Modulatory Role of Autophagy in Metformin Therapeutic Activity toward Doxorubicin-Induced Nephrotoxicity
Samar A. Antar,
Marwa Abd-Elsalam,
Walied Abdo,
Ahmed Abdeen,
Mohamed Abdo,
Liana Fericean,
Nahed A. Raslan,
Samah F. Ibrahim,
Asmaa F. Sharif,
Amira Elalfy,
Hend E. Nasr,
Ahmed B. Zaid,
Rania Atia,
Ahmed M. Atwa,
Mohammed A. Gebba,
Amany A. Alzokaky
Affiliations
Samar A. Antar
Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt
Marwa Abd-Elsalam
Department of Histology, Faculty of Medicine, Kafrelsheikh University, Kafr El-Sheikh 33516, Egypt
Walied Abdo
Department of Pathology, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafr El-Sheikh 33516, Egypt
Ahmed Abdeen
Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Benha University, Toukh 13736, Egypt
Mohamed Abdo
Department of Animal Histology and Anatomy, School of Veterinary Medicine, Badr University in Cairo (BUC), Badr City 32897, Egypt
Liana Fericean
Department of Biology and Plant Protection, Faculty of Agriculture, University of Life Sciences “King Michael I” from Timișoara, Calea Aradului 119, CUI 3487181, 300645 Timisoara, Romania
Nahed A. Raslan
Clinical Pharmacy Program, College of Health Sciences and Nursing, Al-Rayan Colleges, Medina 42541, Saudi Arabia
Samah F. Ibrahim
Department of Clinical Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, P.O. Box 84428, Riyadh 11671, Saudi Arabia
Asmaa F. Sharif
Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Tanta University, Tanta 31111, Egypt
Amira Elalfy
Department of Histology and Cell Biology, Faculty of Medicine, Benha University, Benha 13518, Egypt
Hend E. Nasr
Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Benha University, Benha 13518, Egypt
Ahmed B. Zaid
Department of Clinical Pathology, National Liver Institute, Menoufia University, Shibin Elkom 32511, Egypt
Rania Atia
Department of Physiology, Faculty of Medicine, Zagazig University, Zagazig 44519, Egypt
Ahmed M. Atwa
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Cairo 11829, Egypt
Mohammed A. Gebba
Department of Anatomy and Embryology, Faculty of Medicine, Benha University, Benha 13518, Egypt
Amany A. Alzokaky
Department of Pharmacology and Biochemistry, Faculty of Pharmacy, Horus University-Egypt, New Damietta 34518, Egypt
Doxorubicin (DOX) is a frequent chemotherapeutic drug used to treat various malignant tumors. One of the key factors that diminish its therapeutic importance is DOX-induced nephrotoxicity. The first-line oral antidiabetic drug is metformin (Met), which also has antioxidant properties. The purpose of our study was to investigate the underlying molecular mechanisms for the potential protective effects of Met on DOX-triggered nephrotoxicity. Four animal groups were assigned as follows; animals received vehicle (control group), 200 mg/kg Met (Met group), DOX 15 mg/kg DOX (DOX group), and a combination of DOX and Met (DOX/Met group). Our results demonstrated that DOX administration caused marked histological alterations of widespread inflammation and tubular degeneration. Notably, the DOX-induced dramatic up-regulation of the nuclear factor-kappa B/P65 (NF-κB/P65), microtubule-associated protein light chain 3B (LC3B), neutrophil gelatinase-associated lipocalin (NGAL), interleukin-1beta (IL-1β), 8-hydroxy-2′ -deoxyguanosine (8-OHdG), and Beclin-1 in renal tissue. A marked increase in the malondialdehyde (MDA) tissue level and a decrease in the total antioxidant capacity (TAC) were also recorded in DOX-exposed animals. Interestingly, Met could minimize all histopathological changes as well as the disruptions caused by DOX in the aforementioned measures. Thus, Met provided a workable method for suppressing the nephrotoxicity that occurred during the DOX regimen via the deactivation of the Beclin-1/LC3B pathway.
