VİLDAGLİPTİN, SİKLOFOSFAMİD İLE İNDÜKLENEN AŞIRI AKTİF MESANE FARE MODELİNDE DETRÜSÖR KONTRAKTİLİTESİNİ İYİLEŞTİRİR

Year 2025, Volume: 49 Issue: 1, 53 - 61

Seçkin Engin , Elif Nur Barut , Merve İsmailoğlu Karaca , Melis Nazlı Yanık

https://doi.org/10.33483/jfpau.1507431

Abstract

Amaç: Aşırı aktif mesane (AAM), mesane aşırı duyarlılığına neden olan lokal doku inflamasyonuna bağlı detrüsör aşırı aktivitesi ile ilişkili yaygın bir ürolojik bozukluktur. Bu çalışma, siklofosfamid SFD) ile indüklenen AAM fare modelinde, anti-inflamatuar etkili anti-diyabetik bir ilaç olan vildagliptinin (VIL) terapötik potansiyelini araştırmayı amaçlamıştır.
Gereç ve Yöntem: AAM modelini indüklemek için dişi Balb/c farelere intraperitoneal olarak (i.p) 7 gün boyunca her iki günde bir SFD (80 mg/kg) enjekte edildi. Daha sonra fareler, art arda 7 gün boyunca oral olarak serum fizyolojik (AAM modeli), VIL (10 veya 50 mg/kg/gün) veya solifenasin (10 mg/kg/gün) ile tedavi edildi. Deneyin 17. gününde, mesane kontraktilitesini değerlendirmek için izole fare detrüsör kası kullanılarak organ banyosu deneyleri yapıldı. Başka bir fare grubunda mesane inflamasyonu, Evans mavisi ekstravazasyonu ile değerlendirildi.
Sonuç ve Tartışma: Karbakol ile indüklenen detrüsör kasılması, AAM modeli farelerinde önemli ölçüde arttı ve bu artış, VIL (50 mg/kg) veya solifenasin tedavisi ile düzeldi. Ayrıca; VIL tedavisi (50 mg/kg), SFD enjekte edilmiş farelerde rölatif mesane ağırlığını ve Evans mavi boyasının mesanelere ekstravazasyonunu azalttı. Bu sonuç, VIL'in SFD kaynaklı mesane inflamasyonu üzerindeki inhibitör etkisini ortaya koydu. Sonuçlarımız, VIL’in mesane inflamasyonunu kısmen baskılayarak SFD kaynaklı bir AAM fare modelinde detrüsör aşırı aktivitesini iyileştirdiğini ortaya koydu.

Keywords

Aşırı aktif mesane, detrusor, evans mavisi, mesane inflamasyonu, solifenasin, vildagliptin

VILDAGLIPTIN IMPROVES DETRUSOR CONTRACTILITY IN A MOUSE MODEL OF CYCLOPHOSPHAMIDE-INDUCED OVERACTIVE BLADDER

Abstract

Objective: Overactive bladder (OAB) is a common urological disorder associated with detrusor overactivity linked to local tissue inflammation resulting in bladder hypersensitivity. The present study was aimed to investigate the therapeutic potential of vildagliptin (VIL), an anti-diabetic drug with anti-inflammatory effects, in a mouse model of cyclophosphamide (CP)-induced OAB.
Material and Method: To induce an animal model of OAB, female Balb/c mice were intraperitoneally (i.p) injected with CP (80 mg/kg) every two days for 7 days. Then, mice were orally treated with saline (OAB model), VIL (10 or 50 mg/kg/day) or solifenacin (10 mg/kg/day) for 7 consecutive days. On the 17th day of experiment, organ-bath experiments were performed using isolated mouse detrusor muscle to evaluate tissue contractility. In another set of mice, bladder inflammation was assessed by Evans blue extravasation.
Result and Discussion: Carbachol-induced contraction of detrusor strips significantly increased in OAB mice, which was reversed by treatment with VIL at 50 mg/kg or solifenacin. In addition, VIL treatment (50 mg/kg) reduced relative bladder weight and Evans blue dye extravasation into the bladders in CP-injected mice, demonstrating the inhibitory effect of VIL on CP-induced bladder inflammation. Our results showed that VIL ameliorated detrusor overactivity in a mouse model of CP-induced OAB by partially suppressing bladder inflammation.

Keywords

Bladder inflammation, detrusor, evans blue, overactive bladder, solifenacin, vildagliptin

Ethical Statement

All experimental procedure of the animals was approved by Animal Experiments Local Ethics Committee of Karadeniz Technical University (approval no: 2023/45).

