作者: de Paiva, João Pedro Barros ; de Carvalho, Rosangela Ribeiro ; Carvalho, Rosangela Ribeiro de ; França, Patricia Ribeiro de Carvalho ; Paiva, João Pedro Barros de ; Fernandes, Patricia Dias ; Figueiredo, Claudia Pinto ; Carvalho França, Patricia Ribeiro de ; Sirois, Pierre ; de Figueiredo, Claudia Pinto

Endometriosis is a gynecological condition characterized by the growth of endometrium-like tissues outside of the uterine cavity. Currently available drugs are efficacious in treating endometriosis-related pain, however it's not a targeted treatment. The aim of this work is to evaluate the effects of R-954, a bradykinin B1 receptor antagonist, in a murine model of endometriosis. The model was induced in animals through autologous transplantation of part of the uterine horn. After 51 days, it was observed that implants developed into endometriotic lesions. The administration of R-954 or progesterone, for 15 consecutive days, prevented the progression of cyst development, reduced the size and weight of the cysts. Both treatments also reduced cellular infiltrate and production of inflammatory mediators (interleukin-1β, interleukin-6, tumor necrosis factor). However, only R-954 decreased angiogenic factors (VEGF and VEGF receptor). In addition, treatment with the antagonist did not interfere in the females' estrous cycle, as well as prevented gestational losses (reduction in the number of intermediate resorptions in pregnant females with endometriosis). Data suggested that R-954 has anti-inflammatory and anti-angiogenic effects; does not influence the estrous cycle; and prevents the number of gestational losses suggesting it as a good candidate for endometriosis treatment.

2023-09-26·Journal of clinical medicine

Prevention of Inflammation, Neovascularization, and Retinal Dysfunction by Kinin B₁ Receptor Antagonism in a Mouse Model of Age-Related Macular Degeneration.

Article

作者: Shirzad, Shima ; Couture, Réjean ; Vaucher, Elvire ; Fofana, Abdel-Rahamane Kader ; Gobeil, Fernand ; Bhat, Menakshi

The kallikrein-kinin system (KKS) contributes to vascular inflammation and neovascularization in age-related macular degeneration (AMD), particularly via the kinin B₁ receptor (B₁R). The aim of the present study was to determine the protective effects of the topical administration of the B₁R antagonist (R-954) on inflammation, neovascularization, and retinal dysfunction in a murine model of neovascular AMD. Choroidal neovascularization (CNV) was induced in C57BL6 mice using an argon laser. A treatment with ocular drops of R-954 (100 μg/15 μL, twice daily in both eyes), or vehicle, was started immediately on day 0, for 7, 14, or 21 days. CNV, invasive microglia, and B₁R immunoreactive glial cells, as well as electroretinography alterations, were observed within the retina and choroid of the CNV group but not in the control group. The staining of B₁R was abolished by R-954 treatment as well as the proliferation of microglia. R-954 treatment prevented the CNV development (volume: 20 ± 2 vs. 152 ± 5 × 10⁴ µm³ in R-954 vs. saline treatment). R-954 also significantly decreased photoreceptor and bipolar cell dysfunction (a-wave amplitude: -47 ± 20 vs. -34 ± 14 µV and b-wave amplitude: 101 ± 27 vs. 64 ± 17 µV in R-954 vs. saline treatment, day 7) as well as angiogenesis tufts in the retina. These results suggest that self-administration of R-954 by eye-drop treatment could be a promising therapy in AMD to preserve retinal health and vision.

2023-04-15·Journal of clinical medicine

Genetic Ablation and Pharmacological Blockade of Bradykinin B1 Receptor Unveiled a Detrimental Role for the Kinin System in Chagas Disease Cardiomyopathy.

Article

作者: Sirois, Pierre ; Oliveira, Ana Carolina ; Pereira, Isabela Resende ; Scharfstein, Julio ; Moreira, Otacílio da Cruz ; Campos de Carvalho, Antônio Carlos ; Maciel, Leonardo ; Mota, Julia Barbalho da ; Carvalho-Pinto, Carla Eponina ; Vicentino, Amanda Roberta Revoredo ; Saboia-Vahia, Leonardo ; Andrade, Daniele ; Vilar-Pereira, Glaucia ; Lannes-Vieira, Joseli ; Pesquero, João B

Chagas disease, the parasitic infection caused by Trypanosoma cruzi, afflicts about 6 million people in Latin America. Here, we investigated the hypothesis that T. cruzi may fuel heart parasitism by activating B1R, a G protein-coupled (brady) kinin receptor whose expression is upregulated in inflamed tissues. Studies in WT and B1R^-/- mice showed that T. cruzi DNA levels (15 days post infection-dpi) were sharply reduced in the transgenic heart. FACS analysis revealed that frequencies of proinflammatory neutrophils and monocytes were diminished in B1R^-/- hearts whereas CK-MB activity (60 dpi) was exclusively detected in B1R^+/+ sera. Since chronic myocarditis and heart fibrosis (90 dpi) were markedly attenuated in the transgenic mice, we sought to determine whether a pharmacological blockade of the des-Arg⁹-bradykinin (DABK)/B1R pathway might alleviate chagasic cardiomyopathy. Using C57BL/6 mice acutely infected by a myotropic T. cruzi strain (Colombian), we found that daily treatment (15-60 dpi) with R-954 (B1R antagonist) reduced heart parasitism and blunted cardiac injury. Extending R-954 treatment to the chronic phase (120-160 dpi), we verified that B1R targeting (i) decreased mortality indexes, (ii) mitigated chronic myocarditis, and (iii) ameliorated heart conduction disturbances. Collectively, our study suggests that a pharmacological blockade of the proinflammatory KKS/DABK/B1R pathway is cardioprotective in acute and chronic Chagas disease.

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