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PROTECTIVE EFFECT OF MITOTEMPO IN STREPTOZOTOCIN-INDUCED DIABETIC RAT MODEL: EFFECTS ON CORPUS CAVERNOSUM AND AORTA

Year 2022, Volume: 5 Issue: 2, 82 - 87, 30.06.2022
https://doi.org/10.26650/JARHS2022-1105948

Abstract

Objective: In this study we aimed to evaluate the effect of mitotempo, a mitochondria-specific antioxidant, on endothelial and erectile dysfunction in a Streptozotocin-induced rat diabetes model.
Material and Methods: Wistar Albino rats weighing 280-320 g were used in the study. Diabetes was induced by intraperitoneal 50 mg/kg single dose streptozotocin injection. Blood glucose levels above 300 mg/dl at the end of 1 week were considered diabetes. Blood glucose was monitored for 4 weeks. The treatment group received mitotempo orally at 0.7 mg/kg/ day for 4 weeks. At the end of the 4th week, the aorta and corpus cavernosum contraction and relaxation responses were evaluated in an isolated organ bath after decapitation.
Results: According to our study results, mitotempo 0.7 mg/kg/day for 4 weeks in a diabetes model preserved endothelial relaxation responses in both the thoracic aorta and corpus cavernosum. Phenylephrine contractions calculated according to KCl contraction did not differ between the groups.
Conclusion: Endothelial cells can be identified as one of the first organs to be exposed to circulating substances. The effects of mROS on endothelial dysfunction caused by hyperglycemia is known. In our study, we found that a 0.7 mg/kg/day mitotempo treatment for 4 weeks showed protective effects on STZ-induced diabetic endothelial dysfunction.

