Synergistic effect of rapamycin and metformin against germ cell apoptosis and oxidative stress after testicular torsion/detorsion-induced ischemia/reperfusion in rats

[Display omitted] •Oxidative stress is the major cause of tissue damage after ischemia/ reperfusion.•Metformin protected testes against ischemia/ reperfusion induced oxidative stress.•Rapamycin pretreatment reduced ischemia/ reperfusion induced oxidative stress.•Combined administration of metformin...

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Published in:Biomedicine & pharmacotherapy 2018-09, Vol.105, p.645-651
Main Authors: Ghasemnejad-berenji, Morteza, Ghazi-Khansari, Mahmoud, Pashapour, Sarvin, Jafari, Abbas, Yazdani, Iraj, Ghasemnejad-berenji, Hojjat, Saeedi Saravi, Seyed Soheil, Sadeghpour, Sonia, Nobakht, Maliheh, Abdollahi, Alireza, mohajer Ansari, Javad, Dehpour, Ahmad Reza
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Apoptosis - drug effects
Drug Synergism
Male
Metformin
Metformin - administration & dosage
Metformin - therapeutic use
Oxidative stress
Oxidative Stress - drug effects
Rapamycin
Rats, Wistar
Reperfusion Injury - drug therapy
Reperfusion Injury - etiology
Sirolimus - administration & dosage
Sirolimus - therapeutic use
Spermatic Cord Torsion - complications
Spermatic Cord Torsion - drug therapy
Testicular torsion/detorsion
Testis - drug effects
Testis - metabolism
Testis - pathology
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Summary:[Display omitted] •Oxidative stress is the major cause of tissue damage after ischemia/ reperfusion.•Metformin protected testes against ischemia/ reperfusion induced oxidative stress.•Rapamycin pretreatment reduced ischemia/ reperfusion induced oxidative stress.•Combined administration of metformin and rapamycin indicated a significant synergistic effect. 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).
ISSN:0753-3322
1950-6007
DOI:10.1016/j.biopha.2018.06.012