PMID- 29902763 OWN - NLM STAT- MEDLINE DCOM- 20181115 LR - 20181115 IS - 1950-6007 (Electronic) IS - 0753-3322 (Linking) VI - 105 DP - 2018 Sep TI - Synergistic effect of rapamycin and metformin against germ cell apoptosis and oxidative stress after testicular torsion/detorsion-induced ischemia/reperfusion in rats. PG - 645-651 LID - S0753-3322(18)31179-X [pii] LID - 10.1016/j.biopha.2018.06.012 [doi] AB - 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 degrees 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). CI - Copyright (c) 2018 Elsevier Masson SAS. All rights reserved. FAU - Ghasemnejad-Berenji, Morteza AU - Ghasemnejad-Berenji M AD - 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. FAU - Ghazi-Khansari, Mahmoud AU - Ghazi-Khansari M AD - Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. FAU - Pashapour, Sarvin AU - Pashapour S AD - Department of pediatrics, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran. FAU - Jafari, Abbas AU - Jafari A AD - Department of Occupational Health, Faculty of Health, Urmia University of Medical Sciences, Urmia, Iran. FAU - Yazdani, Iraj AU - Yazdani I AD - Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. FAU - Ghasemnejad-Berenji, Hojjat AU - Ghasemnejad-Berenji H AD - Department of Anatomy and Reproductive Biology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran. FAU - Saeedi Saravi, Seyed Soheil AU - Saeedi Saravi SS AD - 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. FAU - Sadeghpour, Sonia AU - Sadeghpour S AD - Department of Obstetrics & Gynecology, School of Medicine, Urmia University of Medical Science, Urmia, Iran. FAU - Nobakht, Maliheh AU - Nobakht M AD - Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. FAU - Abdollahi, Alireza AU - Abdollahi A AD - Department of Pathology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran. FAU - Mohajer Ansari, Javad AU - Mohajer Ansari J AD - Department of Anatomy, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. FAU - Dehpour, Ahmad Reza AU - Dehpour AR AD - 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. LA - eng PT - Journal Article DEP - 20180611 PL - France TA - Biomed Pharmacother JT - Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie JID - 8213295 RN - 9100L32L2N (Metformin) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Animals MH - Apoptosis/*drug effects MH - Drug Synergism MH - Male MH - Metformin/administration & dosage/*therapeutic use MH - Oxidative Stress/*drug effects MH - Rats, Wistar MH - Reperfusion Injury/*drug therapy/etiology MH - Sirolimus/administration & dosage/*therapeutic use MH - Spermatic Cord Torsion/complications/*drug therapy MH - Testis/*drug effects/metabolism/pathology OTO - NOTNLM OT - Apoptosis OT - Metformin OT - Oxidative stress OT - Rapamycin OT - Testicular torsion/detorsion EDAT- 2018/06/15 06:00 MHDA- 2018/11/16 06:00 CRDT- 2018/06/15 06:00 PHST- 2018/02/25 00:00 [received] PHST- 2018/06/01 00:00 [revised] PHST- 2018/06/02 00:00 [accepted] PHST- 2018/06/15 06:00 [pubmed] PHST- 2018/11/16 06:00 [medline] PHST- 2018/06/15 06:00 [entrez] AID - S0753-3322(18)31179-X [pii] AID - 10.1016/j.biopha.2018.06.012 [doi] PST - ppublish SO - Biomed Pharmacother. 2018 Sep;105:645-651. doi: 10.1016/j.biopha.2018.06.012. Epub 2018 Jun 11.