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References

  • 1. Goldstein İ, Young JM, Fischer J, Bangerter K, Segerson T, Taylor T, Vardenafil Diabetes Study Group et al. Vardenafil, a new phosphodiesterase type 5 inhibitor, in the treatment of erectile dysfunction in men with diabetes: A multicenter double-blind placebo-controlled fixed-dose study. Diabetes Care 2003;26(3):777-83. google scholar
  • 2. Palumbo PJ. Metabolic risk factors, endothelial dysfunction, and erectile dysfunction in men with diabetes. Am J Med Sci 2007;334(6):466-80. google scholar
  • 3. Vlachopoulos C, İoakeimidis N, Terentes-Printzios D, Stefanadis C. The Triad: Erectile Dysfunction - Endothelial Dysfunction -Cardiovascular Disease. Curr Pharm Des 2008;14(35):3700-14. google scholar
  • 4. Azadzoi KM, Schulman RN, Aviram M, Siroky MB. Oxidative stress in arteriogenic erectile dysfunction: Prophylactic role of antioxidants. J Urol 2005;174(1):386-93. google scholar
  • 5. Soner BC, Murat N, Demir O, Guven H, Esen A, Gidener S. Evaluation of vascular smooth muscle and corpus cavernosum on hypercholesterolemia. İs resveratrol promising on erectile dysfunction. Int J Impot Res 2010;22(4):227-33. google scholar
  • 6. Gur S, Peak T, Kadowitz P, Sikka S, Hellstrom W. Review of Erectile Dysfunction in Diabetic Animal Models. Curr Diabetes Rev 2014;10 (1):61-73. google scholar
  • 7. Reiter RJ, Rosales-Corral S, Tan DX, Jou MJ, Galano A, Xu B. Melatonin as a mitochondria-targeted antioxidant: one of evolution’s best ideas. Cell Mol Life Sci 2017;74:3863-81. google scholar
  • 8. Cheng Y, Liu D zhou, Zhang C xiong, Cui H, Liu M, Zhang B le, et al. Mitochondria-targeted antioxidant delivery for precise treatment of myocardial ischemia-reperfusion injury through a multistage continuous targeted strategy. Nanomedicine Nanotechnology, Biol Med 2019;16:236-49. google scholar
  • 9. Czepas J, Koceva-Chyta A, Gwozdzinski K, Jozwiak Z. Different effectiveness of piperidine nitroxides against oxidative stress induced by doxorubicin and hydrogen peroxide. Cell Biol Toxicol 2008;24(1):101-12. google scholar
  • 10. Gioscia-Ryan RA, LaRocca TJ, Sindler AL, Zigler MC, Murphy MP, Seals DR. Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice. J Physiol 2014; 592(12):2549-61. google scholar
  • 11. McCarthy C, Kenny LC. Therapeutically targeting mitochondrial redox signalling alleviates endothelial dysfunction in preeclampsia. Sci Rep 2016;6 :1-11. google scholar
  • 12. Furman BL. Streptozotocin-İnduced Diabetic Models in Mice and Rats. Curr Protoc 2021;1(4):e78. google scholar
  • 13. Furman BL. Streptozotocin-İnduced Diabetic Models in Mice and Rats. Curr Protoc Pharmacol 2015;70:1-21. google scholar
  • 14. Wang Q, Zhang M, Torres G, Wu S, Ouyang C, Xie Z, et al. Metformin suppresses diabetes-accelerated atherosclerosis via the inhibition of Drp1-mediated mitochondrial fission. Diabetes 2017;66(1):193—205. google scholar
  • 15. Laight DW, Carrier MJ, Anggârd EE. Antioxidants, diabetes and endothelial dysfunction. Cardiovasc Res 2000;47(3):457-64. google scholar
  • 16. Sivitz WI, Yorek MA. Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities. Antiox Redox Signal 2010;12(4):537-77. google scholar
  • 17. Dikalova AE, Bikineyeva AT, Budzyn K, Nazarewicz RR, Lewis W, Harrison DG, et al. Therapeutic Targeting of Mitochondrial Superoxide in Hypertension. Circ Res 2010;107(1):106-16. google scholar
  • 18. Dikalov SI, Dikalova AE. Contribution of mitochondrial oxidative stress to hypertension. Physiol Behav 2016;176(1):100-6. google scholar
  • 19. Li X, Fang P, Li Y, Kuo Y-M, Andrews AJ, Nanayakkara G, et al. Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-induced Endothelial Cell Activation. Physiol Behav 2016;36(6):1090-100. google scholar
  • 20. Ni R, Cao T, Xiong S, Ma J , Fan GC, Lacefield JC, Lu Y, et al. Therapeutic inhibition of mitochondrial reactive oxygen species with mito-TEMPO reduces diabetic cardiomyopathy. Free Radic Biol Med 2016;90:12-23. google scholar
  • 21. Xing H, Zhang Z, Shi G, He Y, Song Y, Liu Y, Harrington EO, Sellke FW, Feng J. Chronic Inhibition of mROS Protects Against Coronary Endothelial Dysfunction in Mice with Diabetes. Front Cell Dev Biol 2021;9:643810. google scholar

STREPTOZOTOSİN İLE İNDÜKLENEN DİYABETLİ SIÇAN AORT VE KORPUS KAVERNOZUM DOKULARINDA MİTOTEMPO’NUN ENDOTEL ÜZERİNE MUHTEMEL KORUYUCU ETKİSİ

Year 2022, Volume: 5 Issue: 2, 82 - 87, 30.06.2022
https://doi.org/10.26650/JARHS2022-1105948

