Varenicline limits ischemia reperfusion injury following testicular torsion in mice
| Autor: | Christina P. Ho, Elina Mukherjee, Daniel Paul Casella, Austin G. Hester, Rebecca S. Zee, Nazanin Omidi, Christopher E. Bayne, Sunder Sims-Lucas, Michael H. Hsieh, Evaristus C. Mbanefo |
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| Rok vydání: | 2020 |
| Předmět: |
Male
medicine.medical_specialty Urology Ischemia Cytisine chemistry.chemical_compound Mice Fibrosis Internal medicine Testis medicine Testicular torsion Animals Humans Varenicline Spermatic Cord Torsion Testicular atrophy Renal ischemia business.industry medicine.disease Endocrinology chemistry Reperfusion Injury Pediatrics Perinatology and Child Health Reperfusion business Reperfusion injury |
| Zdroj: | Journal of pediatric urology. 17(5) |
| ISSN: | 1873-4898 |
| Popis: | Summary Background Torsion of the spermatic cord and the resulting testicular ischemia leads to the production of inflammatory cytokines and cell death due to impaired aerobic metabolism. Following reperfusion of the testis, a robust innate inflammatory response furthers tissue injury due to the production of reactive oxygen species and disruption of normal capillary function. Blunting the innate immune response with antioxidants, anti-inflammatory medications and targeted genetic interventions reduces long term testicular injury in animal models of torsion, however these approaches have limited clinical applicability. Mediated via α7 nACh receptors, the cholinergic anti-inflammatory pathway limits NFKB signaling and prevents renal fibrosis following warm renal ischemia. We identified varenicline as an FDA approved α7 nAChR agonist and hypothesized that varenicline administration would decrease long-term testicular atrophy and fibrosis in a murine model of testicular torsion. Methods Using an established model, unilateral testicular torsion was induced in mature male CD1 mice by rotating the right testicle 720° for 2 h. In the treatment group, 4 doses of varenicline (1mg/grm) were administered via intraperitoneal injection every 12 h, with the first dose given 1 h after the creation of testicular torsion. The acute inflammatory response was evaluated 48 h following reperfusion of the testis. Long term outcomes were evaluated 30 days following testicular perfusion. Results 48 h following reperfusion, the testis of animals treated with varenicline demonstrated a significant reduction in the inflammatory response as measured by the acute immune cell infiltrate, myeloperoxidase activity, concentration of reduced glutathione and expression of downstream NF-KB targets. 30 days following reperfusion, animals treated with varenicline, demonstrated decreased testicular atrophy (Summary Figure), fibrosis and expression of pro-fibrotic genes. Conclusion Activation of a central immunosuppressive cascade with varenicline after the onset of testicular torsion reduces ischemia reperfusion injury and prevents long term testicular atrophy and fibrosis. Further studies are needed to define the optimum dose and varenicline administration regimen. Our results suggest that varenicline offers a novel, FDA approved, adjunct to the current management of testicular torsion. Download : Download high-res image (102KB) Download : Download full-size image Summary Figure . Varenicline prevents long term testicular atrophy following testicular torsion. 30 days following reperfusion, untreated animals demonstrated a significant decrease in the weight of the torsed testis when compared to the contralateral control. Animals treated with the α7 nAChR agonist Cytisine or Varenicline demonstrated preservation of testicular weight and a significant decreased in testicular atrophy. |
| Databáze: | OpenAIRE |
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