Effect of a BK Receptor Antagonist (R‐954) in Experimental Endometriosis

Endometriosis is a gynecological condition characterized by the growth of endometrium‐like tissues within and outside of the pelvic cavity. Currently available drugs are only efficacious in treating endometriosis‐related pain, however it's not a targeted treatment. In this sense, the aim of this work is evaluate the effects of R‐954 (a bradykinin B1 receptor antagonist), in a murine model of endometriosis. Female Swiss Webster mice (25–30g, n=7) were anesthetized with intraperitoneal injection of ketamine/xylazine. The abdomen was opened to expose the uterus. One uterine horn was ligated at both the uterotubal junction and the cervical end, and the intermediate segment was removed and split longitudinally. Pieces with 5‐mm were sectioned. These explants were then anchored onto the peritoneum. After 35 days, the abdomen was opened to assess the viability of the endometrial explants. The animals were divided and treated with: R‐954 (2 and 5 mg/kg, s.c), progesterone (1 mg/kg, p.o) or vehicle, for 15 consecutive days. In every day mice were submitted to vaginal smear. At the last day the animals were euthanized and blood, peritoneal fluid and ectopic cyst were collected for quantification of pro‐inflammatory cytokines. The results are presented as mean±SD and statistical analysis were performed by ANOVA followed by Newman‐Keuls post‐test (*p<0.05). Protocols for animal use received number #DFBCICB015‐04/16 (COBEA/UFRJ/Brazil). In vehicle‐treated groups entire cycle remained for 15 days (proestrous, estrous, metaestrous and diestus phases). In progesterone‐treated group animais remained in estrus phase. Pretreatment with R‐954 did not affect changes the phases of estrous cycle. All doses of R‐954 reduced the levels of TNF‐α and IL‐6 in blood, peritoneal fluid and ectopic cyst. In ectopic cyst, levels of TNF‐α were reduced in 47.7% (6.3±1.6*pg/μg of protein) and 79% (2.5±1.4*pg/μg of protein), when compared to vehicle‐treated group (12.0±6.3 pg/μg of protein). IL‐6 levels were reduced in 77.7% (2.0±0.7*pg/μg) and 85.5% (1.3±0.9*pg/μg), when compared to vehicle‐treated group (9±4.2 pg/μg), to 2 and 5 mg/kg, respectively. In the blood, a similar pattern was observed, TNF‐α was reduced in 56.5% (320.0±136.9*pg/mL) and 58.4% (306.3±146.0*pg/mL) when compared to vehicle‐treated group (736.1±298.4 pg/mL) and IL‐6 was significantly reduced in 83.2% (41.8±30.7*pg/mL) and 84.8% (37.8±19.4*pg/mL) when compared to vehicle‐treated group (248.7±106.7 pg/mL), at doses 2 and 5 mg/kg, respectively. In the peritoneal fluid, the production of TNF‐α decreased in 67.6% (222.1±129.7*pg/mL) and 80.3% (134.7±39.5*pg/mL), when compared to vehicle‐treated group (686.8±167.7 pg/mL) and the IL‐6 was reduced in 75.5% (36.3±13* pg/mL) and 52.4% (70.1±44.1* pg/mL) when compared to vehicle‐treated group (146.8±53.3 pg/mL), to 2 and 5 mg/kg, respectively. Our results suggest that R‐954 doesn't have influence in estrous cycle and show significant anti‐inflammatory effects through reduction of production of cytokines. Support or Funding Information This study was financed in part by the CAPES/Finance Code 001, CNPq and FAPERJ. This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

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