References

• 1. Peyronnet, B., Mironska, E., Chapple, C., Cardozo, L., Oelke, M., Dmochowski, R., Amarenco, G., Gamé, X., Kirby, R., Van Der Aa, F., Cornu, J.N. (2019). A comprehensive review of overactive bladder pathophysiology: On the way to tailored treatment. European Urology, 75(6), 988-1000. [CrossRef]
• 2. Latini, J.M., Giannantoni, A. (2011). Pharmacotherapy of overactive bladder: Epidemiology and pathophysiology of overactive bladder. Expert Opinion on Pharmacotherapy, 12(7), 1017-1027. [CrossRef]
• 3. Grundy, L., Caldwell, A., Brierley, S.M. (2018). Mechanisms underlying overactive bladder and interstitial cystitis/painful bladder syndrome. Frontiers in Neuroscience, 12, 931. [CrossRef]
• 4. Boudes, M., Uvin, P., Kerselaers, S., Vennekens, R., Voets, T., De Ridder, D. (2011). Functional characterization of a chronic cyclophosphamide-induced overactive bladder model in mice. Neurourology and Urodynamics, 30(8), 1659-1665. [CrossRef]
• 5. Chen, Y.H., Chen, W.C., Liu, P.L., Chen, H.Y. (2020). Astragalus polysaccharides and astragaloside IV ameliorates cyclophosphamide-induced mouse model of overactive bladder. Taiwanese Journal of Obstetrics & Gynecology, 59(2), 248-255. [CrossRef]
• 6. Zhang, S., Lv, J.W., Yang, P., Yu, Q., Pang, J., Wang, Z., Guo, H., Liu, S., Hu, J., Li, J., Leng, J., Huang, Y., Ye, Z., Wang, C.Y. (2012). Loss of dicer exacerbates cyclophosphamide-induced bladder overactivity by enhancing purinergic signaling. The American Journal of Pathology, 181(3), 937-946. [CrossRef]
• 7. Shen, J.D., Chen, S.J., Chen, H.Y., Chiu, K.Y., Chen, Y.H., Chen, W.C. (2021). Review of animal models to study urinary bladder function. Biology, 10(12), 1316. [CrossRef]
• 8. Kang, S.M., Park, J.H. (2021). Pleiotropic benefits of DPP-4 inhibitors beyond glycemic control. Clinical medicine insights. Endocrinology and Diabetes, 14, 11795514211051698. [CrossRef]
• 9. Liu, Y., Qi, Y. (2020). Vildagliptin, a CD26/DPP4 inhibitor, ameliorates bleomycin-induced pulmonary fibrosis via regulating the extracellular matrix. International Immunopharmacology, 87, 106774. [CrossRef]
• 10. El-Sherbeeny, N.A., Nader, M.A. (2016). The protective effect of vildagliptin in chronic experimental cyclosporine A-induced hepatotoxicity. Canadian Journal of Physiology and Pharmacology, 94(3), 251-256. [CrossRef]
• 11. Sherif, I.O., Al-Shaalan, N.H. (2018). Vildagliptin attenuates hepatic ischemia/reperfusion injury via the TLR4/NF-κB signaling pathway. Oxidative Medicine and Cellular Longevity, 2018, 3509091. [CrossRef]
• 12. Fouad, M.R., Salama, R.M., Zaki, H.F., El-Sahar, A.E. (2021). Vildagliptin attenuates acetic acid-induced colitis in rats via targeting PI3K/Akt/NFκB, Nrf2 and CREB signaling pathways and the expression of lncRNA IFNG-AS1 and miR-146a. International Immunopharmacology, 92, 107354. [CrossRef]
• 13. Zhang, Y., Zhang, X., Wee Yong, V., Xue, M. (2022). Vildagliptin improves neurological function by inhibiting apoptosis and ferroptosis following intracerebral hemorrhage in mice. Neuroscience Letters, 776, 136579. [CrossRef]
• 14. Liu, M., Shen, S., Kendig, D.M., Mahavadi, S., Murthy, K.S., Grider, J.R., Qiao, L.Y. (2015). Inhibition of NMDAR reduces bladder hypertrophy and improves bladder function in cyclophosphamide induced cystitis. The Journal of Urology, 193(5), 1676-1683. [CrossRef]
• 15. de Oliveira, M.G., Calmasini, F.B., Alexandre, E.C., De Nucci, G., Mónica, F.Z., Antunes, E. (2016). Activation of soluble guanylyl cyclase by BAY 58-2667 improves bladder function in cyclophosphamide-induced cystitis in mice. American Journal of Physiology. Renal Physiology, 311(1), 85-93. [CrossRef]
• 16. Engin, S., Barut, E.N., Erac, Y., Sari, S., Kadioglu, M. (2023). The inhibitory effect of escitalopram on mouse detrusor contractility: The role of L-type calcium channels. Toxicology and Applied Pharmacology, 461, 116408. [CrossRef]
• 17. Barut, E.N., Öztürk, A.C., Engin, S., Renda, G. (2023). Investigation of the effects of oleuropein on mouse detrusor muscle contractility. Fabad Journal of Pharmaceutical Sciences, 49(1): 81-90. [CrossRef]
• 18. Radu, M., Chernoff, J. (2013). An in vivo assay to test blood vessel permeability. Journal of Visualized Experiments: JoVE, (73), e50062. [CrossRef]