Abstract

Amaç: Deneysel olarak sıçanlarda Streptozotosin ile oluşturulmuş diyabet modelinde bir mitokondri spesifik antioksidan olan Mitotempo’nun endotelial ve erektil disfonksiyona etkisinin incelenmesi amaçlanmıştır.
Gereç ve Yöntem: Deney için 280-320 g ağırlığında Wistar-Albino soyu sıçanlar kullanılmıştır. Diyabet grubuna 50 mg/kg intraperitoneal tek doz streptozotosin uygulanmıştır. 1 hafta sonunda 300 mg/dl kan glikozu seviyesinin üstünde olanlar diyabet kabul edilmiştir. 4 hafta boyunca kan glikozu takip edilmiştir. Bu 4 hafta boyunca tedavi grubuna 0.7 mg/kg/gün oral mitotempo uygulanmıştır. 4. Hafta sonunda dekapite edilen hayvanların aort ve korpus kavernozum dokuları alınarak kasılma ve gevşeme yanıtları izole organ banyosunda değerlendirilmiştir.
Bulgular: Çalışma sonuçlarımıza göre diyabet modelinde mitotemponun 0.7 mg/kg/gün dozunda 4 hafta süre ile uygulanması hem torasik aorta hem de korpus kavernosum endotel yanıtlarını korumuştur. KCl kasılmasına göre rölatif olarak değerlendirilen fenilefrin kasılma yanıtları gruplar arasında farklılık göstermemiştir.
Sonuç: Endotel hücreleri, dolaşımdaki maddelere ilk maruz kalan organlardan biri olarak tanımlanabilir. Hipergliseminin neden olduğu endotel disfonksiyonda mROS’un etkisi bilinmektedir. Diyabete bağlı oluşan endotel disfonksiyonun engellenebilmesi hastalığa bağlı mortalite ve morbiditenin önüne geçebilir. Çalışmamızda mitotemponun diyabetik endotelial disfonksiyon üzerine olası etkileri değerlendirilmiş ve sınırlı koruyucu etkileri gösterilmiştir.

