Adenosine A1 receptor antagonist, L-97-1, improves survival and protects the kidney in a rat model of cecal ligation and puncture induced sepsis.

Previously it was reported that combining antibiotics with L-97-1, an adenosine A1 receptor antagonist, significantly improves survival and blocks acute lung injury induced by Yersinia pestis CO 99 in a rat model of pneumonic plague. In the current studies using a conscious rat model of cecal ligation and puncture (CLP) sepsis, L-97-1 was administered in daily intravenous infusions in combination with antibiotics to simulate the use of L-97-1 as an anti-sepsis therapeutic in the clinical setting. In these studies, when administered at 12 h following CLP, in combination with broad spectrum antibiotics, ceftriaxone and clindamycin, L-97-1 improves 7 day (d) survival [25%, 35%, and 75% for L-97-1 (10 mg/kg/h, 12.5 mg/kg/h, and 15 mg/kg/h, respectively) versus (vs.) 25% for antibiotics alone] in a dose-dependent manner. The addition of L-97-1, 15 mg/kg/h to antibiotics significantly increased 7 d survival following CLP compared to therapy with either antibiotics alone (P=0.002) or L-97-1 at 15 mg/kg/h alone (P<0.001) and was not significantly different than survival in sham CLP animals (Log-rank (Mantel-Cox) test with Bonferroni׳s correction for multiple comparisons). Moreover, in these studies, in combination with antibiotics L-97-1 dose-dependently protects the kidney, significantly improving renal function at 24 h post CLP at 10 mg/kg/h (P<0.001), 12.5 mg/kg/h (P<0.0001), and 15 mg/kg/h (P<0.0001) vs. antibiotics alone (ANOVA followed by Tukey׳s post-hoc test for pair-wise comparisons). The results of these studies support efficacy for L-97-1 as an anti-sepsis therapeutic.

A novel post-exposure medical countermeasure L-97-1 improves survival and acute lung injury following intratracheal infection with Yersinia pestis.

Yersinia pestis, a Gram-negative bacillus causing plague and Centers for Disease Control and Prevention (CDC) classified Category A pathogen, has high potential as a bioweapon. Lipopolysaccharide, a virulence factor for Y. pestis, binds to and activates A(1) adenosine receptor (AR)s and, in animals, A(1)AR antagonists block induced acute lung injury (ALI) and increase survival following cecal ligation and perforation. In this study, rats were infected intratracheally with viable Y. pestis [CO99 (pCD1( + )/Δpgm) 1 × 10( 8 ) CFU/animal] and treated daily for 3 d with ciprofloxacin (cipro), the A(1)AR antagonist L-97-1, or cipro plus L-97-1 starting at 0, 6, 24, 48, or 72 h post-Y. pestis. At 72 h post-Y. pestis, cipro plus L-97-1 significantly improved 6-d survival to 60-70% vs 28% for cipro plus H(2)O and 33% for untreated Y. pestis controls (P = 0.02, logrank test). Lung edema, hemorrhage and leukocyte infiltration index (LII) were evaluated histologically to produce ALI scores. Cipro plus L-97-1 significantly reduced lung edema, as well as aggregate lung injury scores vs controls or cipro plus H(2)O, and LII vs controls (P < 0.05, Student's unpaired t test). These results support efficacy for L-97-1 as a post-exposure medical countermeasure, adjunctive therapy to antibiotics for Y. pestis.

Adenosine receptors and inflammation.

Extracellular adenosine is produced in a coordinated manner from cells following cellular challenge or tissue injury. Once produced, it serves as an autocrine- and paracrine-signaling molecule through its interactions with seven-membrane-spanning G-protein-coupled adenosine receptors. These signaling pathways have widespread physiological and pathophysiological functions. Immune cells express adenosine receptors and respond to adenosine or adenosine agonists in diverse manners. Extensive in vitro and in vivo studies have identified potent anti-inflammatory functions for all of the adenosine receptors on many different inflammatory cells and in various inflammatory disease processes. In addition, specific proinflammatory functions have also been ascribed to adenosine receptor activation. The potent effects of adenosine signaling on the regulation of inflammation suggest that targeting specific adenosine receptor activation or inactivation using selective agonists and antagonists could have important therapeutic implications in numerous diseases. This review is designed to summarize the current status of adenosine receptor signaling in various inflammatory cells and in models of inflammation, with an emphasis on the advancement of adenosine-based therapeutics to treat inflammatory disorders.