• 19. Hughes, F.M., Jr, McKeithan, P., Ellett, J., Armeson, K.E., Purves, J.T. (2013). Simvastatin suppresses cyclophosphamide-induced changes in urodynamics and bladder inflammation. Urology, 81(1), 209.e9-209.e2.09E14. [CrossRef]
• 20. Wein, A.J., Rackley, R.R. (2006). Overactive bladder: A better understanding of pathophysiology, diagnosis and management. The Journal of Urology, 175(3 Pt 2), 5-10. [CrossRef]
• 21. Palmer, C.J., Choi, J.M. (2017). Pathophysiology of overactive bladder: Current understanding. Current Bladder Dysfunction Reports, 12(1), 74-79. [CrossRef]
• 22. Hutchinson, A., Nesbitt, A., Joshi, A., Clubb, A., Perera, M. (2020). Overactive bladder syndrome: Management and treatment options. Australian Journal of General Practice, 49(9), 593-598. [CrossRef]
• 23. Grover, S., Srivastava, A., Lee, R., Tewari, A.K., Te, A.E. (2011). Role of inflammation in bladder function and interstitial cystitis. Therapeutic Advances in Urology, 3(1), 19-33. [CrossRef]
• 24. Ishizuka, Y., Satake, Y., Kimura, S., Yamashita, S., Kawamorita, N., Ito, A. (2024). Statin administration ameliorates ischemia-induced overactive bladder with improvement of blood flow and anti-inflammatory effects in rats. Neurourology and Urodynamics, 43(4), 991-1002. [CrossRef]
• 25. Wróbel, A., Serefko, A., Bańczerowska-Górska, M., Szopa, A., Dudka, J., Poleszak, E. (2019). Intravesical administration of blebbistatin prevents cyclophosphamide-induced toxicity of the urinary bladder in female Wistar rats. Neurourology and Urodynamics, 38(4), 1044-1052. [CrossRef]
• 26. Tyagi, P., Barclay, D., Zamora, R., Yoshimura, N., Peters, K., Vodovotz, Y., Chancellor, M. (2010). Urine cytokines suggest an inflammatory response in the overactive bladder: A pilot study. International Urology and Nephrology, 42(3), 629-635. [CrossRef]
• 27. Chess-Williams, R., Sellers, D.J. (2023). Pathophysiological mechanisms involved in overactive bladder/detrusor overactivity. Current Bladder Dysfunction Reports, 18(2), 79-88. [CrossRef]
• 28. Sun, Z.G., Li, Z.N., Zhu, H.L. (2020). The research progress of DPP-4 Inhibitors. Mini Reviews in Medicinal Chemistry, 20(17), 1709-1718. [CrossRef]
• 29. Cahn, A., Cernea, S., Raz, I. (2016). An update on DPP-4 inhibitors in the management of type 2 diabetes. Expert Opinion on Emerging Drugs, 21(4), 409-419.
• 30. Yazbeck, R., Howarth, G.S., Abbott, C.A. (2009). Dipeptidyl peptidase inhibitors, an emerging drug class for inflammatory disease? Trends in Pharmacological Sciences, 30(11), 600-607. [CrossRef]
• 31. Tomovic, K., Lazarevic, J., Kocic, G., Deljanin-Ilic, M., Anderluh, M., Smelcerovic, A. (2019). Mechanisms and pathways of anti-inflammatory activity of DPP-4 inhibitors in cardiovascular and renal protection. Medicinal Research Reviews, 39(1), 404-422. [CrossRef]
• 32. Mills, K.A., Chess-Williams, R., McDermott, C. (2019). Novel insights into the mechanism of cyclophosphamide-induced bladder toxicity: Chloroacetaldehyde's contribution to urothelial dysfunction in vitro. Archives of Toxicology, 93(11), 3291-3303. [CrossRef]
• 33. Liu, Q., Long, Z., Dong, X., Zhang, T., Zhao, J., Sun, B., Zhu, J., Li, J., Dang, Q., Yangi, Z., Hu, X., Li, L. (2017). Cyclophosphamide-induced HCN1 channel upregulation in interstitial Cajal-like cells leads to bladder hyperactivity in mice. Experimental & Molecular Medicine, 49(4), e319. [CrossRef]
• 34. Saima-Anjum, I., Najm, S., Barkat, K., Nafidi, H.A., Bin Jardan, Y.A., Bourhia, M. (2023). Caftaric acid ameliorates oxidative stress, inflammation, and bladder overactivity in rats having interstitial cystitis: An in silico study. ACS Omega, 8(31), 28196-28206. [CrossRef]
• 35. Wróbel, A., Doboszewska, U., Rechberger, E., Rojek, K., Serefko, A., Poleszak, E., Skalicka-Woźniak, K., Dudka, J., Wlaź, P. (2017). Rho kinase inhibition ameliorates cyclophosphamide-induced cystitis in rats. Naunyn-Schmiedeberg's Archives of Pharmacology, 390(6), 613-619. [CrossRef]
• 36. Chow, Y.C., Yang, S., Huang, C.J., Tzen, C.Y., Huang, P.L., Su, Y.H., Wang, P.S. (2006). Epinephrine promotes hemostasis in rats with cyclophosphamide-induced hemorrhagic cystitis. Urology, 67(3), 636-641. [CrossRef]