way-202196 and Disease-Models--Animal

Nonsteroidal agonists have been developed that selectively bind to and activate estrogen receptor beta (ERbeta) rather than estrogen receptor alpha (ERalpha). ERbeta is expressed equally in both male and female mammals in multiple extragonadal tissues. Work reported elsewhere has demonstrated that ERbeta agonists have beneficial effects in multiple (but not all) models of inflammatory diseases and also increase survival in experimentally induced sepsis.. In these experiments, ERbeta agonists (ERB-041 or WAY-202196) were compared with vehicle control in the murine cecal ligation and puncture (CLP) model and in the pneumococcal pneumonia model of sepsis. The effect of WAY-202196 on the gene expression profile in the CLP model was further studied by transcriptome analysis of lung and small intestine tissue samples.. ERbeta agonists provided a significant survival benefit in both experimental models of bacterial sepsis. This survival advantage was accompanied by reduced histologic evidence of tissue damage, reduced transcription of multiple proinflammatory proteins by transcriptome analysis and was not associated with increased bacterial outgrowth.. ERbeta agonist administration provided a survival advantage in septic animals and appears to be a promising therapeutic modality in sepsis.

Topics: Animals; Disease Models, Animal; Estrogen Receptor beta; Female; Gene Expression Profiling; Male; Mice; Mice, Inbred BALB C; Naphthols; Oxazoles; Pneumonia, Pneumococcal; Sepsis; Transcription, Genetic

To determine the effect of an estrogen receptor-beta selective agent in experimental models of systemic infection and sepsis.. WAY-202196, a nonsteroidal selective estrogen receptor-beta agonist, was tested in the murine listeriosis model, the neutropenic rat Pseudomonas aeruginosa infection, and the mouse cecal ligation and puncture sepsis models.. University-affiliated biomedical research laboratory.. BALB/c mice and Sprague-Dawley rats.. WAY-202196 or control (vehicle) was administered orally in doses ranging from 1.5 to 50 mg/kg at various time points in the three experimental model systems.. Susceptibility of mice treated with a single oral dose of up to 50 mg/kg WAY-202196 did not differ from those treated with vehicle alone after systemic challenge by Listeria monocytogenes, suggesting a lack of generalized immunosuppression. In the neutropenic rat model, daily administration of WAY-202196 (50 mg/kg) significantly increased survival against an otherwise lethal challenge of P. aeruginosa 12.4.4 compared with the control group (83% vs. 25% survival; p < 0.05). Preservation of intestinal mucosal weight and prevention of histopathologic changes were also observed with the administration of WAY-202196. Similar results were obtained in a cecal ligation and puncture model, in which multiple oral doses of WAY-202196 (50 mg/kg) improved survival (83% vs. 0%; p < 0.05), preserved intestinal epithelial integrity, and significantly reduced systemic bacteremia and peritoneal interleukin-6 and tumor necrosis factor levels. The estrogen receptor-beta agonist provided a comparable level of protection in both male and female animals.. These results indicate that oral administration of WAY-202196 preserved gastrointestinal barrier function and improved outcome in experimental models of systemic infection and inflammation. WAY-202196 and similar agents may prove useful clinically as a novel treatment strategy for the treatment or prevention of severe sepsis.

Topics: Administration, Oral; Animals; Ascitic Fluid; Bacteremia; Disease Models, Animal; Estrogen Receptor beta; Female; Interleukin-6; Intestinal Mucosa; Listeria monocytogenes; Male; Mice; Mice, Inbred BALB C; Naphthols; Neutropenia; Pseudomonas Infections; Rats; Rats, Sprague-Dawley; Shock, Septic; Tumor Necrosis Factor-alpha