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Synergistic effect of rapamycin and metformin against germ cell apoptosis and oxidative stress after testicular torsion/detorsion-induced ischemia/reperfusion in rats.
Biomed Pharmacother. 2018 Sep; 105:645-651.BP

Abstract

The aim of this study was to investigate the effects of rapamycin (rapa) and metformin (met), combined administration on testicular torsion-detorsion (T/D) injury. A total of 108 male rats were divided randomly into six groups (n = 18), control, sham-operated, T/D, T/D + met (100 mg/kg), T/D + rapa (0.25 mg/kg) and T/D + met (100 mg/kg)+rapa (0.25 mg/kg). Except for the control and sham groups, torsion was created by rotating the right testis 720° in a clockwise direction for 1 h. Treatment groups received drug intraperitoneally, 30 min before detorsion. The right testis of 6 animals from each group was excised 4 h after detorsion for the measurement of lipid peroxidation, caspase-3, and antioxidant enzyme activities. Histopathological changes and germ cell apoptosis were determined by measuring mean of seminiferous tubules diameters (MSTD) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) test in rest of animals, 24 h after detorsion. In T/D group tissue malondialdehyde (MDA) level and caspase-3 activity increased and the activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) decreased in comparison with the control group after detorsion. Met and rapa separately pre-treatment reduced MDA and caspase-3 levels, normalized antioxidant enzyme activities, reduced germ cell apoptosis and improved the MSTD in comparison with T/D group. However combined administration of met and rapa indicated a significant augmented effect as compared to the individual drug interventions on the reversal of T/D induced oxidative stress, apoptosis, and histologic changes, suggesting a synergistic response. Thus, this study shows that rapa and met combination have significant synergistic effects against oxidative stress and apoptosis and opens up further possibilities for the design of new combinatorial therapies to prevent tissue damage after ischemia-reperfusion (I/R).

Authors+Show Affiliations

Department of Pharmacology and toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Urmia, Iran; Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.Department of pediatrics, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.Department of Occupational Health, Faculty of Health, Urmia University of Medical Sciences, Urmia, Iran.Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.Department of Anatomy and Reproductive Biology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, United States; Department of Toxicology-Pharmacology, Faculty of Pharmacy, Guilan University of Medical Sciences, Rasht, Iran.Department of Obstetrics & Gynecology, School of Medicine, Urmia University of Medical Science, Urmia, Iran.Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.Department of Pathology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: mghasemnejad@alumnus.tums.ac.ir.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

29902763

Citation

Ghasemnejad-Berenji, Morteza, et al. "Synergistic Effect of Rapamycin and Metformin Against Germ Cell Apoptosis and Oxidative Stress After Testicular Torsion/detorsion-induced Ischemia/reperfusion in Rats." Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, vol. 105, 2018, pp. 645-651.
Ghasemnejad-Berenji M, Ghazi-Khansari M, Pashapour S, et al. Synergistic effect of rapamycin and metformin against germ cell apoptosis and oxidative stress after testicular torsion/detorsion-induced ischemia/reperfusion in rats. Biomed Pharmacother. 2018;105:645-651.
Ghasemnejad-Berenji, M., Ghazi-Khansari, M., Pashapour, S., Jafari, A., Yazdani, I., Ghasemnejad-Berenji, H., Saeedi Saravi, S. S., Sadeghpour, S., Nobakht, M., Abdollahi, A., Mohajer Ansari, J., & Dehpour, A. R. (2018). Synergistic effect of rapamycin and metformin against germ cell apoptosis and oxidative stress after testicular torsion/detorsion-induced ischemia/reperfusion in rats. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie, 105, 645-651. https://doi.org/10.1016/j.biopha.2018.06.012
Ghasemnejad-Berenji M, et al. Synergistic Effect of Rapamycin and Metformin Against Germ Cell Apoptosis and Oxidative Stress After Testicular Torsion/detorsion-induced Ischemia/reperfusion in Rats. Biomed Pharmacother. 2018;105:645-651. PubMed PMID: 29902763.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Synergistic effect of rapamycin and metformin against germ cell apoptosis and oxidative stress after testicular torsion/detorsion-induced ischemia/reperfusion in rats. AU - Ghasemnejad-Berenji,Morteza, AU - Ghazi-Khansari,Mahmoud, AU - Pashapour,Sarvin, AU - Jafari,Abbas, AU - Yazdani,Iraj, AU - Ghasemnejad-Berenji,Hojjat, AU - Saeedi Saravi,Seyed Soheil, AU - Sadeghpour,Sonia, AU - Nobakht,Maliheh, AU - Abdollahi,Alireza, AU - Mohajer Ansari,Javad, AU - Dehpour,Ahmad Reza, Y1 - 2018/06/11/ PY - 2018/02/25/received PY - 2018/06/01/revised PY - 2018/06/02/accepted PY - 2018/6/15/pubmed PY - 2018/11/16/medline PY - 2018/6/15/entrez KW - Apoptosis KW - Metformin KW - Oxidative stress KW - Rapamycin KW - Testicular torsion/detorsion SP - 645 EP - 651 JF - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JO - Biomed Pharmacother VL - 105 N2 - The aim of this study was to investigate the effects of rapamycin (rapa) and metformin (met), combined administration on testicular torsion-detorsion (T/D) injury. A total of 108 male rats were divided randomly into six groups (n = 18), control, sham-operated, T/D, T/D + met (100 mg/kg), T/D + rapa (0.25 mg/kg) and T/D + met (100 mg/kg)+rapa (0.25 mg/kg). Except for the control and sham groups, torsion was created by rotating the right testis 720° in a clockwise direction for 1 h. Treatment groups received drug intraperitoneally, 30 min before detorsion. The right testis of 6 animals from each group was excised 4 h after detorsion for the measurement of lipid peroxidation, caspase-3, and antioxidant enzyme activities. Histopathological changes and germ cell apoptosis were determined by measuring mean of seminiferous tubules diameters (MSTD) and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL) test in rest of animals, 24 h after detorsion. In T/D group tissue malondialdehyde (MDA) level and caspase-3 activity increased and the activities of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx) decreased in comparison with the control group after detorsion. Met and rapa separately pre-treatment reduced MDA and caspase-3 levels, normalized antioxidant enzyme activities, reduced germ cell apoptosis and improved the MSTD in comparison with T/D group. However combined administration of met and rapa indicated a significant augmented effect as compared to the individual drug interventions on the reversal of T/D induced oxidative stress, apoptosis, and histologic changes, suggesting a synergistic response. Thus, this study shows that rapa and met combination have significant synergistic effects against oxidative stress and apoptosis and opens up further possibilities for the design of new combinatorial therapies to prevent tissue damage after ischemia-reperfusion (I/R). SN - 1950-6007 UR - https://www.unboundmedicine.com/medline/citation/29902763/Synergistic_effect_of_rapamycin_and_metformin_against_germ_cell_apoptosis_and_oxidative_stress_after_testicular_torsion/detorsion_induced_ischemia/reperfusion_in_rats_ DB - PRIME DP - Unbound Medicine ER -