reduce bacterial load in the bloodstream through A(2A) AR-dependent mechanisms.
- Targeting adenosine receptors represents a potential novel therapeutic strategy for sepsis management.