Project Number

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References

  • 1. Goldstein İ, Young JM, Fischer J, Bangerter K, Segerson T, Taylor T, Vardenafil Diabetes Study Group et al. Vardenafil, a new phosphodiesterase type 5 inhibitor, in the treatment of erectile dysfunction in men with diabetes: A multicenter double-blind placebo-controlled fixed-dose study. Diabetes Care 2003;26(3):777-83. google scholar
  • 2. Palumbo PJ. Metabolic risk factors, endothelial dysfunction, and erectile dysfunction in men with diabetes. Am J Med Sci 2007;334(6):466-80. google scholar
  • 3. Vlachopoulos C, İoakeimidis N, Terentes-Printzios D, Stefanadis C. The Triad: Erectile Dysfunction - Endothelial Dysfunction -Cardiovascular Disease. Curr Pharm Des 2008;14(35):3700-14. google scholar
  • 4. Azadzoi KM, Schulman RN, Aviram M, Siroky MB. Oxidative stress in arteriogenic erectile dysfunction: Prophylactic role of antioxidants. J Urol 2005;174(1):386-93. google scholar
  • 5. Soner BC, Murat N, Demir O, Guven H, Esen A, Gidener S. Evaluation of vascular smooth muscle and corpus cavernosum on hypercholesterolemia. İs resveratrol promising on erectile dysfunction. Int J Impot Res 2010;22(4):227-33. google scholar
  • 6. Gur S, Peak T, Kadowitz P, Sikka S, Hellstrom W. Review of Erectile Dysfunction in Diabetic Animal Models. Curr Diabetes Rev 2014;10 (1):61-73. google scholar
  • 7. Reiter RJ, Rosales-Corral S, Tan DX, Jou MJ, Galano A, Xu B. Melatonin as a mitochondria-targeted antioxidant: one of evolution’s best ideas. Cell Mol Life Sci 2017;74:3863-81. google scholar
  • 8. Cheng Y, Liu D zhou, Zhang C xiong, Cui H, Liu M, Zhang B le, et al. Mitochondria-targeted antioxidant delivery for precise treatment of myocardial ischemia-reperfusion injury through a multistage continuous targeted strategy. Nanomedicine Nanotechnology, Biol Med 2019;16:236-49. google scholar
  • 9. Czepas J, Koceva-Chyta A, Gwozdzinski K, Jozwiak Z. Different effectiveness of piperidine nitroxides against oxidative stress induced by doxorubicin and hydrogen peroxide. Cell Biol Toxicol 2008;24(1):101-12. google scholar
  • 10. Gioscia-Ryan RA, LaRocca TJ, Sindler AL, Zigler MC, Murphy MP, Seals DR. Mitochondria-targeted antioxidant (MitoQ) ameliorates age-related arterial endothelial dysfunction in mice. J Physiol 2014; 592(12):2549-61. google scholar
  • 11. McCarthy C, Kenny LC. Therapeutically targeting mitochondrial redox signalling alleviates endothelial dysfunction in preeclampsia. Sci Rep 2016;6 :1-11. google scholar
  • 12. Furman BL. Streptozotocin-İnduced Diabetic Models in Mice and Rats. Curr Protoc 2021;1(4):e78. google scholar
  • 13. Furman BL. Streptozotocin-İnduced Diabetic Models in Mice and Rats. Curr Protoc Pharmacol 2015;70:1-21. google scholar
  • 14. Wang Q, Zhang M, Torres G, Wu S, Ouyang C, Xie Z, et al. Metformin suppresses diabetes-accelerated atherosclerosis via the inhibition of Drp1-mediated mitochondrial fission. Diabetes 2017;66(1):193—205. google scholar
  • 15. Laight DW, Carrier MJ, Anggârd EE. Antioxidants, diabetes and endothelial dysfunction. Cardiovasc Res 2000;47(3):457-64. google scholar
  • 16. Sivitz WI, Yorek MA. Mitochondrial Dysfunction in Diabetes: From Molecular Mechanisms to Functional Significance and Therapeutic Opportunities. Antiox Redox Signal 2010;12(4):537-77. google scholar
  • 17. Dikalova AE, Bikineyeva AT, Budzyn K, Nazarewicz RR, Lewis W, Harrison DG, et al. Therapeutic Targeting of Mitochondrial Superoxide in Hypertension. Circ Res 2010;107(1):106-16. google scholar
  • 18. Dikalov SI, Dikalova AE. Contribution of mitochondrial oxidative stress to hypertension. Physiol Behav 2016;176(1):100-6. google scholar
  • 19. Li X, Fang P, Li Y, Kuo Y-M, Andrews AJ, Nanayakkara G, et al. Mitochondrial Reactive Oxygen Species Mediate Lysophosphatidylcholine-induced Endothelial Cell Activation. Physiol Behav 2016;36(6):1090-100. google scholar
  • 20. Ni R, Cao T, Xiong S, Ma J , Fan GC, Lacefield JC, Lu Y, et al. Therapeutic inhibition of mitochondrial reactive oxygen species with mito-TEMPO reduces diabetic cardiomyopathy. Free Radic Biol Med 2016;90:12-23. google scholar
  • 21. Xing H, Zhang Z, Shi G, He Y, Song Y, Liu Y, Harrington EO, Sellke FW, Feng J. Chronic Inhibition of mROS Protects Against Coronary Endothelial Dysfunction in Mice with Diabetes. Front Cell Dev Biol 2021;9:643810. google scholar
There are 21 citations in total.

Details

Primary Language English
Subjects Clinical Sciences
Journal Section Research Articles
Authors

Eser Yıldız 0000-0001-9321-1066

Pınar Ayvat 0000-0002-9941-3109

Ayşegül Şahin 0000-0001-6432-5822

Mehmet Mesut Pişkin 0000-0002-0528-6699

Burak Cem Soner 0000-0002-3712-3210

Project Number -
Publication Date June 30, 2022
Submission Date April 21, 2022
Published in Issue Year 2022 Volume: 5 Issue: 2

Cite

MLA Yıldız, Eser et al. “PROTECTIVE EFFECT OF MITOTEMPO IN STREPTOZOTOCIN-INDUCED DIABETIC RAT MODEL: EFFECTS ON CORPUS CAVERNOSUM AND AORTA”. Sağlık Bilimlerinde İleri Araştırmalar Dergisi, vol. 5, no. 2, 2022, pp. 82-87, doi:10.26650/JARHS2022-1105948.