WAY-202196, a selective estrogen receptor-beta agonist, protects against death in experimental septic shock.
OBJECTIVE
To determine the effect of an estrogen receptor-beta selective agent in experimental models of systemic infection and sepsis.


METHODS
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.


METHODS
University-affiliated biomedical research laboratory.


METHODS
BALB/c mice and Sprague-Dawley rats.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Cristofaro
Patricia A
PA
Infectious Disease Division, Memorial Hospital of Rhode Island, Brown Medical School, Providence, RI, USA.
Opal
Steven M
SM
Palardy
John E
JE
Parejo
Nicolas A
NA
Jhung
Jhung
J
Keith
James C
JC
Harris
Heather A
HA
D000284:Administration, Oral; D000818:Animals; D001202:Ascitic Fluid / Q000378:metabolism; D016470:Bacteremia / Q000188:drug therapy / Q000382:microbiology; D004195:Disease Models, Animal; D047629:Estrogen Receptor beta / Q000819:agonists; D005260:Female; D015850:Interleukin-6 / Q000378:metabolism; D007413:Intestinal Mucosa / Q000187:drug effects / Q000648:ultrastructure; D008089:Listeria monocytogenes; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009284:Naphthols / Q000494:pharmacology*; D009503:Neutropenia / Q000150:complications; D011552:Pseudomonas Infections / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000188:drug therapy* / Q000382:microbiology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D047629:Estrogen Receptor beta; D015850:Interleukin-6; D009284:Naphthols; D014409:Tumor Necrosis Factor-alpha; C501752:3-(3-fluoro-4-hydroxyphenyl)-7-hydroxy-1-naphthonitrile